High Power Amplifier and Power Supply

NASA Technical Reports Server (NTRS)

Duong, Johnny; Stride, Scot; Harvey, Wayne; Haque, Inam; Packard, Newton; Ng, Quintin; Ispirian, Julie Y.; Waian, Christopher; Janes, Drew

2008-01-01

A document discusses the creation of a high-voltage power supply (HVPS) that is able to contain voltages up to -20 kV, keep electrical field strengths to below 200 V/mil (approximately equal to 7.87 kV/mm), and can provide a 200-nanosecond rise/fall time focus modulator swinging between cathode potential of 16.3 kV and -19.3 kV. This HVPS can protect the 95-GHz, pulsed extended interaction klystron (EIK) from arcs/discharges from all sources, including those from within the EIK fs vacuum envelope. This innovation has a multi-winding pulse transformer design, which uses new winding techniques to provide the same delays and rise/fall times (less than 10 nanoseconds) at different potential levels ranging from -20 kV to -16 kV. Another feature involves a high-voltage printed-wiring board that was corona-free at -20 kV DC with a 3- kV AC swing. The corona-free multilayer high-voltage board is used to simulate fields of less than 200 V/mil (approximately equal to 7.87 kV/mm) at 20 kV DC. Drive techniques for the modulator FETs (field-effect transistors) (four to 10 in a series) were created to change states (3,000-V swing) without abrupt steps, while still maintaining required delays and transition times. The packing scheme includes a potting mold to house a ten-stage modulator in the space that, in the past, only housed a four-stage modulator. Problems keeping heat down were solved using aluminum oxide substrate in the high-voltage section to limit temperature rise to less than 10 while withstanding -20 kV DC voltage and remaining corona-free.

Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells

PubMed Central

Mateos-Aparicio, Pedro; Murphy, Ricardo; Storm, Johan F

2014-01-01

The dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium-duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (Rinput) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased Rinput, lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP–spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1-EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate. PMID:24366266

System and method for determining stator winding resistance in an AC motor

DOEpatents

Lu, Bin [Kenosha, WI; Habetler, Thomas G [Snellville, GA; Zhang, Pinjia [Atlanta, GA; Theisen, Peter J [West Bend, WI

2011-05-31

A system and method for determining stator winding resistance in an AC motor is disclosed. The system includes a circuit having an input connectable to an AC source and an output connectable to an input terminal of an AC motor. The circuit includes at least one contactor and at least one switch to control current flow and terminal voltages in the AC motor. The system also includes a controller connected to the circuit and configured to modify a switching time of the at least one switch to create a DC component in an output of the system corresponding to an input to the AC motor and determine a stator winding resistance of the AC motor based on the injected DC component of the voltage and current.

Modulation of A-type potassium channels by a family of calcium sensors.

PubMed

An, W F; Bowlby, M R; Betty, M; Cao, J; Ling, H P; Mendoza, G; Hinson, J W; Mattsson, K I; Strassle, B W; Trimmer, J S; Rhodes, K J

2000-02-03

In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes. Although pore-forming alpha-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 alpha-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 alpha-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.

250 kV 6 mA compact Cockcroft-Walton high-voltage power supply.

PubMed

Ma, Zhan-Wen; Su, Xiao-Dong; Lu, Xiao-Long; Wei, Zhen; Wang, Jun-Run; Huang, Zhi-Wu; Miao, Tian-You; Su, Tong-Ling; Yao, Ze-En

2016-08-01

A compact power supply system for a compact neutron generator has been developed. A 4-stage symmetrical Cockcroft-Walton circuit is adopted to produce 250 kV direct current high-voltage. A 2-stage 280 kV isolation transformer system is used to drive the ion source power supply. For a compact structure, safety, and reliability during the operation, the Cockcroft-Walton circuit and the isolation transformer system are enclosed in an epoxy vessel containing the transformer oil whose size is about ∅350 mm × 766 mm. Test results indicate that the maximum output voltage of the power supply is 282 kV, and the stability of the output voltage is better than 0.63% when the high voltage power supply is operated at 250 kV, 6.9 mA with the input voltage varying ±10%.

250 kV 6 mA compact Cockcroft-Walton high-voltage power supply

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Zhan-Wen; Su, Xiao-Dong; Wei, Zhen

A compact power supply system for a compact neutron generator has been developed. A 4-stage symmetrical Cockcroft-Walton circuit is adopted to produce 250 kV direct current high-voltage. A 2-stage 280 kV isolation transformer system is used to drive the ion source power supply. For a compact structure, safety, and reliability during the operation, the Cockcroft-Walton circuit and the isolation transformer system are enclosed in an epoxy vessel containing the transformer oil whose size is about ∅350 mm × 766 mm. Test results indicate that the maximum output voltage of the power supply is 282 kV, and the stability of themore » output voltage is better than 0.63% when the high voltage power supply is operated at 250 kV, 6.9 mA with the input voltage varying ±10%.« less

A Practical Study of the 66kV Fault Current Limiter (FCL) System with Rectifier

NASA Astrophysics Data System (ADS)

Tokuda, Noriaki; Matsubara, Yoshio; Yuguchi, Kyosuke; Ohkuma, Takeshi; Hobara, Natsuro; Takahashi, Yoshihisa

A fault current limiter (FCL) is extensively expected to suppress fault current, particularly required for trunk power systems heavily connected high-voltage transmission lines, such as 500kV class power system which constitutes the nucleus of the electric power system. By installing such FCL in the power system, the system interconnection is possible without the need to raise the capacity of the circuit breakers, and facilities can be configured for efficiency, among other benefits. For these reasons, fault current limiters based on various principles of operation have been developed both in Japan and abroad. In this paper, we have proposed a new type of FCL system, consisting of solid-state diodes, DC coil and bypass AC coil, and described the specification of distribution power system and 66kV model at the island power system and the superconducting cable power system. Also we have made a practical study of 66kV class, which is the testing items and the future subjects of the rectifier type FCL system.

System and method for monitoring and controlling stator winding temperature in a de-energized AC motor

DOEpatents

Lu, Bin [Kenosha, WI; Luebke, Charles John [Sussex, WI; Habetler, Thomas G [Snellville, GA; Zhang, Pinjia [Atlanta, GA; Becker, Scott K [Oak Creek, WI

2011-12-27

A system and method for measuring and controlling stator winding temperature in an AC motor while idling is disclosed. The system includes a circuit having an input connectable to an AC source and an output connectable to an input terminal of a multi-phase AC motor. The circuit further includes a plurality of switching devices to control current flow and terminal voltages in the multi-phase AC motor and a controller connected to the circuit. The controller is configured to activate the plurality of switching devices to create a DC signal in an output of the motor control device corresponding to an input to the multi-phase AC motor, determine or estimate a stator winding resistance of the multi-phase AC motor based on the DC signal, and estimate a stator temperature from the stator winding resistance. Temperature can then be controlled and regulated by DC injection into the stator windings.

Simulation study on transient electric shock characteristics of human body under high voltage ac transmission lines

NASA Astrophysics Data System (ADS)

Huang, Tao; Zou, Yanhui; Lv, Jianhong; Yang, Jinchun; Tao, Li; Zhou, Jianfei

2017-09-01

Human body under high-voltage AC transmission lines will produce a certain induced voltage due to the electrostatic induction. When the human body contacts with some grounded objects, the charges transfer from the body to the ground and produce contact current which may cause transient electric shock. Using CDEGS and ATP/EMTP, the paper proposes a method for quantitatively calculating the transient electric shock characteristics. It calculates the human body voltage, discharge current and discharge energy under certain 500kV compact-type transmission lines and predicts the corresponding human feelings. The results show that the average root value of discharge current is less than 10mA when the human body is under the 500kV compact-type transmission lines and the human body is overall safe if the transmission lines satisfy the relevant design specifications. It concludes that the electric field strength above the ground should be limited to 4kV/m through the residential area for the purpose of reducing the electromagnetic impact.

Intrinsic Plasticity Induced by Group II Metabotropic Glutamate Receptors via Enhancement of High Threshold KV Currents in Sound Localizing Neurons

PubMed Central

Hamlet, William R.; Lu, Yong

2016-01-01

Intrinsic plasticity has emerged as an important mechanism regulating neuronal excitability and output under physiological and pathological conditions. Here, we report a novel form of intrinsic plasticity. Using perforated patch clamp recordings, we examined the modulatory effects of group II metabotropic glutamate receptors (mGluR II) on voltage-gated potassium (KV) currents and the firing properties of neurons in the chicken nucleus laminaris (NL), the first central auditory station where interaural time cues are analyzed for sound localization. We found that activation of mGluR II by synthetic agonists resulted in a selective increase of the high threshold KV currents. More importantly, synaptically released glutamate (with reuptake blocked) also enhanced the high threshold KV currents. The enhancement was frequency-coding region dependent, being more pronounced in low frequency neurons compared to middle and high frequency neurons. The intracellular mechanism involved the Gβγ signaling pathway associated with phospholipase C and protein kinase C. The modulation strengthened membrane outward rectification, sharpened action potentials, and improved the ability of NL neurons to follow high frequency inputs. These data suggest that mGluR II provides a feedforward modulatory mechanism that may regulate temporal processing under the condition of heightened synaptic inputs. PMID:26964678

Virginia Offshore Wind Technology Advancement Project (VOWTAP) DOE EE0005985 Final Technical Report Rev 1a

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pietryk, Steven

The primary purpose of the VOWTAP was to advance the offshore wind industry in the United States (U.S.) by demonstrating innovative technologies and process solutions that would establish offshore wind as a cost-effective renewable energy resource. The VOWTAP Team proposed to design, construct, and operate a 12 megawatt (MW) offshore wind facility located approximately 27 statute miles (mi) (24 nautical miles [nm], 43 kilometers [km]) off the coast of Virginia. The proposed Project would consist of two Alstom Haliade™ 150-6 MW turbines mounted on inward battered guide structures (IBGS), a 34.5-kilovolt (kV) alternating current (AC) submarine cable interconnecting the WTGsmore » (inter-array cable), a 34.5-kV AC submarine transmission cable (export cable), and a 34.5 kV underground cable (onshore interconnection cable) that would connect the Project with existing Dominion infrastructure located in Virginia Beach, Virginia (Figure 1). Interconnection with the existing Dominion infrastructure would also require an onshore switch cabinet, a fiber optic cable, and new interconnection station to be located entirely within the boundaries of the Camp Pendleton State Military Reservation (Camp Pendleton). The VOWTAP balanced technology innovation with commercial readiness such that turbine operations were anticipated to commence by 2018. Dominion, as the leaseholder of the Virginia Wind Energy Area (WEA), anticipated leveraging lessons learned through the VOWTAP, and applying them to future commercial-scale offshore wind development.« less

Hot electrons injection in carbon nanotubes under the influence of quasi-static ac-field

NASA Astrophysics Data System (ADS)

Amekpewu, M.; Mensah, S. Y.; Musah, R.; Mensah, N. G.; Abukari, S. S.; Dompreh, K. A.

2016-07-01

The theory of hot electrons injection in carbon nanotubes (CNTs) where both dc electric field (Ez), and a quasi-static ac field exist simultaneously (i.e. when the frequency ω of ac field is much less than the scattering frequency v (ω ⪡ v or ωτ ⪡ 1, v =τ-1) where τ is relaxation time) is studied. The investigation is done theoretically by solving semi-classical Boltzmann transport equation with and without the presence of the hot electrons source to derive the current densities. Plots of the normalized current density versus dc field (Ez) applied along the axis of the CNTs in the presence and absence of hot electrons reveal ohmic conductivity initially and finally negative differential conductivity (NDC) provided ωτ ⪡ 1 (i.e. quasi- static case). With strong enough axial injection of the hot electrons, there is a switch from NDC to positive differential conductivity (PDC) about Ez ≥ 75 kV / cm and Ez ≥ 140 kV / cm for a zigzag CNT and an armchair CNT respectively. Thus, the most important tough problem for NDC region which is the space charge instabilities can be suppressed due to the switch from the NDC behaviour to the PDC behaviour predicting a potential generation of terahertz radiations whose applications are relevance in current-day technology, industry, and research.

The investigation of an electric arc in the long cylindrical channel of the powerful high-voltage AC plasma torch

NASA Astrophysics Data System (ADS)

Rutberg, Ph G.; Popov, S. D.; Surov, A. V.; Serba, E. O.; Nakonechny, Gh V.; Spodobin, V. A.; Pavlov, A. V.; Surov, A. V.

2012-12-01

The comparison of conductivity obtained in experiments with calculated values is made in this paper. Powerful stationary plasma torches with prolonged period of continuous work are popular for modern plasmachemical applications. The maximum electrode lifetime with the minimum erosion can be reached while working on rather low currents. Meanwhile it is required to provide voltage arc drop for the high power achievement. Electric field strength in the arc column of the high-voltage plasma torch, using air as a plasma-forming gas, does not exceed 15 V/cm. It is possible to obtain the high voltage drop in the long arc stabilized in the channel by the intensive gas flow under given conditions. Models of high voltage plasma torches with rod electrodes with power up to 50 kW have been developed and investigated. The plasma torch arcs are burning in cylindrical channels. Present investigations are directed at studying the possibility of developing long arc plasma torches with higher power. The advantage of AC power supplies usage is the possibility of the loss minimization due to the reactive power compensation. The theoretical maximum of voltage arc drop for power supplies with inductive current limitations is about 50 % of the no-load voltage for a single-phase circuit and about 30 % for the three-phase circuit. Burning of intensively blown arcs in the long cylindrical channel using the AC power supply with 10 kV no-load voltage is experimentally investigated in the work. Voltage drops close to the maximum possible had been reached in the examined arcs in single-phase and three-phase modes. Operating parameters for single-phase mode were: current -30 A, voltage drop -5 kV, air flow rate 35 g/s; for three-phase mode: current (40-85) A, voltage drop (2.5-3.2) kV, air flow rate (60-100) g/s. Arc length in the installations exceeded 2 m.

Solid-state repetitive generator with a gyromagnetic nonlinear transmission line operating as a peak power amplifier

NASA Astrophysics Data System (ADS)

Gusev, A. I.; Pedos, M. S.; Rukin, S. N.; Timoshenkov, S. P.

2017-07-01

In this work, experiments were made in which gyromagnetic nonlinear transmission line (NLTL) operates as a peak power amplifier of the input pulse. At such an operating regime, the duration of the input pulse is close to the period of generated oscillations, and the main part of the input pulse energy is transmitted only to the first peak of the oscillations. Power amplification is achieved due to the voltage amplitude of the first peak across the NLTL output exceeding the voltage amplitude of the input pulse. In the experiments, the input pulse with an amplitude of 500 kV and a half-height pulse duration of 7 ns is applied to the NLTL with a natural oscillation frequency of ˜300 MHz. At the output of the NLTL in 40 Ω coaxial transmission line, the pulse amplitude is increased to 740 kV and the pulse duration is reduced to ˜2 ns, which correspond to power amplification of the input pulse from ˜6 to ˜13 GW. As a source of input pulses, a solid-state semiconductor opening switch generator was used, which allowed carrying out experiments at pulse repetition frequency up to 1 kHz in the burst mode of operation.

75 FR 63826 - Transmission Infrastructure Program-TransWest Express Transmission Project Capacity

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-18

..., 2009, Western published a Notice of Proposed Program and Request for Public Comments in the Federal... published its final TIP Notice of Program on May 14, 2009 (74 FR 22732). Western also published a Notice of... Gateway project. The southern terminal of the line would be interconnected with the 500-kV AC substations...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaw, R.S.; Myers, B.R.; Vella, M.C.

Representative spectral data from T IV-a are compared with data from T IV-c obtained under similar conditions; i.e., 15 kV cusp bank voltage, 30 kV preionizer bank voltage, 2 kV bias bank voltage and 50 m Torr gas fill pressure. Two spectral lines, HeII 4686 A and D..beta.. 4861 A are studied. Line of sight data from the two devices, taken using a light pipe and mirror arrangement, are compared. The data were also used as inputs to a computer assisted tomogrphic reconstruction, the results of which are discussed. Comparison was made on the basis of the intensity and shapemore » of the spectral lines as functions of position and time.« less

Localization and function of the Kv3.1b subunit in the rat medulla oblongata: focus on the nucleus tractus solitarii

PubMed Central

Dallas, Mark L; Atkinson, Lucy; Milligan, Carol J; Morris, Neil P; Lewis, David I; Deuchars, Susan A; Deuchars, Jim

2005-01-01

The voltage-gated potassium channel subunit Kv3.1 confers fast firing characteristics to neurones. Kv3.1b subunit immunoreactivity (Kv3.1b-IR) was widespread throughout the medulla oblongata, with labelled neurones in the gracile, cuneate and spinal trigeminal nuclei. In the nucleus of the solitary tract (NTS), Kv3.1b-IR neurones were predominantly located close to the tractus solitarius (TS) and could be GABAergic or glutamatergic. Ultrastructurally, Kv3.1b-IR was detected in NTS terminals, some of which were vagal afferents. Whole-cell current-clamp recordings from neurones near the TS revealed electrophysiological characteristics consistent with the presence of Kv3.1b subunits: short duration action potentials (4.2 ± 1.4 ms) and high firing frequencies (68.9 ± 5.3 Hz), both sensitive to application of TEA (0.5 mm) and 4-aminopyridine (4-AP; 30 μm). Intracellular dialysis of an anti-Kv3.1b antibody mimicked and occluded the effects of TEA and 4-AP in NTS and dorsal column nuclei neurones, but not in dorsal vagal nucleus or cerebellar Purkinje cells (which express other Kv3 subunits, but not Kv3.1b). Voltage-clamp recordings from outside-out patches from NTS neurones revealed an outward K+ current with the basic characteristics of that carried by Kv3 channels. In NTS neurones, electrical stimulation of the TS evoked EPSPs and IPSPs, and TEA and 4-AP increased the average amplitude and decreased the paired pulse ratio, consistent with a presynaptic site of action. Synaptic inputs evoked by stimulation of a region lacking Kv3.1b-IR neurones were not affected, correlating the presence of Kv3.1b in the TS with the pharmacological effects. PMID:15528247

Nonreciprocal mechanisms in up- and downregulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels

PubMed Central

Lombardo, Joseph

2016-01-01

KCNQ/Kv7 channels form a slow noninactivating K+ current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/Kv7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K+ current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/Kv7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/Kv7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/Kv7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/Kv7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/Kv7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/Kv7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/Kv7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners. PMID:27512022

Clock Controller For Ac Self-Timing Analysis Of Logic System

DOEpatents

Lo, Tinchee; Flanagan, John D.

2004-05-18

A clock controller and clock generating method are provided for AC self-test timing analysis of a logic system. The controller includes latch circuitry which receives a DC input signal at a data input, and a pair of continuous out-of-phase clock signals at capture and launch clock inputs thereof. The latch circuitry outputs two overlapping pulses responsive to the DC input signal going high. The two overlapping pulses are provided to waveform shaper circuitry which produces therefrom two non-overlapping pulses at clock speed of the logic system to be tested. The two non-overlapping pulses are a single pair of clock pulses which facilitate AC self-test timing analysis of the logic system.

Efficiency estimation method of three-wired AC to DC line transfer

NASA Astrophysics Data System (ADS)

Solovev, S. V.; Bardanov, A. I.

2018-05-01

The development of power semiconductor converters technology expands the scope of their application to medium voltage distribution networks (6-35 kV). Particularly rectifiers and inverters of appropriate power capacity complement the topology of such voltage level networks with the DC links and lines. The article presents a coefficient that allows taking into account the increase of transmission line capacity depending on the parameters of it. The application of the coefficient is presented by the example of transfer three-wired AC line to DC in various methods. Dependences of the change in the capacity from the load power factor of the line and the reactive component of the resistance of the transmission line are obtained. Conclusions are drawn about the most efficient ways of converting a three-wired AC line to direct current.

Input current shaped ac-to-dc converters

NASA Technical Reports Server (NTRS)

1985-01-01

Input current shaping techniques for ac-to-dc converters were investigated. Input frequencies much higher than normal, up to 20 kHz were emphasized. Several methods of shaping the input current waveform in ac-to-dc converters were reviewed. The simplest method is the LC filter following the rectifier. The next simplest method is the resistor emulation approach in which the inductor size is determined by the converter switching frequency and not by the line input frequency. Other methods require complicated switch drive algorithms to construct the input current waveshape. For a high-frequency line input, on the order of 20 kHz, the simple LC cannot be discarded so peremptorily, since the inductor size can be compared with that for the resistor emulation method. In fact, since a dc regulator will normally be required after the filter anyway, the total component count is almost the same as for the resistor emulation method, in which the filter is effectively incorporated into the regulator.

Electroporation of cells using EM induction of ac fields by a magnetic stimulator

NASA Astrophysics Data System (ADS)

Chen, C.; Evans, J. A.; Robinson, M. P.; Smye, S. W.; O'Toole, P.

2010-02-01

This paper describes a method of effectively electroporating mammalian cell membranes with pulsed alternating-current (ac) electric fields at field strengths of 30-160 kV m-1. Although many in vivo electroporation protocols entail applying square wave or monotonically decreasing pulses via needles or electrode plates, relatively few have explored the use of pulsed ac fields. Following our previous study, which established the effectiveness of ac fields for electroporating cell membranes, a primary/secondary coil system was constructed to produce sufficiently strong electric fields by electromagnetic induction. The primary coil was formed from the applicator of an established transcranial magnetic stimulation (TMS) system, while the secondary coil was a purpose-built device of a design which could eventually be implanted into tissue. The effects of field strength, pulse interval and cumulative exposure time were investigated using microscopy and flow cytometry. Results from experiments on concentrated cell suspensions showed an optimized electroporation efficiency of around 50%, demonstrating that electroporation can be practicably achieved by inducing such pulsed ac fields. This finding confirms the possibility of a wide range of in vivo applications based on magnetically coupled ac electroporation.

Double-injection, deep-impurity switch development

NASA Technical Reports Server (NTRS)

Whitson, D. W.

1985-01-01

The overall objective of this program was the development of device design and process techniques for the fabrication of a double-injection, deep-impurity (DI) sup 2 silicon switch that operates in the 2-10 kV range with conduction current values of 5 A at 2 kV and 1 A at 10 kV. Other major specifications include a holding voltage of 10 V with no gate current, 10 microsec switching time, and power dissipation of 50 W at 75 C. It was decided to concentrate on the lateral circular devices in order to optimize the gold diffusion. This resulted in devices that are much better switches (approx.1 micro sec switching time), and in a gold diffusion process that is much more controllable than those previously developed. Some results with injection-gated devices were also obtained. The current conduction for V less than VT was analyzed and seen to agree, for the most part, with Lampert's theory. Various sections of this report describe the device designs, wafer-processing techniques, and various measurements which include ac and dc characteristics and four-point probe.

A Novel Nanosecond Pulsed Power Unit for the Formation of ·OH in Water

NASA Astrophysics Data System (ADS)

Li, Shengli; Hu, Sheng; Zhang, Han

2012-04-01

A novel nanosecond pulsed power unit was developed for plasma treatment of wastewater, based on the theory of magnetic pulse compression and semiconductor opening switch (SOS). The peak value, rise time and pulse duration of the output voltage were observed to be -51 kV, 60 ns and 120 ns, respectively. The concentrations of ·OH generated by the novel nanosecond pulsed plasma power were determined using the method of high-performance liquid chromatography (HPLC). The results showed that the concentrations of ·OH increased with the increase in peak voltage, and the generation rates of ·OH were 4.1 × 10-10 mol/s, 5.7 × 10-10 mol/s, and 7.7 × 10-10 mol/s at 30 kV, 35 kV, and 40 kV, respectively. The efficiency of OH generation was found to be independent of the input parameters for applied power, with an average value of 3.23×10-12 mol/J obtained.

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels.

PubMed

Seagar, Michael; Russier, Michael; Caillard, Olivier; Maulet, Yves; Fronzaroli-Molinieres, Laure; De San Feliciano, Marina; Boumedine-Guignon, Norah; Rodriguez, Léa; Zbili, Mickael; Usseglio, Fabrice; Formisano-Tréziny, Christine; Youssouf, Fahamoe; Sangiardi, Marion; Boillot, Morgane; Baulac, Stéphanie; Benitez, María José; Garrido, Juan-José; Debanne, Dominique; El Far, Oussama

2017-07-18

Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current. LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.

Water treatment by the AC gliding arc air plasma

NASA Astrophysics Data System (ADS)

Gharagozalian, Mehrnaz; Dorranian, Davoud; Ghoranneviss, Mahmood

2017-09-01

In this study, the effects of gliding arc (G Arc) plasma system on the treatment of water have been investigated experimentally. An AC power supply of 15 kV potential difference at 50 Hz frequency was employed to generate plasma. Plasma density and temperature were measured using spectroscopic method. The water was contaminated with staphylococcus aureus (Gram-positive) and salmonella bacteria (Gram-negative), and Penicillium (mold fungus) individually. pH, hydrogen peroxide, and nitride contents of treated water were measured after plasma treatment. Decontamination of treated water was determined using colony counting method. Results indicate that G Arc plasma is a powerful and green tool to decontaminate water without producing any byproducts.

System and method for motor speed estimation of an electric motor

DOEpatents

Lu, Bin [Kenosha, WI; Yan, Ting [Brookfield, WI; Luebke, Charles John [Sussex, WI; Sharma, Santosh Kumar [Viman Nagar, IN

2012-06-19

A system and method for a motor management system includes a computer readable storage medium and a processing unit. The processing unit configured to determine a voltage value of a voltage input to an alternating current (AC) motor, determine a frequency value of at least one of a voltage input and a current input to the AC motor, determine a load value from the AC motor, and access a set of motor nameplate data, where the set of motor nameplate data includes a rated power, a rated speed, a rated frequency, and a rated voltage of the AC motor. The processing unit is also configured to estimate a motor speed based on the voltage value, the frequency value, the load value, and the set of nameplate data and also store the motor speed on the computer readable storage medium.

Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior

PubMed Central

Hermanstyne, Tracey O.; Mellor, Rebecca L.

2017-01-01

Abstract Rapidly activating and inactivating A-type K+ currents (IA) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly (p < 0.0001) increased mean ± SEM repetitive firing rates in SCN neurons during the day (6.4 ± 0.5 Hz) and at night (4.3 ± 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). IA was also significantly (p < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 ± 11.8 pA/pF; night: 55.3 ± 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 ± 10.2 pA/pF; night: 120.6 ± 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and IA was larger at night. In addition, Kv4.1-targeted shRNA expression significantly (p < 0.001) increased mean ± SEM nighttime input resistance (Rin; 2256 ± 166 MΩ), compared to nontargeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly (p < 0.01) shortened, by ∼0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded IA channels in regulating circadian rhythms in neuronal excitability and behavior. PMID:28560311

Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior.

PubMed

Hermanstyne, Tracey O; Granados-Fuentes, Daniel; Mellor, Rebecca L; Herzog, Erik D; Nerbonne, Jeanne M

2017-01-01

Rapidly activating and inactivating A-type K + currents (I A ) encoded by Kv4.2 and Kv4.3 pore-forming (α) subunits of the Kv4 subfamily are key regulators of neuronal excitability. Previous studies have suggested a role for Kv4.1 α-subunits in regulating the firing properties of mouse suprachiasmatic nucleus (SCN) neurons. To test this, we utilized an RNA-interference strategy to knockdown Kv4.1, acutely and selectively, in the SCN. Current-clamp recordings revealed that the in vivo knockdown of Kv4.1 significantly ( p < 0.0001) increased mean ± SEM repetitive firing rates in SCN neurons during the day (6.4 ± 0.5 Hz) and at night (4.3 ± 0.6 Hz), compared with nontargeted shRNA-expressing SCN neurons (day: 3.1 ± 0.5 Hz; night: 1.6 ± 0.3 Hz). I A was also significantly ( p < 0.05) reduced in Kv4.1-targeted shRNA-expressing SCN neurons (day: 80.3 ± 11.8 pA/pF; night: 55.3 ± 7.7 pA/pF), compared with nontargeted shRNA-expressing (day: 121.7 ± 10.2 pA/pF; night: 120.6 ± 16.5 pA/pF) SCN neurons. The magnitude of the effect of Kv4.1-targeted shRNA expression on firing rates and I A was larger at night. In addition, Kv4.1-targeted shRNA expression significantly ( p < 0.001) increased mean ± SEM nighttime input resistance (R in ; 2256 ± 166 MΩ), compared to nontargeted shRNA-expressing SCN neurons (1143 ± 93 MΩ). Additional experiments revealed that acute knockdown of Kv4.1 significantly ( p < 0.01) shortened, by ∼0.5 h, the circadian period of spontaneous electrical activity, clock gene expression and locomotor activity demonstrating a physiological role for Kv4.1-encoded I A channels in regulating circadian rhythms in neuronal excitability and behavior.

Insight into climate change from the carbon exchange of biocrusts utilizing non-rainfall water.

PubMed

Ouyang, Hailong; Hu, Chunxiang

2017-05-31

Biocrusts are model ecosystems of global change studies. However, light and non-rainfall water (NRW) were previously few considered. Different biocrust types further aggravated the inconsistence. So carbon-exchange of biocrusts (cyanobacteria crusts-AC1/AC2; cyanolichen crust-LC1; chlorolichen crust-LC2; moss crust-MC) utilizing NRW at various temperatures and light-intensities were determined under simulated and insitu mesocosm experiments. Carbon input of all biocrusts were negatively correlated with experimental temperature under all light-intensity with saturated water and stronger light with equivalent NRW, but positively correlated with temperature under weak light with equivalent NRW. LCPs and R/Pg of AC1 were lowest, followed in turn by AC2, LC2 and MC. Thus AC1 had most opportunities to use NRW, and 2.5 °C warming did cause significant changes of carbon exchange. Structural equation models further revealed that air-temperature was most important for carbon-exchange of ACs, but equally important as NRW for LC2 and MC; positive influence of warming on carbon-input in ACs was much stronger than the latter. Therefore, temperature effect on biocrust carbon-input depends on both moisture and light. Meanwhile, the role of NRW, transitional states between ACs, and obvious carbon-fixation differences between lichen crusts should be fully considered in the future study of biocrusts responding to climate change.

Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac.

PubMed

Paz, Rodrigo Manuel; Tubert, Cecilia; Stahl, Agostina; Díaz, Analía López; Etchenique, Roberto; Murer, Mario Gustavo; Rela, Lorena

2018-05-11

Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

Diagnostics of AC excited Atmospheric Pressure Plasma Jet with He for Biomedical Applications

NASA Astrophysics Data System (ADS)

Hori, Masaru; Takeda, Keigo; Kumakura, Takumi; Ishikawa, Kenji; Tanaka, Hiromasa; Kondo, Hiroki; Sekine, Makoto; Nakai, Yoshihiro

2014-10-01

Atmospheric pressure plasma jets (APPJ) are frequently used for biomedical applications. Reactive species generated by the APPJ play important roles for treatments of biomedical samples. Therefore, high density APPJ sources are required to realize the high performance. Our group has developed AC excited Ar APPJ with electron density as high as 1015 cm-3, and realized the selective killing of cancer cells and the inactivate spores of Penicillium digitatum. Recently, a new spot-size AC excited APPJ with He gas have been developed. In this study, the He APPJ was characterized by using spectroscopy. The plasma was discharged at a He flow rate of 5 slm and a discharge voltage of AC 9 kV. Gas temperature and electron density of the APPJ were measured by optical emission spectroscopy. From theoretical fitting of 2nd positive system of N2 emission (380.4 nm) and Stark broadening of Balmer β line of H atom (486.1 nm), the gas temperature and the electron density was estimated to be 299 K and 3.4. × 1015 cm-3. The AC excited He APPJ has a potential to realize high density with room temperature and become a very powerful tool for biomedical applications.

Characterization of XLPE cable insulation by dynamic mechanical thermal analyzer (DMTA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Parpal, J.L.; Guddemi, C.; Lamarre, L.

1996-12-31

Polymeric insulated cables and accessories are becoming widely used at voltages over 120 kV, even up to 500 kV. Although high electrical stress presents the greatest challenge, some attention should be given to the fact that the polymeric insulation is also subjected to mechanical stress which can affect the electrical performance of the high-voltage cable system. Thus, the mechanical response to an ac stress induced by oscillating electrostatic forces could be an important factor with regard to long-term degradation of polymeric insulation. This paper presents preliminary mechanical relaxation measurements on XLPE and LDPE specimens taken from unaged transmission type cables.more » Dynamic mechanical relaxation showing radial profiles of the mechanical loss tangent and tensile modulus E{prime} are presented in a temperature range of 40 to 120 C.« less

A 1 MW, 100 kV, less than 100 kg space based dc-dc power converter

NASA Technical Reports Server (NTRS)

Cooper, J. R.; White, C. W.

1991-01-01

A 1 MW dc-dc power converter has been designed which has an input voltage of 5 kV +/-3 percent, an output voltage of 100 kV +/- 0.25 percent, and a run time of 1000 s at full power. The estimated system mass is 83.8 kg, giving a power density of 11.9 kW/kg. The system exceeded the weight goal of 10 kW/kg through the use of innovative components and system concepts. The system volume is approximately 0.1 cu m, and the overall system efficiency is estimated to be 87 percent. Some of the unique system features include a 50-kHz H-bridge inverter using MOS-controlled thyristors as the switching devices, a resonance transformer to step up the voltage, open-cycle cryogenic hydrogen gas cooling, and a nonrigid, inflatable housing which provides on-demand pressurization of the power converter local environment. This system scales very well to higher output powers. The weight of the 10-MW system with the same input and output voltage requirements and overall system configuration is estimated to be 575.3 kg. This gives a power density of 17.4 kW/kg, significantly higher than the 11.9 kW/kg estimated at 1 MW.

A 1 MW, 100 kV, less than 100 kg space based dc-dc power converter

NASA Astrophysics Data System (ADS)

Cooper, J. R.; White, C. W.

A 1 MW dc-dc power converter has been designed which has an input voltage of 5 kV +/-3 percent, an output voltage of 100 kV +/- 0.25 percent, and a run time of 1000 s at full power. The estimated system mass is 83.8 kg, giving a power density of 11.9 kW/kg. The system exceeded the weight goal of 10 kW/kg through the use of innovative components and system concepts. The system volume is approximately 0.1 cu m, and the overall system efficiency is estimated to be 87 percent. Some of the unique system features include a 50-kHz H-bridge inverter using MOS-controlled thyristors as the switching devices, a resonance transformer to step up the voltage, open-cycle cryogenic hydrogen gas cooling, and a nonrigid, inflatable housing which provides on-demand pressurization of the power converter local environment. This system scales very well to higher output powers. The weight of the 10-MW system with the same input and output voltage requirements and overall system configuration is estimated to be 575.3 kg. This gives a power density of 17.4 kW/kg, significantly higher than the 11.9 kW/kg estimated at 1 MW.

Resonant power supplies for a rapid-cycling accelerator

NASA Astrophysics Data System (ADS)

Karady, G.; Thiessen, H. A.; Schneider, E. J.

1988-10-01

A resonant power supply has been proposed as an efficient power supply for a future 60-GeV, Kaon-producing accelerator. The engineering design of the electric system of the main-ring power supplies is described. It is shown that the resonant power supply can be built with standard commercially available components. The most critical component is the bypass switch, which requires gate-turn off thyristors, connected in parallel. Standard metal-clad switchgear can be used for the AC system. The resonant power supplies can be fed directly from the 115-kV utility network, but the resonance power supplies draw pulse loads from the utility network. This pulse may produce disturbances. AC filter and reactive power compensation is needed for economical operation.

Single phase bi-directional AC-DC converter with reduced passive components size and common mode electro-magnetic interference

DOEpatents

Mi, Chris; Li, Siqi

2017-01-31

A bidirectional AC-DC converter is presented with reduced passive component size and common mode electro-magnetic interference. The converter includes an improved input stage formed by two coupled differential inductors, two coupled common and differential inductors, one differential capacitor and two common mode capacitors. With this input structure, the volume, weight and cost of the input stage can be reduced greatly. Additionally, the input current ripple and common mode electro-magnetic interference can be greatly attenuated, so lower switching frequency can be adopted to achieve higher efficiency.

Development of a single-phase 30 m HTS power cable

NASA Astrophysics Data System (ADS)

Cho, Jeonwook; Bae, Joon-Han; Kim, Hae-Jong; Sim, Ki-Deok; Kim, Seokho; Jang, Hyun-Man; Lee, Chang-Young; Kim, Dong-Wook

2006-05-01

HTS power transmission cables appear to be the replacement and retrofitting of underground cables in urban areas and HTS power transmission cable offers a number of technical and economic merits compared to the normal conductor cable system. A 30 m long, single-phase 22.9 kV class HTS power transmission cable system has been developed by Korea Electrotechnology Research Institute (KERI), LS Cable Ltd., and Korea Institute of Machinery and Materials (KIMM), which is one of the 21st century frontier project in Korea since 2001. The HTS power cable has been developed, cooled down and tested to obtain realistic thermal and electrical data on HTS power cable system. The evaluation results clarified such good performance of HTS cable that DC critical current of the HTS cable was 3.6 kA and AC loss was 0.98 W/m at 1260 Arms and shield current was 1000 Arms. These results proved the basic properties for 22.9 kV HTS power cable. As a next step, we have been developing a 30 m, three-phase 22.9 kV, 50 MV A HTS power cable system and long term evaluation is in progress now.

The investigation of a compact auto-connected wire-wrapped pulsed transformer

NASA Astrophysics Data System (ADS)

Wang, Yuwei; Zhang, Jiande; Chen, Dongqun; Cao, Shengguang; Li, Da; Zhang, Tianyang

2012-05-01

For the power conditioning circuit used to deliver power efficiently from flux compression generator (FCG) to the load with high impedance, an air-cored and wire-wrapped transformer convenient in coaxial connection to the other parts is investigated. To reduce the size and enhance the performance, an auto-connection is adopted. A fast and simple model is used to calculate the electrical parameters of the transformer. To evaluate the high voltage capability, the voltages across turns and the electric field distribution in the transformer are investigated. The calculated and the measured electrical parameters of the transformer show good agreements. And the safe operating voltage is predicted to exceed 500 kV. In the preliminary experiments, the transformer is tested in a power conditioning circuit with a capacitive power supply. It is demonstrated that the output voltage of the transformer reaches -342 kV under the input voltage of -81 kV.

The investigation of a compact auto-connected wire-wrapped pulsed transformer.

PubMed

Wang, Yuwei; Zhang, Jiande; Chen, Dongqun; Cao, Shengguang; Li, Da; Zhang, Tianyang

2012-05-01

For the power conditioning circuit used to deliver power efficiently from flux compression generator (FCG) to the load with high impedance, an air-cored and wire-wrapped transformer convenient in coaxial connection to the other parts is investigated. To reduce the size and enhance the performance, an auto-connection is adopted. A fast and simple model is used to calculate the electrical parameters of the transformer. To evaluate the high voltage capability, the voltages across turns and the electric field distribution in the transformer are investigated. The calculated and the measured electrical parameters of the transformer show good agreements. And the safe operating voltage is predicted to exceed 500 kV. In the preliminary experiments, the transformer is tested in a power conditioning circuit with a capacitive power supply. It is demonstrated that the output voltage of the transformer reaches -342 kV under the input voltage of -81 kV.

Safety of high speed guided ground transportation systems. Magnetic and electric field testing of the French Train a Grande Vitesse (TGV) rail systems. Volume 1. Analysis. Final report, September 1992-March 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dietrich, F.M.; Papas, P.N.; Jacobs, W.L.

The safety of magnetically levitated (maglev) and high speed rail (HSR) trains proposed for application in the United States is the responsibility of the Federal Railroad Administration (FRA). A franchise has been awarded to the Texas high Speed Rail Corporation to operate a 200 mph French Train a Grande Vitesse (TGV) in the Texas Triangle (Dallas-Fort Worth, Houston, San Antonio), with construction to begin in 1995. The report provides the Analysis (Vol. I) of results, and detailed data and statistical summaries (Vol. II, Appendices) of representative electric and magnetic field (EMF) profiles on TGV-A trains between Paris and Tours formore » two electro-technologies (1.5 KV DC near Paris, and 2x25 KV at 50 Hz AC).« less

Safety of high speed guided ground transportation systems. Magnetic and electric field testing of the French Train a Grande Vitesse (TGV) rail systems. Volume 2. Appendices. Final report, September 1992-March 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dietrich, F.M.; Jacobs, W.E.

The safety of magnetically levitated (maglev) and high speed rail (HSR) trains proposed for application in the United States is the responsibility of the Federal Railroad Administration (FRA). A franchise has been awarded to the Texas High Speed Rail Corporation to operate a 200 mph French Train a Grande Vitesse (TGV) in the Texas Triangle (Dallas-Fort Worth, Houston, San Antonio), with construction to begin in 1995. The report provides the Analysis (Vol. I) of results, and detailed data and statistical summaries (Vol. II, Appendices) of representative electric and magnetic field (EMF) profiles on TGV-A trains between Paris and Tours formore » two electro-technologies (1.5 KV DC near Paris, and 2x25 KV at 50 Hz AC).« less

Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.

PubMed

Gupte, Raeesa P; Kadunganattil, Suraj; Shepherd, Andrew J; Merrill, Ronald; Planer, William; Bruchas, Michael R; Strack, Stefan; Mohapatra, Durga P

2016-02-01

The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability. Copyright © 2015 Elsevier Ltd. All rights reserved.

Kv4 channels underlie A-currents with highly variable inactivation time courses but homogeneous other gating properties in the nucleus tractus solitarii.

PubMed

Strube, Caroline; Saliba, Layal; Moubarak, Estelle; Penalba, Virginie; Martin-Eauclaire, Marie-France; Tell, Fabien; Clerc, Nadine

2015-04-01

In the nucleus of the tractus solitarii (NTS), a large proportion of neurones express transient A-type potassium currents (I KA) having deep influence on the fidelity of the synaptic transmission of the visceral primary afferent inputs to second-order neurones. Up to now, the strong impact of I KA within the NTS was considered to result exclusively from its variation in amplitude, and its molecular correlate(s) remained unknown. In order to identify which Kv channels underlie I KA in NTS neurones, the gating properties and the pharmacology of this current were determined using whole cell patch clamp recordings in slices. Complementary information was brought by immunohistochemistry. Strikingly, two neurone subpopulations characterized by fast or slow inactivation time courses (respectively about 50 and 200 ms) were discriminated. Both characteristics matched those of the Kv4 channel subfamily. The other gating properties, also matching the Kv4 channel ones, were homogeneous through the NTS. The activation and inactivation occurred at membrane potentials around the threshold for generating action potentials, and the time course of recovery from inactivation was rapid. Pharmacologically, I KA in NTS neurones was found to be resistant to tetraethylammonium (TEA), sea anemone toxin blood-depressing substance (BDS) and dendrotoxin (DTX), whereas Androctonus mauretanicus mauretanicus toxin 3 (AmmTX3), a scorpion toxin of the α-KTX 15 family that has been shown to block all the members of the Kv4 family, inhibited 80 % of I KA irrespectively of its inactivation time course. Finally, immunohistochemistry data suggested that, among the Kv4 channel subfamily, Kv4.3 is the prevalent subunit expressed in the NTS.

Influence of power supply on the generation of ozone and degradation of phenol in a surface discharge reactor

NASA Astrophysics Data System (ADS)

Zhao, Yan; Shang, Kefeng; Duan, Lijuan; Li, Yue; An, Jiutao; Zhang, Chunyang; Lu, Na; Li, Jie; Wu, Yan

2013-03-01

A surface Dielectric Barrier Discharge (DBD) reactor was utilized to degrade phenol in water. Different power supplies applied to the DBD reactor affect the discharge modes, the formation of chemically active species and thus the removal efficiency of pollutants. It is thus important to select an optimized power supply for the DBD reactor. In this paper, the influence of the types of power supplies including alternate current (AC) and bipolar pulsed power supply on the ozone generation in a surface discharge reactor was measured. It was found that compared with bipolar pulsed power supply, higher energy efficiency of O3 generation was obtained when DBD reactor was supplied with 50Hz AC power supply. The highest O3 generation was approximate 4 mg kJ-1 moreover, COD removal efficiency of phenol wastewater reached 52.3% after 3 h treatment under an AC peak voltage of 2.6 kV.

Connections of cat auditory cortex: III. Corticocortical system.

PubMed

Lee, Charles C; Winer, Jeffery A

2008-04-20

The mammalian auditory cortex (AC) is essential for computing the source and decoding the information contained in sound. Knowledge of AC corticocortical connections is modest other than in the primary auditory regions, nor is there an anatomical framework in the cat for understanding the patterns of connections among the many auditory areas. To address this issue we investigated cat AC connectivity in 13 auditory regions. Retrograde tracers were injected in the same area or in different areas to reveal the areal and laminar sources of convergent input to each region. Architectonic borders were established in Nissl and SMI-32 immunostained material. We assessed the topography, convergence, and divergence of the labeling. Intrinsic input constituted >50% of the projection cells in each area, and extrinsic inputs were strongest from functionally related areas. Each area received significant convergent ipsilateral input from several fields (5 to 8; mean 6). These varied in their laminar origin and projection density. Major extrinsic projections were preferentially from areas of the same functional type (tonotopic to tonotopic, nontonotopic to nontonotopic, limbic-related to limbic-related, multisensory-to-multisensory), while smaller projections link areas belonging to different groups. Branched projections between areas were <2% with deposits of two tracers in an area or in different areas. All extrinsic projections to each area were highly and equally topographic and clustered. Intrinsic input arose from all layers except layer I, and extrinsic input had unique, area-specific infragranular and supragranular origins. The many areal and laminar sources of input may contribute to the complexity of physiological responses in AC and suggest that many projections of modest size converge within each area rather than a simpler area-to-area serial or hierarchical pattern of corticocortical connectivity. (c) 2008 Wiley-Liss, Inc.

Power conditioning system for energy sources

DOEpatents

Mazumder, Sudip K [Chicago, IL; Burra, Rajni K [Chicago, IL; Acharya, Kaustuva [Chicago, IL

2008-05-13

Apparatus for conditioning power generated by an energy source includes an inverter for converting a DC input voltage from the energy source to a square wave AC output voltage, and a converter for converting the AC output voltage from the inverter to a sine wave AC output voltage.

Improved quality of intrafraction kilovoltage images by triggered readout of unexposed frames

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulsen, Per Rugaard, E-mail: per.poulsen@rm.dk; Jonassen, Johnny; Jensen, Carsten

2015-11-15

Purpose: The gantry-mounted kilovoltage (kV) imager of modern linear accelerators can be used for real-time tumor localization during radiation treatment delivery. However, the kV image quality often suffers from cross-scatter from the megavoltage (MV) treatment beam. This study investigates readout of unexposed kV frames as a means to improve the kV image quality in a series of experiments and a theoretical model of the observed image quality improvements. Methods: A series of fluoroscopic images were acquired of a solid water phantom with an embedded gold marker and an air cavity with and without simultaneous radiation of the phantom with amore » 6 MV beam delivered perpendicular to the kV beam with 300 and 600 monitor units per minute (MU/min). An in-house built device triggered readout of zero, one, or multiple unexposed frames between the kV exposures. The unexposed frames contained part of the MV scatter, consequently reducing the amount of MV scatter accumulated in the exposed frames. The image quality with and without unexposed frame readout was quantified as the contrast-to-noise ratio (CNR) of the gold marker and air cavity for a range of imaging frequencies from 1 to 15 Hz. To gain more insight into the observed CNR changes, the image lag of the kV imager was measured and used as input in a simple model that describes the CNR with unexposed frame readout in terms of the contrast, kV noise, and MV noise measured without readout of unexposed frames. Results: Without readout of unexposed kV frames, the quality of intratreatment kV images decreased dramatically with reduced kV frequencies due to MV scatter. The gold marker was only visible for imaging frequencies ≥3 Hz at 300 MU/min and ≥5 Hz for 600 MU/min. Visibility of the air cavity required even higher imaging frequencies. Readout of multiple unexposed frames ensured visibility of both structures at all imaging frequencies and a CNR that was independent of the kV frame rate. The image lag was 12.2%, 2.2%, and 0.9% in the first, second, and third frame after an exposure. The CNR model predicted the CNR with triggered image readout with a mean absolute error of 2.0% for the gold marker. Conclusions: A device that triggers readout of unexposed frames during kV fluoroscopy was built and shown to greatly improve the quality of intratreatment kV images. A simple theoretical model successfully described the CNR improvements with the device.« less

Design versions of HTS three-phase cables with the minimized value of AC losses

NASA Astrophysics Data System (ADS)

Altov, V. A.; Balashov, N. N.; Degtyarenko, P. N.; Ivanov, S. S.; Kopylov, S. I.; Lipa, DA; Samoilenkov, S. V.; Sytnikov, V. E.; Zheltov, V. V.

2018-03-01

Design versions of HTS three-phase cables consisting of 2G HTS tapes have been investigated by the numerical simulation method with the aim of AC losses minimization. Two design versions of cables with the coaxial and extended rectangular cross-section shape are considered – the non-sectioned and sectioned one. In the latter each cable phase consists of sections connected in parallel. The optimal dimensions of sections and order of their alteration are chosen by appropriate calculations. The model used takes into account the current distribution between the sections and its non-uniformity within each single HTS tape as well. The following characteristics are varied: design version, dimension, positioning of extra copper layer in a cable, design of HTS tapes themselves and their mutual position. The dependence of AC losses on the latter two characteristics is considered in details, and the examples of cable designs optimized by the total set of characteristics for the medium class of voltages (10 – 60 kV) are given. At the critical current JC=5.1 кA per phase and current amplitudes lower than 0.85JC, the level of total AC losses does not exceed the natural cryostat heat losses.

Megawatt Space Power Conditioning, Distribution, and Control Study

DTIC Science & Technology

1988-03-01

also must be given to the design of an ac transmission line for this relatively high frequency . 2.3.2 Medium High Voltage Systems. Figure 2-4 shows a...systems are designed to exploit the use of 2 MW klystrode tubes (see Section 3.1) which require a dc voltage of about 140 kV. This high voltage can be...the concerns is that to date there have been no three-phase high voltage, high frequency transmission lines designed . Figure 5-6. While the previous

Joint HVAC transmission EMF environmental study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stormshak, F.; Thompson, J.

1992-05-01

This document describes the rationale, procedures, and results of a carefully controlled study conducted to establish whether chronic exposure of female (ewe) Suffolk lambs to the environment of a 500-kV 60-Hz transmission line would affect various characteristics of growth, endocrine function, and reproductive development. This experiment used identical housing and management schemes for control and line-exposed ewes, thus minimizing these factors as contributors to between-group experimental error. Further, throughout the 10-month duration of this study, changes in electric and magnetic fields, audible noise, and weather conditions were monitored continuously by a computerized system. Such measurements provided the opportunity to identifymore » any relationship between environmental factors and biological responses. Because of reports in the literature that electric and magnetic fields alter concentrations of melatonin in laboratory animals, the primary objective of this study was to ascertain whether a similar effect occurs in lambs exposed to a 500-kV a-c line in a natural setting. In addition, onset of puberty, changes in body weight, wool growth, and behavior were monitored. To determine whether the environment of a 500-kV line caused stress in the study animals, serum levels of cortisol were measured. The study was conducted at Bonneville Power Administration's Ostrander Substation near Estacada, Oregon.« less

Joint HVAC Transmission EMF Environmental Study : Final Report on Experiment 1.

DOE Office of Scientific and Technical Information (OSTI.GOV)

United States. Bonneville Power Administration; Oregon Regional Primate Research Center

1992-05-01

This document describes the rationale, procedures, and results of a carefully controlled study conducted to establish whether chronic exposure of female (ewe) Suffolk lambs to the environment of a 500-kV 60-Hz transmission line would affect various characteristics of growth, endocrine function, and reproductive development. This experiment used identical housing and management schemes for control and line-exposed ewes, thus minimizing these factors as contributors to between-group experimental error. Further, throughout the 10-month duration of this study, changes in electric and magnetic fields, audible noise, and weather conditions were monitored continuously by a computerized system. Such measurements provided the opportunity to identifymore » any relationship between environmental factors and biological responses. Because of reports in the literature that electric and magnetic fields alter concentrations of melatonin in laboratory animals, the primary objective of this study was to ascertain whether a similar effect occurs in lambs exposed to a 500-kV a-c line in a natural setting. In addition, onset of puberty, changes in body weight, wool growth, and behavior were monitored. To determine whether the environment of a 500-kV line caused stress in the study animals, serum levels of cortisol were measured. The study was conducted at Bonneville Power Administration`s Ostrander Substation near Estacada, Oregon.« less

Transmission line component testing for the ITER Ion Cyclotron Heating and Current Drive System

NASA Astrophysics Data System (ADS)

Goulding, Richard; Bell, G. L.; Deibele, C. E.; McCarthy, M. P.; Rasmussen, D. A.; Swain, D. W.; Barber, G. C.; Barbier, C. N.; Cambell, I. H.; Moon, R. L.; Pesavento, P. V.; Fredd, E.; Greenough, N.; Kung, C.

2014-10-01

High power RF testing is underway to evaluate transmission line components for the ITER Ion Cyclotron Heating and Current Drive System. The transmission line has a characteristic impedance Z0 = 50 Ω and a nominal outer diameter of 305 mm. It is specified to carry up to 6 MW at VSWR = 1.5 for 3600 s pulses, with transient voltages up to 40 kV. The transmission line is actively cooled, with turbulent gas flow (N2) used to transfer heat from the inner to outer conductor, which is water cooled. High voltage and high current testing of components has been performed using resonant lines generating steady state voltages of 35 kV and transient voltages up to 60 kV. A resonant ring, which has operated with circulating power of 6 MW for 1 hr pulses, is being used to test high power, low VSWR operation. Components tested to date include gas barriers, straight sections of various lengths, and 90 degree elbows. Designs tested include gas barriers fabricated from quartz and aluminum nitride, and transmission lines with quartz and alumina inner conductor supports. The latest results will be presented. This manuscript has been authored by UT-Battelle, LLC, under Contract No. DE-AC05-00OR22725 with the U.S. Department of Energy.

Reliability Improvement of Ground Fault Protection System Using an S-Type Horn Attachment Gap in AC Feeding System

NASA Astrophysics Data System (ADS)

Ajiki, Kohji; Morimoto, Hiroaki; Shimokawa, Fumiyuki; Sakai, Shinya; Sasaki, Kazuomi; Sato, Ryogo

Contact wires used in feeding system for electric railroad are insulated by insulators. However, insulation of an insulator sometimes breaks down by surface dirt of an insulator and contact with a bird. The insulator breakdown derives a ground fault in feeding system. Ground fault will cause a human electric shock and a destruction of low voltage electric equipment. In order to prevent the damage by ground fault, an S-type horn has been applicable as equipped on insulators of negative feeder and protective wire until present. However, a concrete pole breaks down at the time of the ground fault because a spark-over voltage of the S-type horn is higher than a breakdown voltage of a concrete pole. Farther, the S-type horn installed in the steel tube pole does not discharge a case, because the earth resistance of a steel tube pole is very small. We assumed that we could solve these troubles by changing the power frequency spark-over voltage of the S-type horn from 12kV to 3kV. Accordingly, we developed an attachment gap that should be used to change the power frequency spark-over voltage of the S-type horn from 12kV to 3kV. The attachment gap consists of a gas gap arrester and a zinc oxide element. By the dynamic current test and the artificial ground fault test, we confirmed that the attachment gap in the S-type horn could prevent a trouble at the time of the ground fault.

A Single-Phase Embedded Z-Source DC-AC Inverter

PubMed Central

Kim, Se-Jin; Lim, Young-Cheol

2014-01-01

In the conventional DC-AC inverter consisting of two DC-DC converters with unipolar output capacitors, the output capacitor voltages of the DC-DC converters must be higher than the DC input voltage. To overcome this weakness, this paper proposes a single-phase DC-AC inverter consisting of two embedded Z-source converters with bipolar output capacitors. The proposed inverter is composed of two embedded Z-source converters with a common DC source and output AC load. Though the output capacitor voltages of the converters are relatively low compared to those of a conventional inverter, an equivalent level of AC output voltages can be obtained. Moreover, by controlling the output capacitor voltages asymmetrically, the AC output voltage of the proposed inverter can be higher than the DC input voltage. To verify the validity of the proposed inverter, experiments were performed with a DC source voltage of 38 V. By controlling the output capacitor voltages of the converters symmetrically or asymmetrically, the proposed inverter can produce sinusoidal AC output voltages. The experiments show that efficiencies of up to 95% and 97% can be achieved with the proposed inverter using symmetric and asymmetric control, respectively. PMID:25133241

A single-phase embedded Z-source DC-AC inverter.

PubMed

Kim, Se-Jin; Lim, Young-Cheol

2014-01-01

In the conventional DC-AC inverter consisting of two DC-DC converters with unipolar output capacitors, the output capacitor voltages of the DC-DC converters must be higher than the DC input voltage. To overcome this weakness, this paper proposes a single-phase DC-AC inverter consisting of two embedded Z-source converters with bipolar output capacitors. The proposed inverter is composed of two embedded Z-source converters with a common DC source and output AC load. Though the output capacitor voltages of the converters are relatively low compared to those of a conventional inverter, an equivalent level of AC output voltages can be obtained. Moreover, by controlling the output capacitor voltages asymmetrically, the AC output voltage of the proposed inverter can be higher than the DC input voltage. To verify the validity of the proposed inverter, experiments were performed with a DC source voltage of 38 V. By controlling the output capacitor voltages of the converters symmetrically or asymmetrically, the proposed inverter can produce sinusoidal AC output voltages. The experiments show that efficiencies of up to 95% and 97% can be achieved with the proposed inverter using symmetric and asymmetric control, respectively.

Capabilities of the new “Universal” AC-DC monitor for electropenetrography (EPG)

USDA-ARS?s Scientific Manuscript database

Electropenetrography (EPG), invented over 50 years ago, is the most rigorous and important means of studying the feeding of piercing-sucking crop pests. The 1st-generation monitor (or AC monitor) used AC applied signal voltage and had fixed amplifier sensitivity (input resistor or Ri) of 106 Ohms. T...

Nitric Oxide Is an Activity-Dependent Regulator of Target Neuron Intrinsic Excitability

PubMed Central

Steinert, Joern R.; Robinson, Susan W.; Tong, Huaxia; Haustein, Martin D.; Kopp-Scheinpflug, Cornelia; Forsythe, Ian D.

2011-01-01

Summary Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours. PMID:21791288

The anode power supply for the ECRH system on the J-TEXT tokamak

NASA Astrophysics Data System (ADS)

Donghui, XIA; Fangtai, CUI; Changhai, LIU; Zhenxiong, YU; Yikun, JIN; Zhijiang, WANG; J-TEXT, Team1

2018-01-01

The electron cyclotron resonance heating (ECRH) system with a 60 GHz/200 kW/0.5 s gyrotron donated by the Culham Science Center is being developed on the J-TEXT tokamak for plasma heating, current drive and MHD studies. Simultaneously, an anode power supply (APS) has been rebuilt and tested for the output power control of the gyrotron, of which the input voltage is derived from an 80 kV negative cathode power supply. The control strategy by controlling the grid voltage of the tetrode TH5186 is applied to obtain an accurate anode climbing voltage, of which the output voltage can be obtained from 0-30 kV with respect to the cathode power supply. The characteristics of the APS, including control, protection, modulation, and output waveform, were tested with a 100 kV/60 A negative cathode power supply, a dummy load and the ECRH control system. The results indicate that the APS can meet the requirements of the ECRH system on J-TEXT.

HERG1A potassium channel is the predominant isoform in head and neck squamous cell carcinomas: evidence for regulation by epigenetic mechanisms

PubMed Central

Menéndez, Sofía T.; Villaronga, M. Ángeles; Rodrigo, Juan P.; Álvarez-Teijeiro, Saúl; Urdinguio, Rocío G.; Fraga, Mario F.; Suárez, Carlos; García-Pedrero, Juana M.

2016-01-01

Evidences indicate that HERG1 voltage-gated potassium channel is frequently aberrantly expressed in various cancers including head and neck squamous cell carcinomas (HNSCC), representing a clinically and biologically relevant feature during disease progression and a potential therapeutic target. The present study further and significantly extends these data investigating for the first time the expression and individual contribution of HERG1 isoforms, their clinical significance during disease progression and also the underlying regulatory mechanisms. Analysis of HERG1A and HERG1B expression using real-time RT-PCR consistently showed that HERG1A is the predominant isoform in ten HNSCC-derived cell lines tested. HERG2 and HERG3 were also detected. Immunohistochemical analysis of HERG1A expression on 133 HNSCC specimens demonstrated that HERG1A expression increased during tumour progression and correlated significantly with reduced disease-specific survival. Furthermore, our study provides original evidence supporting the involvement of histone acetylation (i.e. H3Ac and H4K16Ac activating marks) in the regulation of HERG1 expression in HNSCC. Interestingly, this mechanism was also found to regulate the expression of another oncogenic channel (Kv3.4) as well as HERG2 and HERG3. These data demonstrate that HERG1A is the predominant and disease-relevant isoform in HNSCC progression, while histone acetylation emerges as an important regulatory mechanism underlying Kv gene expression. PMID:26785772

HERG1A potassium channel is the predominant isoform in head and neck squamous cell carcinomas: evidence for regulation by epigenetic mechanisms.

PubMed

Menéndez, Sofía T; Villaronga, M Ángeles; Rodrigo, Juan P; Álvarez-Teijeiro, Saúl; Urdinguio, Rocío G; Fraga, Mario F; Suárez, Carlos; García-Pedrero, Juana M

2016-01-20

Evidences indicate that HERG1 voltage-gated potassium channel is frequently aberrantly expressed in various cancers including head and neck squamous cell carcinomas (HNSCC), representing a clinically and biologically relevant feature during disease progression and a potential therapeutic target. The present study further and significantly extends these data investigating for the first time the expression and individual contribution of HERG1 isoforms, their clinical significance during disease progression and also the underlying regulatory mechanisms. Analysis of HERG1A and HERG1B expression using real-time RT-PCR consistently showed that HERG1A is the predominant isoform in ten HNSCC-derived cell lines tested. HERG2 and HERG3 were also detected. Immunohistochemical analysis of HERG1A expression on 133 HNSCC specimens demonstrated that HERG1A expression increased during tumour progression and correlated significantly with reduced disease-specific survival. Furthermore, our study provides original evidence supporting the involvement of histone acetylation (i.e. H3Ac and H4K16Ac activating marks) in the regulation of HERG1 expression in HNSCC. Interestingly, this mechanism was also found to regulate the expression of another oncogenic channel (Kv3.4) as well as HERG2 and HERG3. These data demonstrate that HERG1A is the predominant and disease-relevant isoform in HNSCC progression, while histone acetylation emerges as an important regulatory mechanism underlying Kv gene expression.

A novel wireless power and data transmission AC to DC converter for an implantable device.

PubMed

Liu, Jhao-Yan; Tang, Kea-Tiong

2013-01-01

This article presents a novel AC to DC converter implemented by standard CMOS technology, applied for wireless power transmission. This circuit combines the functions of the rectifier and DC to DC converter, rather than using the rectifier to convert AC to DC and then supplying the required voltage with regulator as in the transitional method. This modification can reduce the power consumption and the area of the circuit. This circuit also transfers the loading condition back to the external circuit by the load shift keying(LSK), determining if the input power is not enough or excessive, which increases the efficiency of the total system. The AC to DC converter is fabricated with the TSMC 90nm CMOS process. The circuit area is 0.071mm(2). The circuit can produce a 1V DC voltage with maximum output current of 10mA from an AC input ranging from 1.5V to 2V, at 1MHz to 10MHz.

Electrical Evaluation of RCA MWS5001D Random Access Memory, Volume 5, Appendix D

NASA Technical Reports Server (NTRS)

Klute, A.

1979-01-01

The electrical characterization and qualification test results are presented for the RCA MWS 5001D random access memory. The tests included functional tests, AC and DC parametric tests, AC parametric worst-case pattern selection test, determination of worst-case transition for setup and hold times, and a series of schmoo plots. Average input high current, worst case input high current, output low current, and data setup time are some of the results presented.

Development of 50kV air-core transformer for electron gun static power source of 3MeV DC accelerator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dewangan, S.; Bakhtsingh, R.I.; Rajan, R.N.

A 3 MeV, 10 mA DC Electron Beam Accelerator based on the capacitively coupled parallel-fed voltage multiplier in 6 kg/cm{sup 2} SF{sub 6} gas environment is under commissioning at Electron Beam Centre, Kharghar, Navi Mumbai. Electron Gun is situated at -3 MV terminal which requires a constant power for its anode and filament. Gun power source has been derived by suitably coupling the ac components present in the HV Multiplier column. An aircore step down transformer rated for 50kV/600V/120kHz floating at 3 MV to extract the required power for electron gun from high voltage column has been developed. The transformermore » has been operated for 7 kW, 1 MeV of electron beam in 6 kg/cm{sup 2} nitrogen gas environment. The paper describes briefly about the design aspects and test results. (author)« less

10 CFR 431.192 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

..., and which has a rated primary voltage between 601 V and 34.5 kV. No-load loss means those losses that... no-load loss, 55 °C for load loss of liquid-immersed distribution transformers at 50 percent load... input. Excitation current or no-load current means the current that flows in any winding used to excite...

10 CFR 431.192 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

..., and which has a rated primary voltage between 601 V and 34.5 kV. No-load loss means those losses that... no-load loss, 55 °C for load loss of liquid-immersed distribution transformers at 50 percent load... input. Excitation current or no-load current means the current that flows in any winding used to excite...

10 CFR 431.192 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

..., and which has a rated primary voltage between 601 V and 34.5 kV. No-load loss means those losses that... no-load loss, 55 °C for load loss of liquid-immersed distribution transformers at 50 percent load... input. Excitation current or no-load current means the current that flows in any winding used to excite...

10 CFR 431.192 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

..., and which has a rated primary voltage between 601 V and 34.5 kV. No-load loss means those losses that... no-load loss, 55 °C for load loss of liquid-immersed distribution transformers at 50 percent load... input. Excitation current or no-load current means the current that flows in any winding used to excite...

Ferroresonant flux coupled battery charger

NASA Technical Reports Server (NTRS)

McLyman, Colonel W. T. (Inventor)

1987-01-01

A battery charger for incorporation into an electric-powered vehicle is disclosed. The charger includes a ferroresonant voltage-regulating circuit for providing an output voltage proportional to the frequency of an input AC voltage. A high frequency converter converts a DC voltage supplied, for example, from a rectifier connected to a standard AC outlet, to a controlled frequency AC voltage which is supplied to the input of the ferroresonant circuit. The ferroresonant circuit includes an output, a saturable core transformer connected across the output, and a first linear inductor and a capacitor connected in series across the saturable core transformer and tuned to resonate at the third harmonic of the AC voltage from the high frequency converter. The ferroresonant circuit further includes a second linear inductor connected between the input of the ferroresonant circuit and the saturable core transformer. The output voltage from the ferroresonant circuit is rectified and applied across a pair of output terminals adapted to be connected to the battery to be charged. A feedback circuit compares the voltage across the output terminals with a reference voltage and controls the frequency of the AC voltage produced by the high frequency converter to maintain the voltage across the output terminals at a predetermined value. The second linear inductor provides a highly reactive load in the event of a fault across the output terminals to render the charger short-circuit proof.

Multiple piezo-patch energy harvesters on a thin plate with respective AC-DC conversion

NASA Astrophysics Data System (ADS)

Aghakhani, Amirreza; Basdogan, Ipek

2018-03-01

Piezoelectric patch energy harvesters can be directly integrated to plate-like structures which are widely used in automotive, marine and aerospace applications, to convert vibrational energy to electrical energy. This paper presents two different AC-DC conversion techniques for multiple patch harvesters, namely single rectifier and respective rectifiers. The first case considers all the piezo-patches are connected in parallel to a single rectifier, whereas in the second case, each harvester is respectively rectified and then connected in parallel to a smoothing capacitor and a resistive load. The latter configuration of AC-DC conversion helps to avoid the electrical charge cancellation which is a problem with the multiple harvesters attached to different locations of the host plate surface. Equivalent circuit model of the multiple piezo-patch harvesters is developed in the SPICE software to simulate the electrical response. The system parameters are obtained from the modal analysis solution of the plate. Simulations of the voltage frequency response functions (FRFs) for the standard AC input - AC output case are conducted and validated by experimental data. Finally, for the AC input - DC output case, numerical simulation and experimental results of the power outputs of multiple piezo-patch harvesters with multiple AC-DC converters are obtained for a wide range of resistive loads and compared with the same array of harvesters connected to a single AC-DC converter.

Degradation of Acid Orange 7 Dye in Two Hybrid Plasma Discharge Reactors

NASA Astrophysics Data System (ADS)

Shen, Yongjun; Lei, Lecheng; Zhang, Xingwang; Ding, Jiandong

2014-11-01

To get an optimized pulsed electrical plasma discharge reactor and to increase the energy utilization efficiency in the removal of pollutants, two hybrid plasma discharge reactors were designed and optimized. The reactors were compared via the discharge characteristics, energy transfer efficiency, the yields of the active species and the energy utilization in dye wastewater degradation. The results showed that under the same AC input power, the characteristics of the discharge waveform of the point-to-plate reactor were better. Under the same AC input power, the two reactors both had almost the same peak voltage of 22 kV. The peak current of the point-to-plate reactor was 146 A, while that of the wire-to-cylinder reactor was only 48.8 A. The peak powers of the point-to-plate reactor and the wire-to-cylinder reactor were 1.38 MW and 1.01 MW, respectively. The energy per pulse of the point-to-plate reactor was 0.2221 J, which was about 29.4% higher than that of the wire-to-cylinder reactor (0.1716 J). To remove 50% Acid Orange 7 (AO7), the energy utilizations of the point-to-plate reactor and the wire-to-cylinder reactor were 1.02 × 10-9 mol/L and 0.61 × 10-9 mol/L, respectively. In the point-to-plate reactor, the concentration of hydrogen peroxide in pure water was 3.6 mmol/L after 40 min of discharge, which was higher than that of the wire-to-cylinder reactor (2.5 mmol/L). The concentration of liquid phase ozone in the point-to-plate reactor (5.7 × 10-2 mmol/L) was about 26.7% higher than that in the wire-to-cylinder reactor (4.5 × 10-2 mmol/L). The analysis results of the variance showed that the type of reactor and reaction time had significant impacts on the yields of the hydrogen peroxide and ozone. The main degradation intermediates of AO7 identified by gas chromatography and mass spectrometry (GCMS) were acetic acid, maleic anhydride, p-benzoquinone, phenol, benzoic acid, phthalic anhydride, coumarin and 2-naphthol. Proposed degradation pathways were elucidated in light of the analyzed degradation products.

Equations For Rotary Transformers

NASA Technical Reports Server (NTRS)

Salomon, Phil M.; Wiktor, Peter J.; Marchetto, Carl A.

1988-01-01

Equations derived for input impedance, input power, and ratio of secondary current to primary current of rotary transformer. Used for quick analysis of transformer designs. Circuit model commonly used in textbooks on theory of ac circuits.

Hydrogen peroxide stimulation of CFTR reveals an Epac-mediated, soluble AC-dependent cAMP amplification pathway common to GPCR signalling

PubMed Central

Ivonnet, P; Salathe, M; Conner, G E

2015-01-01

BACKGROUND AND PURPOSE H2O2 is widely understood to regulate intracellular signalling. In airway epithelia, H2O2 stimulates anion secretion primarily by activating an autocrine PGE2 signalling pathway via EP4 and EP1 receptors to initiate cytic fibrosis transmembrane regulator (CFTR)-mediated Cl− secretion. This study investigated signalling downstream of the receptors activated by H2O2. EXPERIMENTAL APPROACH Anion secretion by differentiated bronchial epithelial cells was measured in Ussing chambers during stimulation with H2O2, an EP4 receptor agonist or β2-adrenoceptor agonist in the presence and absence of inhibitors of ACs and downstream effectors. Intracellular calcium ([Ca2+]I) changes were followed by microscopy using fura–2-loaded cells and PKA activation followed by FRET microscopy. KEY RESULTS Transmembrane adenylyl cyclase (tmAC) and soluble AC (sAC) were both necessary for H2O2 and EP4 receptor-mediated CFTR activation in bronchial epithelia. H2O2 and EP4 receptor agonist stimulated tmAC to increase exchange protein activated by cAMP (Epac) activity that drives PLC activation to raise [Ca2+]i via Ca2+ store release (and not entry). Increased [Ca2+]i led to sAC activation and further increases in CFTR activity. Stimulation of sAC did not depend on changes in [HCO3−]. Ca2+-activated apical KCa1.1 channels and cAMP-activated basolateral KV7.1 channels contributed to H2O2-stimulated anion currents. A similar Epac-mediated pathway was seen following β2-adrenoceptor or forskolin stimulation. CONCLUSIONS AND IMPLICATIONS H2O2 initiated a complex signalling cascade that used direct stimulation of tmACs by Gαs followed by Epac-mediated Ca2+ crosstalk to activate sAC. The Epac-mediated Ca2+ signal constituted a positive feedback loop that amplified CFTR anion secretion following stimulation of tmAC by a variety of stimuli. PMID:25220136

Input-current shaped ac to dc converters

NASA Technical Reports Server (NTRS)

1986-01-01

The problem of achieving near unity power factor while supplying power to a dc load from a single phase ac source of power is examined. Power processors for this application must perform three functions: input current shaping, energy storage, and output voltage regulation. The methods available for performing each of these three functions are reviewed. Input current shaping methods are either active or passive, with the active methods divided into buck-like and boost-like techniques. In addition to large reactances, energy storage methods include resonant filters, active filters, and active storage schemes. Fast voltage regulation can be achieved by post regulation or by supplementing the current shaping topology with an extra switch. Some indications of which methods are best suited for particular applications concludes the discussion.

Use of MV and kV imager correlation for maintaining continuous real-time 3D internal marker tracking during beam interruptions

NASA Astrophysics Data System (ADS)

Wiersma, R. D.; Riaz, N.; Dieterich, Sonja; Suh, Yelin; Xing, L.

2009-01-01

The integration of onboard kV imaging together with a MV electronic portal imaging device (EPID) on linear accelerators (LINAC) can provide an easy to implement real-time 3D organ position monitoring solution for treatment delivery. Currently, real-time MV-kV tracking has only been demonstrated by simultaneous imagining by both MV and kV imaging devices. However, modalities such as step-and-shoot IMRT (SS-IMRT), which inherently contain MV beam interruptions, can lead to loss of target information necessary for 3D localization. Additionally, continuous kV imaging throughout the treatment delivery can lead to high levels of imaging dose to the patient. This work demonstrates for the first time how full 3D target tracking can be maintained even in the presence of such beam interruption, or MV/kV beam interleave, by use of a relatively simple correlation model together with MV-kV tracking. A moving correlation model was constructed using both present and prior positions of the marker in the available MV or kV image to compute the position of the marker on the interrupted imager. A commercially available radiotherapy system, equipped with both MV and kV imaging devices, was used to deliver typical SS-IMRT lung treatment plans to a 4D phantom containing internally embedded metallic markers. To simulate actual lung tumor motion, previous recorded 4D lung patient motion data were used. Lung tumor motion data of five separate patients were inputted into the 4D phantom, and typical SS-IMRT lung plans were delivered to simulate actual clinical deliveries. Application of the correlation model to SS-IMRT lung treatment deliveries was found to be an effective solution for maintaining continuous 3D tracking during 'step' beam interruptions. For deliveries involving five or more gantry angles with 50 or more fields per plan, the positional errors were found to have <=1 mm root mean squared error (RMSE) in all three spatial directions. In addition to increasing the robustness of MV-kV tracking against beam interruption, it was also found that use of correlation can be an effective way of lowering kV dose to the patient and for increasing kV image quality by reduction of MV scatter interference.

Determination of ac conductor and pipe loss in pipe-type cable systems. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silver, D.A.; Seman, G.W.

1982-02-01

The results are presented of investigations into the determination of the ac/dc resistance ratios of high and extra high voltage pipe-type cables with conventional and large size segmental conductors in carbon steel, stainless steel and aluminum pipes in three cable per pipe and single cable per pipe configurations. The measurements included 115 through 765 kV cables with copper, enamel coated copper, and aluminum conductors in sizes of 2000 kcmil (1015 mm/sup 2/), 3250 kcmil (1650 mm/sup 2/), and 3500 kcmil (1776 mm/sup 2/). Calculations using presently available techniques were employed to provide correlation between measured and calculated values in bothmore » magnetic and non-magnetic pipes. In addition, a number of new techniques in conductor construction, pipe material and pipe liners and cable wraps were investigated as means of decreasing the ac/dc resistance ratios of pipe-type cables. Finally, the various systems studied were compared on the basis of system MVA rating and by evaluation of installed and overall operating costs as compared to conventional three cable per pipe systems installed in carbon steel pipes.« less

Effects of atmospheric nonthermal plasma on invasion of colorectal cancer cells

NASA Astrophysics Data System (ADS)

Kim, Chul-Ho; Kwon, Seyeoul; Bahn, Jae Hoon; Lee, Keunho; Jun, Seung Ik; Rack, Philip D.; Baek, Seung Joon

2010-06-01

The effect that the gas content and plasma power of atmospheric, nonthermal plasma has on the invasion activity in colorectal cancer cells has been studied. Helium and helium plus oxygen plasmas were induced through a nozzle and operated with an ac power of less than 10 kV which exhibited a length of 2.5 cm and a diameter of 3-4 mm in ambient air. Treatment of cancer cells with the plasma jet resulted in a decrease in cell migration/invasion with higher plasma intensity and the addition of oxygen to the He flow gas.

A Global Circuit Diagram to Contrast the Behavior of the DC and AC Global Circuits

NASA Astrophysics Data System (ADS)

Williams, E.; Boldi, R. A.; Markson, R. J.

2017-12-01

The Earth-ionosphere cavity is home to both the classical DC and the AC (Schumann resonances) global circuits. The predominant source for the AC global circuit is lightning, but the sources for the DC global circuit source remains controversial. Separate measurements over many years have shown that the amplitude variation of global lightning and the AC global circuit is about twice that of the DC global circuit on both the diurnal and annual time scales. A global diagram is used to shed further light on this result and to explore the co-variation of the two global circuits. Actual measurements of the ionospheric potential (Vi) are plotted against the simultaneous global lightning flash rate F. The latter estimates are drawn from a global climatology of LIS/OTD satellite observations (Cecil et al., 2014) giving flash rate as a function of both Day of Year and UT time, and are used as best guesses for F at the time of the Vi observations. A least-squares linear fit through the data points on this diagram show a zero-flash-rate intercept for Vi that is more than half of the mean Vi ( 250 kV). This result suggests that electrified shower clouds (without lightning), possibly supplemented by convective transport of positive space charge in the marine boundary layer, are playing a greater role in driving the DC global circuit than previously suspected.

Converter topologies and control

DOEpatents

Rodriguez, Fernando; Qin, Hengsi; Chapman, Patrick

2018-05-01

An inverter includes a transformer that includes a first winding, a second winding, and a third winding, a DC-AC inverter electrically coupled to the first winding of the transformer, a cycloconverter electrically coupled to the second winding of the transformer, an active filter electrically coupled to the third winding of the transformer. The DC-AC inverter is adapted to convert the input DC waveform to an AC waveform delivered to the transformer at the first winding. The cycloconverter is adapted to convert an AC waveform received at the second winding of the transformer to the output AC waveform having a grid frequency of the AC grid. The active filter is adapted to sink and source power with one or more energy storage devices based on a mismatch in power between the DC source and the AC grid.

Series resonance inverter with triggered vacuum gaps

NASA Astrophysics Data System (ADS)

Damstra, Geert C.; Zhang, X.

1994-05-01

Series resonance inverters based on semi-conductor switching elements are well-known and have a wide range of application, mainly for lower voltages. For high voltage application many switching elements have to be put in series to obtain sufficient blocking voltage. Voltage grinding and multiple gate control elements are needed. There is much experience with the triggered vacuum gaps as high voltage/high current single shot elements, for example in reignition circuits for synthetic circuit breaker tests. These elements have a blocking voltage of 50 - 100 kV and are triggerable by a light fiber control device. A prototype inverter has been developed that generates 0.1 Hz, 30 kV AC voltages with a flat top for tests on cables and capacitors of many micro farads fed from a low voltage supply of about 600 V. Only two TVG elements are needed to switch the resonant circuit alternatively on the positive or negative supply. The resonant circuit itself consists of the capacitance of the testobject and a high quality inductor that determines the frequency and the peak current of the voltage reversing process.

Effect of pulsed corona discharge voltage and feed gas flow rate on dissolved ozone concentration

NASA Astrophysics Data System (ADS)

Prasetyaningrum, A.; Ratnawati, Jos, B.

2015-12-01

Ozonization is one of the methods extensively used for water purification and degradation of organic materials. Ozone (O3) is recognized as a powerful oxidizing agent. Due to its strong oxidability and better environmental friendless, ozone increasing being used in domestic and industrial applications. Current technology in ozone production utilizes several techniques (corona discharge, ultra violet radiation and electrolysis). This experiment aimed to evaluating effect of voltage and gas flow rate on ozone production with corona discharge. The system consists of two net-type stainless steel electrode placed in a dielectric barrier. Three pulsed voltage (20, 30, 40 KV) and flow rate (5, 10, 15 L/min) were prepare for operation variable at high frequency (3.7 kHz) with AC pulsed power supply. The dissolved ozone concentration depends on the applied high-voltage level, gas flow rate and the discharge exposure duration. The ozone concentration increases with decreasing gas flow rate. Dissolved ozone concentrations greater than 200 ppm can be obtained with a minimum voltage 40 kV.

Action potential processing in a detailed Purkinje cell model reveals a critical role for axonal compartmentalization

PubMed Central

Masoli, Stefano; Solinas, Sergio; D'Angelo, Egidio

2015-01-01

The Purkinje cell (PC) is among the most complex neurons in the brain and plays a critical role for cerebellar functioning. PCs operate as fast pacemakers modulated by synaptic inputs but can switch from simple spikes to complex bursts and, in some conditions, show bistability. In contrast to original works emphasizing dendritic Ca-dependent mechanisms, recent experiments have supported a primary role for axonal Na-dependent processing, which could effectively regulate spike generation and transmission to deep cerebellar nuclei (DCN). In order to account for the numerous ionic mechanisms involved (at present including Nav1.6, Cav2.1, Cav3.1, Cav3.2, Cav3.3, Kv1.1, Kv1.5, Kv3.3, Kv3.4, Kv4.3, KCa1.1, KCa2.2, KCa3.1, Kir2.x, HCN1), we have elaborated a multicompartmental model incorporating available knowledge on localization and gating of PC ionic channels. The axon, including initial segment (AIS) and Ranvier nodes (RNs), proved critical to obtain appropriate pacemaking and firing frequency modulation. Simple spikes initiated in the AIS and protracted discharges were stabilized in the soma through Na-dependent mechanisms, while somato-dendritic Ca channels contributed to sustain pacemaking and to generate complex bursting at high discharge regimes. Bistability occurred only following Na and Ca channel down-regulation. In addition, specific properties in RNs K currents were required to limit spike transmission frequency along the axon. The model showed how organized electroresponsive functions could emerge from the molecular complexity of PCs and showed that the axon is fundamental to complement ionic channel compartmentalization enabling action potential processing and transmission of specific spike patterns to DCN. PMID:25759640

Rapid activity-dependent modulation of the intrinsic excitability through up-regulation of KCNQ/Kv7 channel function in neonatal spinal motoneurons.

PubMed

Lombardo, Joseph; Sun, Jianli; Harrington, Melissa A

2018-01-01

Activity-dependent changes in the properties of the motor system underlie the necessary adjustments in its responsiveness on the basis of the environmental and developmental demands of the organism. Although plastic changes in the properties of the spinal cord have historically been neglected because of the archaic belief that the spinal cord is constituted by a hardwired network that simply relays information to muscles, plenty of evidence has been accumulated showing that synapses impinging on spinal motoneurons undergo short- and long-term plasticity. In the brain, brief changes in the activity level of the network have been shown to be paralleled by changes in the intrinsic excitability of the neurons and are suggested to either reinforce or stabilize the changes at the synaptic level. However, rapid activity-dependent changes in the intrinsic properties of spinal motoneurons have never been reported. In this study, we show that in neonatal mice the intrinsic excitability of spinal motoneurons is depressed after relatively brief but sustained changes in the spinal cord network activity. Using electrophysiological techniques together with specific pharmacological blockers of KCNQ/Kv7 channels, we demonstrate their involvement in the reduction of the intrinsic excitability of spinal motoneurons. This action results from an increased M-current, the product of the activation of KCNQ/Kv7 channels, which leads to a hyperpolarization of the resting membrane potential and a decrease in the input resistance of spinal motoneurons. Computer simulations showed that specific up-regulations in KCNQ/Kv7 channels functions lead to a modulation of the intrinsic excitability of spinal motoneurons as observed experimentally. These results indicate that KCNQ/Kv7 channels play a fundamental role in the activity-dependent modulation of the excitability of spinal motoneurons.

Equivalent circuit modeling of a piezo-patch energy harvester on a thin plate with AC-DC conversion

NASA Astrophysics Data System (ADS)

Bayik, B.; Aghakhani, A.; Basdogan, I.; Erturk, A.

2016-05-01

As an alternative to beam-like structures, piezoelectric patch-based energy harvesters attached to thin plates can be readily integrated to plate-like structures in automotive, marine, and aerospace applications, in order to directly exploit structural vibration modes of the host system without mass loading and volumetric occupancy of cantilever attachments. In this paper, a multi-mode equivalent circuit model of a piezo-patch energy harvester integrated to a thin plate is developed and coupled with a standard AC-DC conversion circuit. Equivalent circuit parameters are obtained in two different ways: (1) from the modal analysis solution of a distributed-parameter analytical model and (2) from the finite-element numerical model of the harvester by accounting for two-way coupling. After the analytical modeling effort, multi-mode equivalent circuit representation of the harvester is obtained via electronic circuit simulation software SPICE. Using the SPICE software, electromechanical response of the piezoelectric energy harvester connected to linear and nonlinear circuit elements are computed. Simulation results are validated for the standard AC-AC and AC-DC configurations. For the AC input-AC output problem, voltage frequency response functions are calculated for various resistive loads, and they show excellent agreement with modal analysis-based analytical closed-form solution and with the finite-element model. For the standard ideal AC input-DC output case, a full-wave rectifier and a smoothing capacitor are added to the harvester circuit for conversion of the AC voltage to a stable DC voltage, which is also validated against an existing solution by treating the single-mode plate dynamics as a single-degree-of-freedom system.

Converter topologies for common mode voltage reduction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rodriguez, Fernando

An inverter includes a three-winding transformer, a DC-AC inverter electrically coupled to the first winding of the transformer, a cycloconverter electrically coupled to the second winding of the transformer, and an active filter electrically coupled to the third winding of the transformer. The DC-AC inverter is adapted to convert the input DC waveform to an AC waveform delivered to the transformer at the first winding. The cycloconverter is adapted to convert an AC waveform received at the second winding of the transformer to the output AC waveform having a grid frequency of the AC grid. The active filter is adaptedmore » to sink and source power with one or more energy storage devices based on a mismatch in power between the DC source and the AC grid. At least two of the DC-AC inverter, the cycloconverter, or the active filter are electrically coupled via a common reference electrical interconnect.« less

High average power magnetic modulator for metal vapor lasers

DOEpatents

Ball, Don G.; Birx, Daniel L.; Cook, Edward G.; Miller, John L.

1994-01-01

A three-stage magnetic modulator utilizing magnetic pulse compression designed to provide a 60 kV pulse to a copper vapor laser at a 4.5 kHz repetition rate is disclosed. This modulator operates at 34 kW input power. The circuit includes a step up auto transformer and utilizes a rod and plate stack construction technique to achieve a high packing factor.

Coupling apparatus for a metal vapor laser

DOEpatents

Ball, D.G.; Miller, J.L.

1993-02-23

Coupling apparatus for a large bore metal vapor laser is disclosed. The coupling apparatus provides for coupling high voltage pulses (approximately 40 KV) to a metal vapor laser with a high repetition rate (approximately 5 KHz). The coupling apparatus utilizes existing thyratron circuits and provides suitable power input to a large bore metal vapor laser while maintaining satisfactory operating lifetimes for the existing thyratron circuits.

Coupling apparatus for a metal vapor laser

DOEpatents

Ball, Don G.; Miller, John L.

1993-01-01

Coupling apparatus for a large bore metal vapor laser is disclosed. The coupling apparatus provides for coupling high voltage pulses (approximately 40 KV) to a metal vapor laser with a high repetition rate (approximately 5 KHz). The coupling apparatus utilizes existing thyratron circuits and provides suitable power input to a large bore metal vapor laser while maintaining satisfactory operating lifetimes for the existing thyratron circuits.

Novel High-Voltage, High-Power Piezoelectric Transformer Developed and Demonstrated for Space Communications Applications

NASA Technical Reports Server (NTRS)

Carazo, Alfredo V.; Wintucky, Edwin G.

2004-01-01

Improvements in individual piezoelectric transformer (PT) performance and the combination of these PTs in a unique modular topology under a Phase I contract with the NASA Glenn Research Center have enabled for the first time the simultaneous achievement of both high voltage and high power at much higher levels than previously obtained with any PT. Feasibility was demonstrated by a prototype transformer (called a Tap-Soner), which is shown in the preceding photograph as part of a direct-current to direct-current (dc-dc) converter having two outputs rated at 1.5 kV/5 W and 4.5 kV/20 W. The power density of 3.5 W/cm3 is significantly lower than for magnetic transformers with the same voltage and power output. This development, which is being done under a Small Business Innovation Research (SBIR) contract by Face Electronics, LC (Norfolk, VA), is based on improvements in the materials and design of Face's basic patented Transoner-T3 PT, shown in the left in the following figure. The T3 PT is most simply described as a resonant multilayer transducer where electrical energy at the input section is efficiently mechanically coupled to the output section, which then vibrates in a fundamental longitudinal mode to generate a high gain in voltage. The piezoelectric material used is a modified lead-zirconium-titanate-based ceramic. One of the significant improvements in PT design was the incorporation of a symmetrical double input layer, shown on the right in the following figure, which eliminated the lossy bending vibration modes characteristic of a single input layer. The performance of the improved PT was optimized to 1.5 kV/5 W. The next step was devising a way to combine the individual PTs in a modular circuit topology needed to achieve the desired high voltage and power output. Since the optimum performance of the individual PT occurs at resonance, the most efficient operation of the modular transformer was achieved by using a separate drive circuit for each PT. The output section consists of a separate output rectifier for each PT connected in series.

Compact pulse transformer for 85 kV, 3.5 μs electron gun anode of compact X-ray cargo scanner

DOE Office of Scientific and Technical Information (OSTI.GOV)

Patel, R.; Sharma, D.K.; Dixit, K.

Design of compact and reliable 85kV HV pulse transformer for electron gun anode pulsing is a major concern, when size and space are constraints. This paper describes design procedures and optimization of various parameters like HV insulation, step up ratio, rise time and flat top of Pulse transformer, operating with input from a 10 stage PFN of 50 ohm impedance and charged at 14kV. The transformer should deliver rated output voltage of negative polarity 85kV, 3 to 4μs pulse width, less than 2μs rise time and flat top within 10% across an electron gun load, equivalent to a parallel combinationmore » of 10kΩ and 200pF load at a PRF of 250 Hz. Since the Cargo Scanner has to operate on movable carrier, this transformer is designed to operate even in the inclined positions. This transformer has given voltage step up, rise time and flat top of 13.75, 1.5 μs and 4.5% respectively for a 10kΩ and 200pF load at 250Hz PRF and also demonstrated operation in 90{sup °} tilted transformer positions. An effort has been put to achieve maintenance free Pulse transformer by providing effective sealing in the transformer tank to stop breathing action. Also, special flexing walls of transformer tank accommodate for small changes in volume of oil due to temperature variations. (author)« less

Power factor control system for AC induction motors

NASA Technical Reports Server (NTRS)

Nola, F. J. (Inventor)

1977-01-01

A power factor control system for use with ac induction motors was designed which samples lines voltage and current through the motor and decreases power input to the motor proportional to the detected phase displacement between current and voltage. This system provides, less power to the motor, as it is less loaded.

Blind Deconvolution for Distributed Parameter Systems with Unbounded Input and Output and Determining Blood Alcohol Concentration from Transdermal Biosensor Data.

PubMed

Rosen, I G; Luczak, Susan E; Weiss, Jordan

2014-03-15

We develop a blind deconvolution scheme for input-output systems described by distributed parameter systems with boundary input and output. An abstract functional analytic theory based on results for the linear quadratic control of infinite dimensional systems with unbounded input and output operators is presented. The blind deconvolution problem is then reformulated as a series of constrained linear and nonlinear optimization problems involving infinite dimensional dynamical systems. A finite dimensional approximation and convergence theory is developed. The theory is applied to the problem of estimating blood or breath alcohol concentration (respectively, BAC or BrAC) from biosensor-measured transdermal alcohol concentration (TAC) in the field. A distributed parameter model with boundary input and output is proposed for the transdermal transport of ethanol from the blood through the skin to the sensor. The problem of estimating BAC or BrAC from the TAC data is formulated as a blind deconvolution problem. A scheme to identify distinct drinking episodes in TAC data based on a Hodrick Prescott filter is discussed. Numerical results involving actual patient data are presented.

Utilizing zero-sequence switchings for reversible converters

DOEpatents

Hsu, John S.; Su, Gui-Jia; Adams, Donald J.; Nagashima, James M.; Stancu, Constantin; Carlson, Douglas S.; Smith, Gregory S.

2004-12-14

A method for providing additional dc inputs or outputs (49, 59) from a dc-to-ac inverter (10) for controlling motor loads (60) comprises deriving zero-sequence components (V.sub.ao, V.sub.bo, and V.sub.co) from the inverter (10) through additional circuit branches with power switching devices (23, 44, 46), transforming the voltage between a high voltage and a low voltage using a transformer or motor (42, 50), converting the low voltage between ac and dc using a rectifier (41, 51) or an H-bridge (61), and providing at least one low voltage dc input or output (49, 59). The transformation of the ac voltage may be either single phase or three phase. Where less than a 100% duty cycle is acceptable, a two-phase modulation of the switching signals controlling the inverter (10) reduces switching losses in the inverter (10). A plurality of circuits for carrying out the invention are also disclosed.

Non-linear transfer characteristics of stimulation and recording hardware account for spurious low-frequency artifacts during amplitude modulated transcranial alternating current stimulation (AM-tACS).

PubMed

Kasten, Florian H; Negahbani, Ehsan; Fröhlich, Flavio; Herrmann, Christoph S

2018-05-31

Amplitude modulated transcranial alternating current stimulation (AM-tACS) has been recently proposed as a possible solution to overcome the pronounced stimulation artifact encountered when recording brain activity during tACS. In theory, AM-tACS does not entail power at its modulating frequency, thus avoiding the problem of spectral overlap between brain signal of interest and stimulation artifact. However, the current study demonstrates how weak non-linear transfer characteristics inherent to stimulation and recording hardware can reintroduce spurious artifacts at the modulation frequency. The input-output transfer functions (TFs) of different stimulation setups were measured. Setups included recordings of signal-generator and stimulator outputs and M/EEG phantom measurements. 6 th -degree polynomial regression models were fitted to model the input-output TFs of each setup. The resulting TF models were applied to digitally generated AM-tACS signals to predict the frequency of spurious artifacts in the spectrum. All four setups measured for the study exhibited low-frequency artifacts at the modulation frequency and its harmonics when recording AM-tACS. Fitted TF models showed non-linear contributions significantly different from zero (all p < .05) and successfully predicted the frequency of artifacts observed in AM-signal recordings. Results suggest that even weak non-linearities of stimulation and recording hardware can lead to spurious artifacts at the modulation frequency and its harmonics. These artifacts were substantially larger than alpha-oscillations of a human subject in the MEG. Findings emphasize the need for more linear stimulation devices for AM-tACS and careful analysis procedures, taking into account low-frequency artifacts to avoid confusion with effects of AM-tACS on the brain. Copyright © 2018 Elsevier Inc. All rights reserved.

20 kHz main inverter unit. [for space station power supplies

NASA Technical Reports Server (NTRS)

Hussey, S.

1989-01-01

A proof-of-concept main inverter unit has demonstrated the operation of a pulse-width-modulated parallel resonant power stage topology as a 20-kHz ac power source driver, showing simple output regulation, parallel operation, power sharing and short-circuit operation. The use of a two-stage dc input filter controls the electromagnetic compatibility (EMC) characteristics of the dc power bus, and the use of an ac harmonic trap controls the EMC characteristics of the 20-kHz ac power bus.

Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

PubMed

Parrilla-Carrero, Jeffrey; Buchta, William C; Goswamee, Priyodarshan; Culver, Oliver; McKendrick, Greer; Harlan, Benjamin; Moutal, Aubin; Penrod, Rachel; Lauer, Abigail; Ramakrishnan, Viswanathan; Khanna, Rajesh; Kalivas, Peter; Riegel, Arthur C

2018-04-25

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues. SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability. Copyright © 2018 the authors 0270-6474/18/384212-18$15.00/0.

Single-stage three-phase boost power factor correction circuit for AC-DC converter

NASA Astrophysics Data System (ADS)

Azazi, Haitham Z.; Ahmed, Sayed M.; Lashine, Azza E.

2018-01-01

This article presents a single-stage three-phase power factor correction (PFC) circuit for AC-to-DC converter using a single-switch boost regulator, leading to improve the input power factor (PF), reducing the input current harmonics and decreasing the number of required active switches. A novel PFC control strategy which is characterised as a simple and low-cost control circuit was adopted, for achieving a good dynamic performance, unity input PF, and minimising the harmonic contents of the input current, at which it can be applied to low/medium power converters. A detailed analytical, simulation and experimental studies were therefore conducted. The effectiveness of the proposed controller algorithm is validated by the simulation results, which were carried out using MATLAB/SIMULINK environment. The proposed system is built and tested in the laboratory using DSP-DS1104 digital control board for an inductive load. The results revealed that the total harmonic distortion in the supply current was very low. Finally, a good agreement between simulation and experimental results was achieved.

High-frequency ac power distribution in Space Station

NASA Technical Reports Server (NTRS)

Tsai, Fu-Sheng; Lee, Fred C. Y.

1990-01-01

A utility-type 20-kHz ac power distribution system for the Space Station, employing resonant power-conversion techniques, is presented. The system converts raw dc voltage from photovoltaic cells or three-phase LF ac voltage from a solar dynamic generator into a regulated 20-kHz ac voltage for distribution among various loads. The results of EASY5 computer simulations of the local and global performance show that the system has fast response and good transient behavior. The ac bus voltage is effectively regulated using the phase-control scheme, which is demonstrated with both line and load variations. The feasibility of paralleling the driver-module outputs is illustrated with the driver modules synchronized and sharing a common feedback loop. An HF sinusoidal ac voltage is generated in the three-phase ac input case, when the driver modules are phased 120 deg away from one another and their outputs are connected in series.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aeloiza, Eddy C.; Burgos, Rolando P.

A step-down AC/AC converter for use in an electric distribution system includes at least one chopper circuit for each one of a plurality of phases of the AC power, each chopper circuit including a four-quadrant switch coupled in series between primary and secondary sides of the chopper circuit and a current-bidirectional two-quadrant switch coupled between the secondary side of the chopper circuit and a common node. Each current-bidirectional two-quadrant switch is oriented in the same direction, with respect to the secondary side of the corresponding chopper circuit and the common node. The converter further includes a control circuit configured tomore » pulse-width-modulate control inputs of the switches, to convert a first multiphase AC voltage at the primary sides of the chopper circuits to a second multiphase AC voltage at the secondary sides of the chopper circuits, the second multiphase AC voltage being lower in voltage than the first multiphase AC voltage.« less

Neutralization by a Corona Discharge Ionizer in Nitrogen Atmosphere

NASA Astrophysics Data System (ADS)

Ikeuchi, Toru; Takahashi, Kazunori; Ohkubo, Takahiro; Fujiwara, Tamiya

An electrostatic neutralization of multilayer-loading silicon wafers is demonstrated using a corona discharge ionizer in nitrogen atmosphere, where ac and dc voltages are applied to two needle electrodes for generation of the negative- and positive-charged particles, respectively. We observe a surface potential of the silicon wafer decreases from ±1kV to ±20V within three seconds. Moreover, the density profiles of the charged particles generated by the electrodes are experimentally and theoretically investigated in nitrogen and air atmospheres. Our results show the possibility that the negative-charged particles contributing to the electrostatic neutralization are electrons and negative ions in nitrogen and air atmospheres, respectively.

A Ku-band magnetically insulated transmission line oscillator with overmoded slow-wave-structure

NASA Astrophysics Data System (ADS)

Jiang, Tao; He, Jun-Tao; Zhang, Jian-De; Li, Zhi-Qiang; Ling, Jun-Pu

2016-12-01

In order to enhance the power capacity, an improved Ku-band magnetically insulated transmission line oscillator (MILO) with overmoded slow-wave-structure (SWS) is proposed and investigated numerically and experimentally. The analysis of the dispersion relationship and the resonant curve of the cold test indicate that the device can operate at the near π mode of the TM01 mode, which is useful for mode selection and control. In the particle simulation, the improved Ku-band MILO generates a microwave with a power of 1.5 GW and a frequency of 12.3 GHz under an input voltage of 480 kV and input current of 42 kA. Finally, experimental investigation of the improved Ku-band MILO is carried out. A high-power microwave (HPM) with an average power of 800 MW, a frequency of 12.35 GHz, and pulse width of 35 ns is generated under a diode voltage of 500 kV and beam current of 43 kA. The consistency between the experimental and simulated far-field radiation pattern confirms that the operating mode of the improved Ku-band MILO is well controlled in π mode of the TM01 mode. Project supported partly by the National Natural Science Foundation of China (Grant No. 61171021).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, Mark A.; Bigelow, Matthew; Gilkey, Jeff C.

The Super Strypi SWIL is a six degree-of-freedom (6DOF) simulation for the Super Strypi Launch Vehicle that includes a subset of the Super Strypi NGC software (guidance, ACS and sequencer). Aerodynamic and propulsive forces, mass properties, ACS (attitude control system) parameters, guidance parameters and Monte-Carlo parameters are defined in input files. Output parameters are saved to a Matlab mat file.

Changes in behavioral responses of Lygus lineolaris (Hemiptera: Miridae) from various applied signal voltages during EPG recordings

USDA-ARS?s Scientific Manuscript database

A 3rd-generation AC-DC electrical penetration graph (EPG) monitor was used to study feeding behaviors of pre-reproductive adult Lygus lineolaris (Hemiptera: Miridae) on pinhead (<3mm) cotton squares, applying different signal voltages at several input impedances. The AC-DC monitor allows a user to s...

Cascaded Quadruple Active Bridge Structures for Multilevel DC to Three-Phase AC Conversion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Brian B; Achanta, Prasanta K; Maksimovic, Dragan

This paper introduces a multilevel architecture comprised of interconnected dc to three-phase ac converter units. To enable series connected operation, each converter unit contains a quadruple active bridge (QAB) converter that provides isolation between the dc side and each of the three ac sides. Since each converter unit transfers dc-side power as constant balanced three-phase power on the ac side, this implies instantaneous input-output power balance and allows elimination of bulk capacitive energy storage. In addition to minimizing required capacitance, the proposed approach simultaneously enables simplified dc-link controllers amenable to decentralized implementation, supports bidirectional power transfer, and exhibits a modularmore » structure to enhance scalability. Isolation provided by the QAB allows a wide range of electrical configurations among multiple units in various dc-ac, ac-dc or ac-ac applications. In this paper, the focus is on series connections on the ac side to emphasize multilevel operation, and the approach is experimentally validated in a dc-ac system containing two cascaded converter units.« less

New low-level a-c amplifier provides adjustable noise cancellation and automatic temperature compensation

NASA Technical Reports Server (NTRS)

Smith, J. R., Jr.

1964-01-01

Circuit utilizing a transistorized differential amplifier is developed for biomedical use. This low voltage operating circuit provides adjustable cancellation at the input for unbalanced noise signals, and automatic temperature compensation is accomplished by a single active element across the input-output ends.

Nitrous oxide emissions from intensively managed agroecosystems: The role of carbon inputs

USDA-ARS?s Scientific Manuscript database

In agroecosystems, many reports demonstrate a positive relationship between N2O emissions and N fertilizer inputs. This relationship has been incorporated into IPCC model estimates of N2O emissions and implies that inorganic N limits N2O emissions. However, evidence indicates that denitrification ac...

Pulsed Power Supply Based on Magnetic Energy Storage for Non-Destructive High Field Magnets

NASA Astrophysics Data System (ADS)

Aubert, G.; Defoug, S.; Joss, W.; Sala, P.; Dubois, M.; Kuchinsk, V.

2004-11-01

The first test results of a recently built pulsed power supply based on magnetic energy storage will be described. The system consists of the 16 kV shock alternator with a short-circuit power of 3600 MVA of the VOLTA Testing Center of the Schneider Electric SA company, a step-down transformer with a ratio of 1/24, a three-phase diode bridge designed for a current rising exponentially to 120 kA, and a big, 10 ton, heavy, 10 mH aluminum storage coil. The system is designed to store 72 MJ, normal operation will be at 50 MJ, and will work with voltages up to 20 kV. A transfer of 20% of the stored energy into the high field coil should be possible. Special making switches and interrupters have been developed to switch the high currents in a very short time. For safety and redundancy two independent monitoring systems control the energy transfer. A sequencing control system operates the switches on the ac side and protective switches on the dc side, a specially developed real-time control-monitoring system checks several currents and voltages and commands the dc circuit breakers and making switches.

Comparison of the surface dielectric barrier discharge characteristics under different electrode gaps

NASA Astrophysics Data System (ADS)

Gao, Guoqiang; Dong, Lei; Peng, Kaisheng; Wei, Wenfu; Li, Chunmao; Wu, Guangning

2017-01-01

Currently, great interests are paid to the surface dielectric barrier discharge due to the diverse and interesting application. In this paper, the influences of the electrode gap on the discharge characteristics have been studied. Aspects of the electrical parameters, the optical emission, and the discharge induced gas flow were considered. The electrode gap varied from 0 mm to 21 mm, while the applied AC voltage was studied in the range of 17 kV-27 kV. Results indicate that with the increase of the electrode gap, the variation of discharge voltage exhibits an increasing trend, while the other parameters (i.e., the current, power, and induced flow velocity) increase first, and then decrease once the gap exceeded the critical value. Mechanisms of the electrode gap influencing these key parameters were discussed from the point of equivalent circuit. The experimental results reveal that an optimal discharge gap can be obtained, which is closely related to the applied voltage. Visualization of the induced flow with different electrode gaps was realized by the Schlieren diagnostic technique. Finally, the velocities of induced gas flow determined by the pitot tube were compared with the results of intensity-integral method, and good agreements were found.

AC instrumentation amplifier for bioimpedance measurements.

PubMed

Pallás-Areny, R; Webster, J G

1993-08-01

We analyze the input impedance and CMRR requirements for an amplifier for bioimpedance measurements when considering the capacitive components of the electrode-skin contact impedance. We describe an ac-coupled instrumentation amplifier (IA) that, in addition to fulfilling those requirements, both provides interference and noise reduction, and yields a zero phase shift over a wide frequency band without using broadband op amps.

Performance of McRAS-AC in the GEOS-5 AGCM: Part 1, Aerosol-Activated Cloud Microphysics, Precipitation, Radiative Effects, and Circulation

NASA Technical Reports Server (NTRS)

Sud, Y. C.; Lee, D.; Oreopoulos, L.; Barahona, D.; Nenes, A.; Suarez, M. J.

2012-01-01

A revised version of the Microphysics of clouds with Relaxed Arakawa-Schubert and Aerosol-Cloud interaction (McRAS-AC), including, among others, the Barahona and Nenes ice nucleation parameterization, is implemented in the GEOS-5 AGCM. Various fields from a 10-year long integration of the AGCM with McRAS-AC were compared with their counterparts from an integration of the baseline GEOS-5 AGCM, and with satellite data as observations. Generally using McRAS-AC reduced biases in cloud fields and cloud radiative effects are much better over most of the regions of the Earth. Two weaknesses are identified in the McRAS-AC runs, namely, too few cloud particles around 40S-60S, and too high cloud water path during northern hemisphere summer over the Gulf Stream and North Pacific. Sensitivity analyses showed that these biases potentially originated from biases in the aerosol input. The first bias is largely eliminated in a sensitivity test using 50% smaller aerosol particles, while the second bias is much reduced when interactive aerosol chemistry was turned on. The main drawback of McRAS-AC is dearth of low-level marine stratus clouds, probably due to lack of dry-convection, not yet implemented into the cloud scheme. Despite these biases, McRAS-AC does simulate realistic clouds and their optical properties that can improve with better aerosol-input and thereby has the potential to be a valuable tool for climate modeling research because of its aerosol indirect effect simulation capabilities involving prediction of cloud particle number concentration and effective particle size for both convective and stratiform clouds is quite realistic.

An adenylyl cyclase signaling pathway predicts direct dopaminergic input to vestibular hair cells.

PubMed

Drescher, M J; Cho, W J; Folbe, A J; Selvakumar, D; Kewson, D T; Abu-Hamdan, M D; Oh, C K; Ramakrishnan, N A; Hatfield, J S; Khan, K M; Anne, S; Harpool, E C; Drescher, D G

2010-12-29

Adenylyl cyclase (AC) signaling pathways have been identified in a model hair cell preparation from the trout saccule, for which the hair cell is the only intact cell type. The use of degenerate primers targeting cDNA sequence conserved across AC isoforms, and reverse transcription-polymerase chain reaction (RT-PCR), coupled with cloning of amplification products, indicated expression of AC9, AC7 and AC5/6, with cloning efficiencies of 11:5:2. AC9 and AC5/6 are inhibited by Ca(2+), the former in conjunction with calcineurin, and message for calcineurin has also been identified in the trout saccular hair cell layer. AC7 is independent of Ca(2+). Given the lack of detection of calcium/calmodulin-activated isoforms previously suggested to mediate AC activation in the absence of Gαs in mammalian cochlear hair cells, the issue of hair-cell Gαs mRNA expression was re-examined in the teleost vestibular hair cell model. Two full-length coding sequences were obtained for Gαs/olf in the vestibular type II-like hair cells of the trout saccule. Two messages for Gαi have also been detected in the hair cell layer, one with homology to Gαi1 and the second with homology to Gαi3 of higher vertebrates. Both Gαs/olf protein and Gαi1/Gαi3 protein were immunolocalized to stereocilia and to the base of the hair cell, the latter consistent with sites of efferent input. Although a signaling event coupling to Gαs/olf and Gαi1/Gαi3 in the stereocilia is currently unknown, signaling with Gαs/olf, Gαi3, and AC5/6 at the base of the hair cell would be consistent with transduction pathways activated by dopaminergic efferent input. mRNA for dopamine receptors D1A4 and five forms of dopamine D2 were found to be expressed in the teleost saccular hair cell layer, representing information on vestibular hair cell expression not directly available for higher vertebrates. Dopamine D1A receptor would couple to Gαolf and activation of AC5/6. Co-expression with dopamine D2 receptor, which itself couples to Gαi3 and AC5/6, will down-modulate levels of cAMP, thus fine-tuning and gradating the hair-cell response to dopamine D1A. As predicted by the trout saccular hair cell model, evidence has been obtained for the first time that hair cells of mammalian otolithic vestibular end organs (rat/mouse saccule/utricle) express dopamine D1A and D2L receptors, and each receptor co-localizes with AC5/6, with a marked presence of all three proteins in subcuticular regions of type I vestibular hair cells. A putative efferent, presynaptic source of dopamine was identified in tyrosine hydroxylase-positive nerve fibers which passed from underlying connective tissue to the sensory epithelia, ending on type I and type II vestibular hair cells and on afferent calyces. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Methods, systems and apparatus for controlling operation of two alternating current (AC) machines

DOEpatents

Gallegos-Lopez, Gabriel [Torrance, CA; Nagashima, James M [Cerritos, CA; Perisic, Milun [Torrance, CA; Hiti, Silva [Redondo Beach, CA

2012-06-05

A system is provided for controlling two alternating current (AC) machines via a five-phase PWM inverter module. The system comprises a first control loop, a second control loop, and a current command adjustment module. The current command adjustment module operates in conjunction with the first control loop and the second control loop to continuously adjust current command signals that control the first AC machine and the second AC machine such that they share the input voltage available to them without compromising the target mechanical output power of either machine. This way, even when the phase voltage available to either one of the machines decreases, that machine outputs its target mechanical output power.

A Power-Efficient Wireless Capacitor Charging System Through an Inductive Link

PubMed Central

Lee, Hyung-Min; Ghovanloo, Maysam

2014-01-01

A power-efficient wireless capacitor charging system for inductively powered applications has been presented. A bank of capacitors can be directly charged from an ac source by generating a current through a series charge injection capacitor and a capacitor charger circuit. The fixed charging current reduces energy loss in switches, while maximizing the charging efficiency. An adaptive capacitor tuner compensates for the resonant capacitance variations during charging to keep the amplitude of the ac input voltage at its peak. We have fabricated the capacitor charging system prototype in a 0.35-μm 4-metal 2-poly standard CMOS process in 2.1 mm2 of chip area. It can charge four pairs of capacitors sequentially. While receiving 2.7-V peak ac input through a 2-MHz inductive link, the capacitor charging system can charge each pair of 1 μF capacitors up to ±2 V in 420 μs, achieving a high measured charging efficiency of 82%. PMID:24678284

A Power-Efficient Wireless Capacitor Charging System Through an Inductive Link.

PubMed

Lee, Hyung-Min; Ghovanloo, Maysam

2013-10-01

A power-efficient wireless capacitor charging system for inductively powered applications has been presented. A bank of capacitors can be directly charged from an ac source by generating a current through a series charge injection capacitor and a capacitor charger circuit. The fixed charging current reduces energy loss in switches, while maximizing the charging efficiency. An adaptive capacitor tuner compensates for the resonant capacitance variations during charging to keep the amplitude of the ac input voltage at its peak. We have fabricated the capacitor charging system prototype in a 0.35- μ m 4-metal 2-poly standard CMOS process in 2.1 mm 2 of chip area. It can charge four pairs of capacitors sequentially. While receiving 2.7-V peak ac input through a 2-MHz inductive link, the capacitor charging system can charge each pair of 1 μ F capacitors up to ±2 V in 420 μ s, achieving a high measured charging efficiency of 82%.

Mathematical model for the dc-ac inverter for the Space Shuttle

NASA Technical Reports Server (NTRS)

Berry, Frederick C.

1987-01-01

The reader is informed of what was done for the mathematical modeling of the dc-ac inverter for the Space Shuttle. The mathematical modeling of the dc-ac inverter is an essential element in the modeling of the electrical power distribution system of the Space Shuttle. The electrical power distribution system which is present on the Space Shuttle is made up to 3 strings each having a fuel cell which provides dc to those systems which require dc, and the inverters which convert the dc to ac for those elements which require ac. The inverters are units which are 2 wire structures for the main dc inputs and 2 wire structures for the ac output. When 3 are connected together a 4 wire wye connection results on the ac side. The method of modeling is performed by using a Least Squares curve fitting method. A computer program is presented for implementation of the model along with graphs and tables to demonstrate the accuracy of the model.

Full wave modulator-demodulator amplifier apparatus. [for generating rectified output signal

NASA Technical Reports Server (NTRS)

Black, J. M. (Inventor)

1974-01-01

A full-wave modulator-demodulator apparatus is described including an operational amplifier having a first input terminal coupled to a circuit input terminal, and a second input terminal alternately coupled to the circuit input terminal. A circuit is ground by a switching circuit responsive to a phase reference signal and the operational amplifier is alternately switched between a non-inverting mode and an inverting mode. The switching circuit includes three field-effect transistors operatively associated to provide the desired switching function in response to an alternating reference signal of the same frequency as an AC input signal applied to the circuit input terminal.

An 11 cm long atmospheric pressure cold plasma plume for applications of plasma medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu Xinpei; Jiang Zhonghe; Xiong Qing

2008-02-25

In this letter, a room temperature atmospheric pressure plasma jet device is reported. The high voltage electrode of the device is covered by a quartz tube with one end closed. The device, which is driven by a kilohertz ac power supply, is capable of generating a plasma plume up to 11 cm long in the surrounding room air. The rotational and vibrational temperatures of the plasma plume are 300 and 2300 K, respectively. A simple electrical model shows that, when the plasma plume is contacted with a human, the voltage drop on the human is less than 66 V formore » applied voltage of 5 kV (rms)« less

Laser-guided energetic discharges over large air gaps by electric-field enhanced plasma filaments

NASA Astrophysics Data System (ADS)

Théberge, Francis; Daigle, Jean-François; Kieffer, Jean-Claude; Vidal, François; Châteauneuf, Marc

2017-01-01

Recent works on plasma channels produced during the propagation of ultrashort and intense laser pulses in air demonstrated the guiding of electric discharges along the laser path. However, the short plasma lifetime limits the length of the laser-guided discharge. In this paper, the conductivity and lifetime of long plasma channels produced by ultrashort laser pulses is enhanced efficiently over many orders of magnitude by the electric field of a hybrid AC-DC high-voltage source. The AC electric pulse from a Tesla coil allowed to stimulate and maintain the highly conductive channel during few milliseconds in order to guide a subsequent 500 times more energetic discharge from a 30-kV DC source. This DC discharge was laser-guided over an air gap length of two metres, which is more than two orders of magnitude longer than the expected natural discharge length. Long plasma channel induced by laser pulses and stimulated by an external high-voltage source opens the way for wireless and efficient transportation of energetic current pulses over long air gaps and potentially for guiding lightning.

Laser-guided energetic discharges over large air gaps by electric-field enhanced plasma filaments

PubMed Central

Théberge, Francis; Daigle, Jean-François; Kieffer, Jean-Claude; Vidal, François; Châteauneuf , Marc

2017-01-01

Recent works on plasma channels produced during the propagation of ultrashort and intense laser pulses in air demonstrated the guiding of electric discharges along the laser path. However, the short plasma lifetime limits the length of the laser-guided discharge. In this paper, the conductivity and lifetime of long plasma channels produced by ultrashort laser pulses is enhanced efficiently over many orders of magnitude by the electric field of a hybrid AC-DC high-voltage source. The AC electric pulse from a Tesla coil allowed to stimulate and maintain the highly conductive channel during few milliseconds in order to guide a subsequent 500 times more energetic discharge from a 30-kV DC source. This DC discharge was laser-guided over an air gap length of two metres, which is more than two orders of magnitude longer than the expected natural discharge length. Long plasma channel induced by laser pulses and stimulated by an external high-voltage source opens the way for wireless and efficient transportation of energetic current pulses over long air gaps and potentially for guiding lightning. PMID:28053312

Mode control in a high-gain relativistic klystron amplifier

NASA Astrophysics Data System (ADS)

Li, Zheng-Hong; Zhang, Hong; Ju, Bing-Quan; Su, Chang; Wu, Yang

2010-05-01

Middle cavities between the input and output cavity can be used to decrease the required input RF power for the relativistic klystron amplifier. Meanwhile higher modes, which affect the working mode, are also easy to excite in a device with more middle cavities. In order for the positive feedback process for higher modes to be excited, a special measure is taken to increase the threshold current for such modes. Higher modes' excitation will be avoided when the threshold current is significantly larger than the beam current. So a high-gain S-band relativistic klystron amplifier is designed for the beam of current 5 kA and beam voltage 600 kV. Particle in cell simulations show that the gain is 1.6 × 105 with the input RF power of 6.8 kW, and that the output RF power reaches 1.1 GW.

Hybrid superconducting a.c. current limiter extrapolation 63 kV-1 250 A

NASA Astrophysics Data System (ADS)

Tixador, P.; Levêque, J.; Brunet, Y.; Pham, V. D.

1994-04-01

Following the developement of a.c. superconducting wires a.c. current superconducting limiters have emerged. These limiters limit the fault currents nearly instantaneously, without detection nor order giver and may be suitable for high voltages. They are based on the natural transition from the superconducting state to the normal resistive state by overstepping the critical current of a superconducting coil which limits or triggers the limitation. Our limiter device consists essentially of two copper windings coupled through a saturable magnetic circuit and of a non inductively wound superconducting coil with a reduced current compared to the line current. This design allows a simple superconducting cable and reduced cryogenic losses but the dielectric stresses are high during faults. A small model (150 V/50 A) has experimentally validated our design. An industrial scale current limiter is designed and the comparisons between this design and other superconducting current limiters are given. Les courants de court-circuit sur les grands réseaux électriques ne cessent d'augmenter. Dans ce contexte sont apparus les limiteurs supraconducteurs de courant suite au développement des brins supraconducteurs alternatifs. Ces limiteurs peuvent limiter les courants de défaut presque instantanément, sans détection de défaut ni donneur d'ordre et ils sont extrapolables aux hautes tensions. Ils sont fondés sur la transition naturelle de l'état supraconducteur à l'état normal très résistif par dépassement du courant critique d'un enroulement supraconducteur qui limite ou déclenche la limitation. Notre limiteur est composé de deux enroulements en cuivre couplés par un circuit magnétique saturable et d'une bobine supraconductrice à courant réduit par rapport au courant de la ligne. Cette conception permet un câble supraconducteur simple et des pertes cryogéniques réduites mais les contraintes diélectriques en régime de défaut sont importantes. Une maquette (150 V/50 A) a permis de valider expérimentalement cette conception. Nous aborderons l'extrapolation d'un limiteur de taille industrielle (63 kV/1 250 A). Les résultats seront comparés à des limiteurs supraconducteurs résistifs et de type DASC.

Electronic filters, signal conversion apparatus, hearing aids and methods

NASA Technical Reports Server (NTRS)

Morley, Jr., Robert E. (Inventor); Engebretson, A. Maynard (Inventor); Engel, George L. (Inventor); Sullivan, Thomas J. (Inventor)

1992-01-01

An electronic filter for filtering an electrical signal. Signal processing circuitry therein includes a logarithmic filter having a series of filter stages with inputs and outputs in cascade and respective circuits as GOVERNMENT SUPPORT This invention was made with U.S. Government support under Veterans Administration Contract VA KV 674P857 and National Aeronautics and Space Administration (NASA) Research Grant No. NAG10-0040. The U.S. Government has certain rights in this invention.

Non-solenoidal Startup via Local Helicity Injection on Pegasus: Progress and Plans

NASA Astrophysics Data System (ADS)

Reusch, J. A.; Barr, J. L.; Bodner, G. M.; Bongard, M. W.; Burke, M. G.; Fonck, R. J.; Hinson, E. T.; Lewicki, B. T.; Perry, J. M.; Schlossberg, D. J.

2015-11-01

Non-solenoidal plasma startup via local helicity injection (LHI) at the Pegasus toroidal experiment now provides routine operation at Ip ~ 0.17MA with Iinj ~ 5kA and Vinj ~ 1kV from four active arc injectors. Experiments in the past year have advanced the understanding of the governing physics of LHI and its supporting technology. Injector impedance scales as Vinj3/ 2 and is governed by two effects: a quasineutrality constraint on electron beam propagation, related to the tokamak edge density, and double-layer sheath expansion, related to narc. Injector design improvements permit operation at Vinj >= 1 kV without deleterious PMI or impurity generation. Discharges with varied shape, Ip(t), and helicity input test a predictive 0D power-balance model for LHI startup. Anomalous, reconnection-driven Ti >800 eV and strong MHD activity localized near the injectors are observed during LHI. Preliminary core Thomson scattering measurements indicate surprisingly high Te >300 eV, which if verified may indicate the dominance of high-energy electron fueling from the injector current streams. A new divertor injector system has been designed to substantially increase the available helicity input rate and support critical studies of confinement during LHI and reconnection activity at high Ip. A proposed upgrade to the Pegasus experiment will extend these studies to NSTX-U relevant parameters. Support: US DOE grants DE-FG02-96ER54375; and DE-SC0006928.

Functional assembly of Kv7.1/Kv7.5 channels with emerging properties on vascular muscle physiology.

PubMed

Oliveras, Anna; Roura-Ferrer, Meritxell; Solé, Laura; de la Cruz, Alicia; Prieto, Angela; Etxebarria, Ainhoa; Manils, Joan; Morales-Cano, Daniel; Condom, Enric; Soler, Concepció; Cogolludo, Angel; Valenzuela, Carmen; Villarroel, Alvaro; Comes, Núria; Felipe, Antonio

2014-07-01

Voltage-dependent K(+) (Kv) channels from the Kv7 family are expressed in blood vessels and contribute to cardiovascular physiology. Although Kv7 channel blockers trigger muscle contractions, Kv7 activators act as vasorelaxants. Kv7.1 and Kv7.5 are expressed in many vessels. Kv7.1 is under intense investigation because Kv7.1 blockers fail to modulate smooth muscle reactivity. In this study, we analyzed whether Kv7.1 and Kv7.5 may form functional heterotetrameric channels increasing the channel diversity in vascular smooth muscles. Kv7.1 and Kv7.5 currents elicited in arterial myocytes, oocyte, and mammalian expression systems suggest the formation of heterotetrameric complexes. Kv7.1/Kv7.5 heteromers, exhibiting different pharmacological characteristics, participate in the arterial tone. Kv7.1/Kv7.5 associations were confirmed by coimmunoprecipitation, fluorescence resonance energy transfer, and fluorescence recovery after photobleaching experiments. Kv7.1/Kv7.5 heterotetramers were highly retained at the endoplasmic reticulum. Studies in HEK-293 cells, heart, brain, and smooth and skeletal muscles demonstrated that the predominant presence of Kv7.5 stimulates release of Kv7.1/Kv7.5 oligomers out of lipid raft microdomains. Electrophysiological studies supported that KCNE1 and KCNE3 regulatory subunits further increased the channel diversity. Finally, the analysis of rat isolated myocytes and human blood vessels demonstrated that Kv7.1 and Kv7.5 exhibited a differential expression, which may lead to channel diversity. Kv7.1 and Kv7.5 form heterotetrameric channels increasing the diversity of structures which fine-tune blood vessel reactivity. Because the lipid raft localization of ion channels is crucial for cardiovascular physiology, Kv7.1/Kv7.5 heteromers provide efficient spatial and temporal regulation of smooth muscle function. Our results shed light on the debate about the contribution of Kv7 channels to vasoconstriction and hypertension. © 2014 American Heart Association, Inc.

Increased exposure to pollutant aerosols under high voltage power lines.

PubMed

Fews, A P; Henshaw, D L; Keitch, P A; Close, J J; Wilding, R J

1999-12-01

To assess increased exposure to airborne pollutants near power lines by investigating theoretically and experimentally the behaviour of 222Rn decay product marker aerosols in the 50 Hz electric field under power lines. The behaviour of aerosols in outdoor air including those carrying 222Rn decay products was modelled theoretically in the presence of an AC field. TASTRAK alpha-particle spectroscopy was used to characterize 218Po and 214Po aerosols outdoors. Sampling points were chosen along a line at right angles up to 200 m from a number of high voltage power (transmission) lines. Each sampling point comprised an arrangement of mutually orthogonal TASTRAK detectors. Exposures were carried out at different power line locations in various weather conditions. The model predicts a two- to three-fold increase in deposition of aerosols on spherical surfaces mimicking the human head under high voltage power lines. Experimental measurements using detectors mounted on grounded metal spheres showed an enhanced deposition of both 218Po and 214Po aerosols. Enhanced 218Po deposition on 400 kV lines ranged from 1.96+/-0.15 to 2.86+/-0.32. Enhanced 214Po deposition on 275 kV and 132 kV lines were 1.43+/-0.07 and 1.11+/-0.21, respectively, where the latter value was not significant. The observations demonstrate a mode of increased exposure to pollutant aerosols under high voltage power lines by increased deposition on the body. The total (indoor + outdoor) 218Po and 214Po dose to the basal layer of facial skin is estimated to be increased by between 1.2 and 2.0 for 10% of time spent outdoors under high voltage power lines.

High reliability megawatt transformer/rectifier

NASA Technical Reports Server (NTRS)

Zwass, Samuel; Ashe, Harry; Peters, John W.

1991-01-01

The goal of the two phase program is to develop the technology and design and fabricate ultralightweight high reliability DC to DC converters for space power applications. The converters will operate from a 5000 V dc source and deliver 1 MW of power at 100 kV dc. The power weight density goal is 0.1 kg/kW. The cycle to cycle voltage stability goals was + or - 1 percent RMS. The converter is to operate at an ambient temperature of -40 C with 16 minute power pulses and one hour off time. The uniqueness of the design in Phase 1 resided in the dc switching array which operates the converter at 20 kHz using Hollotron plasma switches along with a specially designed low loss, low leakage inductance and a light weight high voltage transformer. This approach reduced considerably the number of components in the converter thereby increasing the system reliability. To achieve an optimum transformer for this application, the design uses four 25 kV secondary windings to produce the 100 kV dc output, thus reducing the transformer leakage inductance, and the ac voltage stresses. A specially designed insulation system improves the high voltage dielectric withstanding ability and reduces the insulation path thickness thereby reducing the component weight. Tradeoff studies and tests conducted on scaled-down model circuits and using representative coil insulation paths have verified the calculated transformer wave shape parameters and the insulation system safety. In Phase 1 of the program a converter design approach was developed and a preliminary transformer design was completed. A fault control circuit was designed and a thermal profile of the converter was also developed.

Forward and reverse control system for induction motors

DOEpatents

Wright, J.T.

1987-09-15

A control system for controlling the direction of rotation of a rotor of an induction motor includes an array of five triacs with one of the triacs applying a current of fixed phase to the windings of the rotor and four of the triacs being switchable to apply either hot ac current or return ac current to the stator windings so as to reverse the phase of current in the stator relative to that of the rotor and thereby reverse the direction of rotation of the rotor. Switching current phase in the stator is accomplished by operating the gates of pairs of the triacs so as to connect either hot ac current or return ac current to the input winding of the stator. 1 fig.

Hybrid flow control of a transport truck side-mirror using AC-DBD plasma actuated guide vane

NASA Astrophysics Data System (ADS)

Michelis, Theodoros; Kotsonis, Marios

2014-11-01

A wind-tunnel study is conducted towards hybrid flow control of a full-scale transport truck side-mirror (Re = 4 ×105) . The mirror is mounted on a structure that models the truck cabin. PIV measurements are performed at a range of velocities from 15 to 25 m/s and from leeward to windward angles of -5° to +5° . A slim guide vane of 6cm chord is employed along the span of the hub of the mirror for redirecting high momentum flow towards the wake region. Separation from the leading edge of the guide vane is reduced or eliminated by means of AC-DBD plasma actuator, operating at voltage of 35 kV peak-to-peak and frequency of 200 Hz. Time-averaged velocity fields are obtained at the centre of the mirror for three scenarios: a) reference case lacking any control elements; b) guide vane only and c) combination of the guide vane and the AC-DBD. The comparison of cases demonstrates that at 25 m/s windward conditions (-5°) the guide vane is capable of increasing momentum (+20%) in the wake of the mirror with additional improvement when plasma actuation is applied (+21%). In contrast, at leeward conditions (+5°) , the guide vane reduces momentum (-20%), though with actuation an increase is observed (+5%). Total recovered momentum is 25%.

Enhanced excitability and down-regulated voltage-gated potassium channels in colonic drg neurons from neonatal maternal separation rats.

PubMed

Luo, Jia-Lie; Qin, Hong-Yan; Wong, Chun-Kit; Tsang, Suk-Ying; Huang, Yu; Bian, Zhao-Xiang

2011-05-01

Irritable bowel syndrome (IBS), characterized mainly by abdominal pain, is a functional bowel disorder. The present study aimed to examine changes in the excitability and the activity of the voltage-gated K(+) channel in dorsal root ganglia (DRG) neurons innervating the colon of rats subjected to neonatal maternal separation (NMS). Colonic DRG neurons from NMS rats as identified by FAST DiI™ labeling showed an increased cell size compared with those from nonhandled (NH) rats. Whole cell current-clamp recordings showed that colonic DRG neurons from NMS rats displayed: 1) depolarized resting membrane potential; 2) increased input resistance; 3) a dramatic reduction in rheobase; and 4) a significant increase in the number of action potentials evoked at twice rheobase. Whole cell voltage-clamp recordings revealed that neurons from both groups exhibited transient A-type (I(A)) and delayed rectifier (I(K)) K(+) currents. Compared with NH rat neurons, the averaged density of I(K) was significantly reduced in NMS rat neurons. Furthermore, the Kv1.2 expression was significantly decreased in NMS rat colonic DRG neurons. These results suggest that NMS increases the excitability of colonic DRG neurons mainly by suppressing the I(K) current, which is likely accounted for by the downregulation of the Kv1.2 expression and somal hypertrophy. This study demonstrates the alteration of delayed rectifier K current and Kv1.2 expression in DRG neurons from IBS model rats, representing a molecular mechanism underlying visceral pain and sensitization in IBS, suggesting the potential of Kv1.2 as a therapeutic target for the treatment of IBS. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Down-regulation of delayed rectifier K+ channels in the hippocampus of seizure sensitive gerbils.

PubMed

Lee, Sang-Moo; Kim, Ji-Eun; Sohn, Jong-Hee; Choi, Hui-Chul; Lee, Ju-Sang; Kim, Sung-Hun; Kim, Min-Ju; Choi, Ihn-Geun; Kang, Tae-Cheon

2009-12-16

In order to confirm the species-specific distribution of voltage-gated K(+) (Kv) channels and the definitive relationship between their immunoreactivities and seizure activity, we investigated Kv2.x, Kv3.x and Kv4.x channel immunoreactivities in the hippocampi of seizure-resistant (SR) and seizure-sensitive (SS) gerbils. There was no difference in Kv2.1, Kv3.4, Kv4.2 and Kv4.3 immunoreactivity in the hippocampus between SR and SS gerbils. In comparison to SR gerbils, Kv3.1b immunoreactivity in neurons was significantly lower in SS gerbils instead Kv3.1b-immunoreactive astrocytes were clearly observed in SS gerbils (p<0.05). Kv3.2 immunoreactivity was also significantly lower in neurons of SS gerbils than in those of SR gerbils (p<0.05). Considering the findings of our previous study, these findings suggest that delayed rectifier K(+) channels (Kv1.1, Kv1.2, Kv1.5, Kv1.6, Kv2.1 and Kv3.1-2), not A-type K(+) channels (Kv1.4, Kv3.4 and Kv4.x), may be down-regulated in the SS gerbil hippocampus, as compared to SR gerbils.

Active Flow Control with Thermoacoustic Actuators

DTIC Science & Technology

2014-01-31

AC power has been shown to produce large-amplitude acoustic waves [6]. The input AC current sinusoidally heats this device due to joule heating and...conventional metals, the heat capacity value for carbon-based material (carbon nanotubes/graphene) in consideration here is at least 2 orders of...magnitude smaller. Since the output acoustic power delivered to the surrounding flow field is related inversely to the material heat capacity C (i.e., Poutput

Characterization testing of Lockheed Martin high-power micro pulse tube cryocooler

NASA Astrophysics Data System (ADS)

McKinley, I. M.; Hummel, C. D.; Johnson, D. L.; Rodriguez, J. I.

2017-12-01

This paper describes the thermal vacuum, microphonics, magnetics, and radiation testing and results of a Lockheed Martin high-power micro pulse tube cryocooler. The thermal performance of the microcooler was measured in vacuum for heat reject temperatures between 185 and 300 K. The cooler was driven with a Chroma 61602 AC power source for input powers ranging from 10 to 60 W and drive frequency between 115 and 140 Hz during thermal performance testing. The optimal drive frequency was dependent on both input power and heat reject temperature. In addition, the microphonics of the cooler were measured with the cooler driven by Iris Technologies LCCE-2 and HP-LCCE drive electronics for input powers ranging from 10 to 60 W and drive frequency between 135 and 145 Hz. The exported forces were strongly dependent on input power while only weakly dependent on the drive frequency. Moreover, the exported force in the compressor axis was minimized by closed loop control with the HP-LCCE. The cooler also survived a 500 krad radiation dose while being continuously operated with 30 W of input power at 220 K heat rejection temperature in vacuum. Finally, the DC and AC magnetic fields around the cooler were measured at various locations.

Compatibility of lithium plasma-facing surfaces with high edge temperatures in the Lithium Tokamak Experiment (LTX)

NASA Astrophysics Data System (ADS)

Majeski, Dick

2016-10-01

High edge electron temperatures (200 eV or greater) have been measured at the wall-limited plasma boundary in the Lithium Tokamak eXperiment (LTX). High edge temperatures, with flat electron temperature profiles, are a long-predicted consequence of low recycling boundary conditions. The temperature profile in LTX, measured by Thomson scattering, varies by as little as 10% from the plasma axis to the boundary, determined by the lithium-coated high field-side wall. The hydrogen plasma density in the outer scrape-off layer is very low, 2-3 x 1017 m-3 , consistent with a low recycling metallic lithium boundary. The plasma surface interaction in LTX is characterized by a low flux of high energy protons to the lithium PFC, with an estimated Debye sheath potential approaching 1 kV. Plasma-material interactions in LTX are consequently in a novel regime, where the impacting proton energy exceeds the peak in the sputtering yield for the lithium wall. In this regime, further increases in the edge temperature will decrease, rather than increase, the sputtering yield. Despite the high edge temperature, the core impurity content is low. Zeff is 1.2 - 1.5, with a very modest contribution (<0.1) from lithium. So far experiments are transient. Gas puffing is used to increase the plasma density. After gas injection stops, the discharge density is allowed to drop, and the edge is pumped by the low recycling lithium wall. An upgrade to LTX which includes a 35A, 20 kV neutral beam injector to provide core fueling to maintain constant density, as well as auxiliary heating, is underway. Two beam systems have been loaned to LTX by Tri Alpha Energy. Additional results from LTX, as well as progress on the upgrade - LTX- β - will be discussed. Work supported by US DOE contracts DE-AC02-09CH11466 and DE-AC05-00OR22725.

Tamoxifen Inhibition of Kv7.2/Kv7.3 Channels

PubMed Central

Ferrer, Tania; Aréchiga-Figueroa, Ivan Arael; Shapiro, Mark S.; Tristani-Firouzi, Martin; Sanchez-Chapula, José A.

2013-01-01

KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels. PMID:24086693

Tamoxifen inhibition of kv7.2/kv7.3 channels.

PubMed

Ferrer, Tania; Aréchiga-Figueroa, Ivan Arael; Shapiro, Mark S; Tristani-Firouzi, Martin; Sanchez-Chapula, José A

2013-01-01

KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels.

AN ADENYLYL CYCLASE SIGNALING PATHWAY PREDICTS DIRECT DOPAMINERGIC INPUT TO VESTIBULAR HAIR CELLS

PubMed Central

DRESCHER, M. J.; CHO, W. J.; FOLBE, A. J.; SELVAKUMAR, D.; KEWSON, D. T.; ABU-HAMDAN, M. D.; OH, C. K.; RAMAKRISHNAN, N. A.; HATFIELD, J. S.; KHAN, K. M.; ANNE, S.; HARPOOL, E. C.; DRESCHER, D. G.

2010-01-01

Adenylyl cyclase signaling pathways have been identified in a model hair cell preparation from the trout saccule, for which the hair cell is the only intact cell type. The use of degenerate primers targeting cDNA sequence conserved across adenylyl cyclase (AC) isoforms, and RT-PCR, coupled with cloning of amplification products, indicated expression of AC9, AC7 and AC5/6, with cloning efficiencies of 11:5:2. AC9 and AC5/6 are inhibited by Ca2+, the former in conjunction with calcineurin, and message for calcineurin has also been identified in the trout saccular hair cell layer. AC7 is independent of Ca2+. Given the lack of detection of calcium/calmodulin-activated isoforms previously suggested to mediate adenylyl cyclase activation in the absence of Gαs in mammalian cochlear hair cells, the issue of hair-cell Gαs mRNA expression was re-examined in the teleost vestibular hair cell model. Two full-length coding sequences were obtained for Gαs/olf in the vestibular type II-like hair cells of the trout saccule. Two messages for Gαi have also been detected in the hair cell layer, one with homology to Gαi1 and the second with homology to Gαi3 of higher vertebrates. Both Gαs/olf protein and Gαi1/Gαi3 protein were immunolocalized to stereocilia and to the base of the hair cell, the latter consistent with sites of efferent input. While a signaling event coupling to Gαs/olf and Gαi1/Gαi3 in the stereocilia is currently unknown, signaling with Gαs/olf, Gαi3, and AC5/6 at the base of the hair cell would be consistent with transduction pathways activated by dopaminergic efferent input. mRNA for dopamine receptors D1A4 and five forms of dopamine D2 were found to be expressed in the teleost saccular hair cell layer, representing information on vestibular hair cell expression not directly available for higher vertebrates. Dopamine D1A receptor would couple to Gαolf and activation of AC5/6. Co-expression with dopamine D2 receptor, which itself couples to Gαi3 and AC5/6, will down-modulate levels of cAMP, thus fine-tuning and gradating the hair-cell response to dopamine D1A. As predicted by the trout saccular hair cell model, evidence has been obtained for the first time that hair cells of mammalian otolithic vestibular end organs (rat/mouse saccule/utricle) express dopamine D1A and D2L receptors, and each receptor co-localizes with AC5/6, with a marked presence of all three proteins in subcuticular regions of type I vestibular hair cells. A putative efferent, presynaptic source of dopamine was identified in tyrosine hydroxylase-positive nerve fibers which passed from underlying connective tissue to the sensory epithelia, ending on type I and type II vestibular hair cells and on afferent calyces. PMID:20883745

A method to test the performance of an energy-dispersive X-ray spectrometer (EDS).

PubMed

Hodoroaba, Vasile-Dan; Procop, Mathias

2014-10-01

A test material for routine performance evaluation of energy-dispersive X-ray spectrometers (EDS) is presented. It consists of a synthetic, thick coating of C, Al, Mn, Cu, and Zr, in an elemental composition that provides interference-free characteristic X-ray lines of similar intensities at 10 kV scanning electron microscope voltage. The EDS energy resolution at the C-K, Mn-Lα, Cu-Lα, Al-K, Zr-Lα, and Mn-Kα lines, the calibration state of the energy scale, and the Mn-Lα/Mn-Kα intensity ratio as a measure for the low-energy detection efficiency are calculated by a dedicated software package from the 10 kV spectrum. Measurements at various input count rates and processor shaping times enable an estimation of the operation conditions for which the X-ray spectrum is not yet corrupted by pile-up events. Representative examples of EDS systems characterized with the test material and the related software are presented and discussed.

Increasing the magnetic helicity content of a plasma by pulsing a magnetized source.

PubMed

Woodruff, S; Stallard, B W; McLean, H S; Hooper, E B; Bulmer, R; Cohen, B I; Hill, D N; Holcomb, C T; Moller, J; Wood, R D

2004-11-12

By operating a magnetized coaxial gun in a pulsed mode it is possible to produce large voltage pulses of duration approximately 500 mus while reaching a few kV, giving a discrete input of helicity into a spheromak. In the sustained spheromak physics experiment (SSPX), it is observed that pulsing serves to nearly double the stored magnetic energy and double the temperature. We discuss these results by comparison with 3D MHD simulations of the same phenomenon.

A 7.8 kV nanosecond pulse generator with a 500 Hz repetition rate

NASA Astrophysics Data System (ADS)

Lin, M.; Liao, H.; Liu, M.; Zhu, G.; Yang, Z.; Shi, P.; Lu, Q.; Sun, X.

2018-04-01

Pseudospark switches are widely used in pulsed power applications. In this paper, we present the design and performance of a 500 Hz repetition rate high-voltage pulse generator to drive TDI-series pseudospark switches. A high-voltage pulse is produced by discharging an 8 μF capacitor through a primary windings of a setup isolation transformer using a single metal-oxide-semiconductor field-effect transistor (MOSFET) as a control switch. In addition, a self-break spark gap is used to steepen the pulse front. The pulse generator can deliver a high-voltage pulse with a peak trigger voltage of 7.8 kV, a peak trigger current of 63 A, a full width at half maximum (FWHM) of ~30 ns, and a rise time of 5 ns to the trigger pin of the pseudospark switch. During burst mode operation, the generator achieved up to a 500 Hz repetition rate. Meanwhile, we also provide an AC heater power circuit for heating a H2 reservoir. This pulse generator can be used in circuits with TDI-series pseudospark switches with either a grounded cathode or with a cathode electrically floating operation. The details of the circuits and their implementation are described in the paper.

Effects of surface dielectric barrier discharge on aerodynamic characteristic of train

NASA Astrophysics Data System (ADS)

Dong, Lei; Gao, Guoqiang; Peng, Kaisheng; Wei, Wenfu; Li, Chunmao; Wu, Guangning

2017-07-01

High-speed railway today has become an indispensable means of transportation due to its remarkable advantages, including comfortability, convenience and less pollution. The increase in velocity makes the air drag become the main source of energy consumption, leading to receiving more and more concerns. The surface dielectric barrier discharge has shown some unique characteristics in terms of active airflow control. In this paper, the influences of surface dielectric barrier discharge on the aerodynamic characteristics of a scaled train model have been studied. Aspects of the discharge power consumption, the temperature distribution, the velocity of induced flow and the airflow field around the train model were considered. The applied AC voltage was set in the range of 20 kV to 28 kV, with a fixed frequency of 9 kHz. Results indicated that the discharge power consumption, the maximum temperature and the induced flow velocity increased with increasing applied voltage. Mechanisms of applied voltage influencing these key parameters were discussed from the point of the equivalent circuit. The airflow field around the train model with different applied voltages was observed by the smoke visualization experiment. Finally, the effects of surface dielectric barrier discharge on the train drag reduction with different applied voltages were analyzed.

Capillary zone electrophoresis determination of aniline and pyridine in sewage samples using transient isotachophoresis with a system-induced terminator.

PubMed

Hattori, Takanari; Okamura, Hideo; Asaoka, Satoshi; Fukushi, Keiichi

2017-08-18

Transient isotachophoresis (tITP) with a system-induced terminator (SIT) was developed for capillary zone electrophoresis (CZE) determination of aniline (An + ) and pyridine (Py + ) in sewage samples. After sample injection, a water vial was set at the sample-inlet side. Then voltage was applied to generate a system-induced terminator (H + ). Experiments and simulations revealed a concentration effect by tITP with an SIT: background electrolyte (BGE) - 100mM acetic acid (AcOH) and 50mM NaOH (pH 4.6); detection wavelength - 200nm for An + and 254nm for Py + ; vacuum injection period - 15s (190nL); SIT generation - 10kV applied for 80s with the sample inlet side anode; separation voltage - 20kV with the sample inlet side anode. The limits of detection (LODs, S/N=3) of An + and Py + respectively reached 10 and 42μg/L, with good repeatability (peak area RSDs≤6.9%) and calibration graph linearity (R 2 =0.9997). The proposed method was applied for determination of An + and Py + in sewage samples. Recoveries of An + (0.50mg/L) and Py + (2.0mg/L) in spiked sewage samples were 94-104%. Copyright © 2017 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milkov, Mihail M.

A comparator circuit suitable for use in a column-parallel single-slope analog-to-digital converter comprises a comparator, an input voltage sampling switch, a sampling capacitor arranged to store a voltage which varies with an input voltage when the sampling switch is closed, and a local ramp buffer arranged to buffer a global voltage ramp applied at an input. The comparator circuit is arranged such that its output toggles when the buffered global voltage ramp exceeds the stored voltage. Both DC- and AC-coupled comparator embodiments are disclosed.

Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells.

PubMed

Yuan, X J; Wang, J; Juhaszova, M; Golovina, V A; Rubin, L J

1998-04-01

K(+)-channel activity-mediated alteration of the membrane potential and cytoplasmic free Ca2+ concentration ([Ca2+]cyt) is a pivotal mechanism in controlling pulmonary vasomotor tone. By using combined approaches of patch clamp, imaging fluorescent microscopy, and molecular biology, we examined the electrophysiological properties of K+ channels and the role of different K+ currents in regulating [Ca2+]cyt and explored the molecular identification of voltage-gated K+ (KV)- and Ca(2+)-activated K+ (KCa)-channel genes expressed in pulmonary arterial smooth muscle cells (PASMC). Two kinetically distinct KV currents [IK(V)], a rapidly inactivating (A-type) and a noninactivating delayed rectifier, as well as a slowly activated KCa current [IK(Ca)] were identified. IK(V) was reversibly inhibited by 4-aminopyridine (5 mM), whereas IK(Ca) was significantly inhibited by charybdotoxin (10-20 nM). K+ channels are composed of pore-forming alpha-subunits and auxiliary beta-subunits. Five KV-channel alpha-subunit genes from the Shaker subfamily (KV1.1, KV1.2, KV1.4, KV1.5, and KV1.6), a KV-channel alpha-subunit gene from the Shab subfamily (KV2.1), a KV-channel modulatory alpha-subunit (KV9.3), and a KCa-channel alpha-subunit gene (rSlo), as well as three KV-channel beta-subunit genes (KV beta 1.1, KV beta 2, and KV beta 3) are expressed in PASMC. The data suggest that 1) native K+ channels in PASMC are encoded by multiple genes; 2) the delayed rectifier IK(V) may be generated by the KV1.1, KV1.2, KV1.5, KV1.6, KV2.1, and/or KV2.1/KV9.3 channels; 3) the A-type IK(V) may be generated by the KV1.4 channel and/or the delayed rectifier KV channels (KV1 subfamily) associated with beta-subunits; and 4) the IK(Ca) may be generated by the rSlo gene product. The function of the KV channels plays an important role in the regulation of membrane potential and [Ca2+]cyt in PASMC.

Sound Sequence Discrimination Learning Motivated by Reward Requires Dopaminergic D2 Receptor Activation in the Rat Auditory Cortex

ERIC Educational Resources Information Center

Kudoh, Masaharu; Shibuki, Katsuei

2006-01-01

We have previously reported that sound sequence discrimination learning requires cholinergic inputs to the auditory cortex (AC) in rats. In that study, reward was used for motivating discrimination behavior in rats. Therefore, dopaminergic inputs mediating reward signals may have an important role in the learning. We tested the possibility in the…

Driver circuit for solid state light sources

DOEpatents

Palmer, Fred; Denvir, Kerry; Allen, Steven

2016-02-16

A driver circuit for a light source including one or more solid state light sources, a luminaire including the same, and a method of so driving the solid state light sources are provided. The driver circuit includes a rectifier circuit that receives an alternating current (AC) input voltage and provides a rectified AC voltage. The driver circuit also includes a switching converter circuit coupled to the light source. The switching converter circuit provides a direct current (DC) output to the light source in response to the rectified AC voltage. The driver circuit also includes a mixing circuit, coupled to the light source, to switch current through at least one solid state light source of the light source in response to each of a plurality of consecutive half-waves of the rectified AC voltage.

System for transmitting low frequency analog signals over AC power lines

DOEpatents

Baker, Steven P.; Durall, Robert L.; Haynes, Howard D.

1989-01-01

A system for transmitting low frequency analog signals over AC power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an AC power line. The modulation signal frequency range in selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the AC power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal.

System for transmitting low frequency analog signals over AC power lines

DOEpatents

Baker, Steven P.; Durall, Robert L.; Haynes, Howard D.

1989-09-05

A system for transmitting low frequency analog signals over AC power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an AC power line. The modulation signal frequency range in selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the AC power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal.

A system for tranmitting low frequency analog signals over ac power lines

DOEpatents

Baker, S.P.; Durall, R.L.; Haynes, H.D.

1987-07-30

A system for transmitting low frequency analog signals over ac power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an ac power line. The modulation signal frequency range is selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the ac power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal. 4 figs.

Observer-based higher order sliding mode control of power factor in three-phase AC/DC converter for hybrid electric vehicle applications

NASA Astrophysics Data System (ADS)

Liu, Jianxing; Laghrouche, Salah; Wack, Maxime

2014-06-01

In this paper, a full-bridge boost power converter topology is studied for power factor control, using output higher order sliding mode control. The AC/DC converters are used for charging the battery and super-capacitor in hybrid electric vehicles from the utility. The proposed control forces the input currents to track the desired values, which can control the output voltage while keeping the power factor close to one. Super-twisting sliding mode observer is employed to estimate the input currents and load resistance only from the measurement of output voltage. Lyapunov analysis shows the asymptotic convergence of the closed-loop system to zero. Multi-rate simulation illustrates the effectiveness and robustness of the proposed controller in the presence of measurement noise.

Dorsoventral differences in Kv7/M-current and its impact on resonance, temporal summation and excitability in rat hippocampal pyramidal cells

PubMed Central

Hönigsperger, Christoph; Marosi, Máté; Murphy, Ricardo; Storm, Johan F

2015-01-01

Key points Kv7 (KCNQ/M) channels are known to control excitability and generate subthreshold M-resonance in CA1 hippocampal pyramidal cells, but their properties and functions have not previously been compared along the dorsoventral (septotemporal) axis We used whole-cell recordings to compare electrophysiological properties of dorsal and ventral CA1 pyramidal cells in hippocampal slices from 3- to 4-week-old rats Blockade of Kv7/M-channels with 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) had a stronger impact on electrical properties in dorsal than ventral pyramidal cells, including input resistance, temporal summation, M-resonance, spike threshold, medium after-hyperpolarization, excitability, and spike frequency adaptation. Voltage-clamp recordings revealed a larger amplitude and left-shifted voltage dependence of XE991-sensitive current (IM) in dorsal vs. ventral cells. IM-dependent differences in excitability and resonance may be important for rate and phase coding of CA1 place cells along the dorsoventral axis and may enhance epileptiform activity in ventral pyramidal cells. Abstract In rodent hippocampi, the connections, gene expression and functions differ along the dorsoventral (D–V) axis. CA1 pyramidal cells show increasing excitability along the D–V axis, although the underlying mechanism is not known. In the present study, we investigated how the M-current (IM), caused by Kv7/M (KCNQ) potassium channels, and known to often control neuronal excitability, contributes to D–V differences in intrinsic properties of CA1 pyramidal cells. Using whole-cell patch clamp recordings and the selective Kv7/M blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE991) in hippocampal slices from 3- to 4-week-old rats, we found that: (i) IM had a stronger impact on subthreshold electrical properties in dorsal than ventral CA1 pyramidal cells, including input resistance, temporal summation of artificial synaptic potentials, and M-resonance; (ii) IM activated at more negative potentials (left-shifted) and had larger peak amplitude in the dorsal than ventral CA1; and (iii) the initial spike threshold (during ramp depolarizations) was elevated, and the medium after-hyperpolarization and spike frequency adaptation were increased (i.e. excitability was lower) in the dorsal rather than ventral CA1. These differences were abolished or reduced by application of XE991, indicating that they were caused by IM. Thus, it appears that IM has stronger effects in dorsal than in ventral rat CA1 pyramidal cells because of a larger maximal M-conductance and left-shifted activation curve in the dorsal cells. These mechanisms may contribute to D–V differences in the rate and phase coding of position by CA1 place cells, and may also enhance epileptiform activity in ventral CA1. PMID:25656084

Regulation of Kv7.2/Kv7.3 channels by cholesterol: Relevance of an optimum plasma membrane cholesterol content.

PubMed

Delgado-Ramírez, Mayra; Sánchez-Armass, Sergio; Meza, Ulises; Rodríguez-Menchaca, Aldo A

2018-05-01

Kv7.2/Kv7.3 channels are the molecular correlate of the M-current, which stabilizes the membrane potential and controls neuronal excitability. Previous studies have shown the relevance of plasma membrane lipids on both M-currents and Kv7.2/Kv7.3 channels. Here, we report the sensitive modulation of Kv7.2/Kv7.3 channels by membrane cholesterol level. Kv7.2/Kv7.3 channels transiently expressed in HEK-293 cells were significantly inhibited by decreasing the cholesterol level in the plasma membrane by three different pharmacological strategies: methyl-β-cyclodextrin (MβCD), Filipin III, and cholesterol oxidase treatment. Surprisingly, Kv7.2/Kv7.3 channels were also inhibited by membrane cholesterol loading with the MβCD/cholesterol complex. Depletion or enrichment of plasma membrane cholesterol differentially affected the biophysical parameters of the macroscopic Kv7.2/Kv7.3 currents. These results indicate a complex mechanism of Kv7.2/Kv7.3 channels modulation by membrane cholesterol. We propose that inhibition of Kv7.2/Kv7.3 channels by membrane cholesterol depletion involves a loss of a direct cholesterol-channel interaction. However, the inhibition of Kv7.2/Kv7.3 channels by membrane cholesterol enrichment could include an additional direct cholesterol-channel interaction, or changes in the physical properties of the plasma membrane. In summary, our results indicate that an optimum cholesterol level in the plasma membrane is required for the proper functioning of Kv7.2/Kv7.3 channels. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular expression and pharmacological evidence for a functional role of kv7 channel subtypes in Guinea pig urinary bladder smooth muscle.

PubMed

Afeli, Serge A Y; Malysz, John; Petkov, Georgi V

2013-01-01

Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction.

Differential Activation of Vascular Smooth Muscle Kv7.4, Kv7.5, and Kv7.4/7.5 Channels by ML213 and ICA-069673

PubMed Central

Brueggemann, Lyubov I.; Haick, Jennifer M.; Cribbs, Leanne L.

2014-01-01

Recent research suggests that smooth muscle cells express Kv7.4 and Kv7.5 voltage-activated potassium channels, which contribute to maintenance of their resting membrane voltage. New pharmacologic activators of Kv7 channels, ML213 (N-mesitybicyclo[2.2.1]heptane-2-carboxamide) and ICA-069673 N-(6-chloropyridin-3-yl)-3,4-difluorobenzamide), have been reported to discriminate among channels formed from different Kv7 subtypes. We compared the effects of ML213 and ICA-069673 on homomeric human Kv7.4, Kv7.5, and heteromeric Kv7.4/7.5 channels exogenously expressed in A7r5 vascular smooth muscle cells. We found that, despite its previous description as a selective activator of Kv7.2 and Kv7.4, ML213 significantly increased the maximum conductance of homomeric Kv7.4 and Kv7.5, as well as heteromeric Kv7.4/7.5 channels, and induced a negative shift of their activation curves. Current deactivation rates decreased in the presence of the ML213 (10 μM) for all three channel combinations. Mutants of Kv7.4 (W242L) and Kv7.5 (W235L), previously found to be insensitive to another Kv7 channel activator, retigabine, were also insensitive to ML213 (10 μM). In contrast to ML213, ICA-069673 robustly activated Kv7.4 channels but was significantly less effective on homomeric Kv7.5 channels. Heteromeric Kv7.4/7.5 channels displayed intermediate responses to ICA-069673. In each case, ICA-069673 induced a negative shift of the activation curves without significantly increasing maximal conductance. Current deactivation rates decreased in the presence of ICA-069673 in a subunit-specific manner. Kv7.4 W242L responded to ICA-069673-like wild-type Kv7.4, but a Kv7.4 F143A mutant was much less sensitive to ICA-069673. Based on these results, ML213 and ICA-069673 likely bind to different sites and are differentially selective among Kv7.4, Kv7.5, and Kv7.4/7.5 channel subtypes. PMID:24944189

A comprehensive in vitro study of image accuracy and quality for periodontal diagnosis. Part 1: the influence of X-ray generator on periodontal measurements using conventional and digital receptors.

PubMed

Vandenberghe, Bart; Corpas, Livia; Bosmans, Hilde; Yang, Jie; Jacobs, Reinhilde

2011-08-01

The aim of this study was the determination of image accuracy and quality for periodontal diagnosis using various X-ray generators with conventional and digital radiographs. Thirty-one in vitro periodontal defects were evaluated on intraoral conventional (E-, F/E-speed) and digital images (three indirect, two direct sensors). Standardised radiographs were made with an alternating current (AC), a high-frequency (HF) and a direct current (DC) X-ray unit at rising exposure times (20-160 ms with 20-ms interval) with a constant kV of 70. Three observers assessed bone levels for comparison to the gold standard. Lamina dura, contrast, trabecularisation, crater and furcation involvements were evaluated. Irrespective X-ray generator-type, measurement deviations increased at higher exposure times for solid-state, but decreased for photostimulable storage phosphor (PSP) systems. Accuracy for HF or DC was significantly higher than AC (p < 0.0001), especially at low exposure times. At 0.5- to 1-mm clinical deviation, 27-53% and 32-55% dose savings were demonstrated when using HF or DC generators compared to AC, but only for PSP. No savings were found for solid-state sensors, indicating their higher sensitivity. The use of digital sensors compared to film allowed 15-90% dose savings using the AC tube, whilst solid-state sensors allowed approximately 50% savings compared to PSP, depending on tube type and threshold level.. Accuracy of periodontal diagnosis increases when using HF or DC generators and/or digital receptors with adequate diagnostic information at lower exposure times.

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents.

PubMed

Mani, Bharath K; Robakowski, Christina; Brueggemann, Lyubov I; Cribbs, Leanne L; Tripathi, Abhishek; Majetschak, Matthias; Byron, Kenneth L

2016-03-01

Kv7 (KCNQ) channels, formed as homo- or heterotetramers of Kv7.4 and Kv7.5 α-subunits, are important regulators of vascular smooth muscle cell (VSMC) membrane voltage. Recent studies demonstrate that direct pharmacological modulation of VSMC Kv7 channel activity can influence blood vessel contractility and diameter. However, the physiologic regulation of Kv7 channel activity is still poorly understood. Here, we study the effect of cAMP/protein kinase A (PKA) activation on whole cell K(+) currents through endogenous Kv7.5 channels in A7r5 rat aortic smooth muscle cells or through Kv7.4/Kv7.5 heteromeric channels natively expressed in rat mesenteric artery smooth muscle cells. The contributions of specific α-subunits are further dissected using exogenously expressed human Kv7.4 and Kv7.5 homo- or heterotetrameric channels in A7r5 cells. Stimulation of Gαs-coupled β-adrenergic receptors with isoproterenol induced PKA-dependent activation of endogenous Kv7.5 currents in A7r5 cells. The receptor-mediated enhancement of Kv7.5 currents was mimicked by pharmacological agents that increase [cAMP] (forskolin, rolipram, 3-isobutyl-1-methylxanthine, and papaverine) or mimic cAMP (8-bromo-cAMP); the 2- to 4-fold PKA-dependent enhancement of currents was also observed with exogenously expressed Kv7.5 channels. In contrast, exogenously-expressed heterotetrameric Kv7.4/7.5 channels in A7r5 cells or native mesenteric artery smooth muscle Kv7.4/7.5 channels were only modestly enhanced, and homo-tetrameric Kv7.4 channels were insensitive to this regulatory pathway. Correspondingly, proximity ligation assays indicated that isoproterenol induced PKA-dependent phosphorylation of exogenously expressed Kv7.5 channel subunits, but not of Kv7.4 subunits. These results suggest that signal transduction-mediated responsiveness of vascular smooth muscle Kv7 channel subunits to cAMP/PKA activation follows the order of Kv7.5 > Kv7.4/Kv7.5 > Kv7.4. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Kv7.5 Potassium Channel Subunits Are the Primary Targets for PKA-Dependent Enhancement of Vascular Smooth Muscle Kv7 Currents

PubMed Central

Mani, Bharath K.; Robakowski, Christina; Brueggemann, Lyubov I.; Cribbs, Leanne L.; Tripathi, Abhishek; Majetschak, Matthias

2016-01-01

Kv7 (KCNQ) channels, formed as homo- or heterotetramers of Kv7.4 and Kv7.5 α-subunits, are important regulators of vascular smooth muscle cell (VSMC) membrane voltage. Recent studies demonstrate that direct pharmacological modulation of VSMC Kv7 channel activity can influence blood vessel contractility and diameter. However, the physiologic regulation of Kv7 channel activity is still poorly understood. Here, we study the effect of cAMP/protein kinase A (PKA) activation on whole cell K+ currents through endogenous Kv7.5 channels in A7r5 rat aortic smooth muscle cells or through Kv7.4/Kv7.5 heteromeric channels natively expressed in rat mesenteric artery smooth muscle cells. The contributions of specific α-subunits are further dissected using exogenously expressed human Kv7.4 and Kv7.5 homo- or heterotetrameric channels in A7r5 cells. Stimulation of Gαs-coupled β-adrenergic receptors with isoproterenol induced PKA-dependent activation of endogenous Kv7.5 currents in A7r5 cells. The receptor-mediated enhancement of Kv7.5 currents was mimicked by pharmacological agents that increase [cAMP] (forskolin, rolipram, 3-isobutyl-1-methylxanthine, and papaverine) or mimic cAMP (8-bromo-cAMP); the 2- to 4-fold PKA-dependent enhancement of currents was also observed with exogenously expressed Kv7.5 channels. In contrast, exogenously-expressed heterotetrameric Kv7.4/7.5 channels in A7r5 cells or native mesenteric artery smooth muscle Kv7.4/7.5 channels were only modestly enhanced, and homo-tetrameric Kv7.4 channels were insensitive to this regulatory pathway. Correspondingly, proximity ligation assays indicated that isoproterenol induced PKA-dependent phosphorylation of exogenously expressed Kv7.5 channel subunits, but not of Kv7.4 subunits. These results suggest that signal transduction-mediated responsiveness of vascular smooth muscle Kv7 channel subunits to cAMP/PKA activation follows the order of Kv7.5 >> Kv7.4/Kv7.5 > Kv7.4. PMID:26700561

Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels*

PubMed Central

Brueggemann, Lioubov I.; Mackie, Alexander R.; Cribbs, Leanne L.; Freda, Jessica; Tripathi, Abhishek; Majetschak, Matthias; Byron, Kenneth L.

2014-01-01

The Kv7 family (Kv7.1–7.5) of voltage-activated potassium channels contributes to the maintenance of resting membrane potential in excitable cells. Previously, we provided pharmacological and electrophysiological evidence that Kv7.4 and Kv7.5 form predominantly heteromeric channels and that Kv7 activity is regulated by protein kinase C (PKC) in response to vasoconstrictors in vascular smooth muscle cells. Direct evidence for Kv7.4/7.5 heteromer formation, however, is lacking. Furthermore, it remains to be determined whether both subunits are regulated by PKC. Utilizing proximity ligation assays to visualize single molecule interactions, we now show that Kv7.4/Kv.7.5 heteromers are endogenously expressed in vascular smooth muscle cells. Introduction of dominant-negative Kv7.4 and Kv7.5 subunits in mesenteric artery myocytes reduced endogenous Kv7 currents by 84 and 76%, respectively. Expression of an inducible protein kinase Cα (PKCα) translocation system revealed that PKCα activation is sufficient to suppress endogenous Kv7 currents in A7r5 rat aortic and mesenteric artery smooth muscle cells. Arginine vasopressin (100 and 500 pm) and the PKC activator phorbol 12-myristate 13-acetate (1 nm) each inhibited human (h) Kv7.5 and hKv7.4/7.5, but not hKv7.4 channels expressed in A7r5 cells. A decrease in hKv7.5 and hKv7.4/7.5 current densities was associated with an increase in PKC-dependent phosphorylation of the channel proteins. These findings provide further evidence for a differential regulation of Kv7.4 and Kv7.5 channel subunits by PKC-dependent phosphorylation and new mechanistic insights into the role of heteromeric subunit assembly for regulation of vascular Kv7 channels. PMID:24297175

I(A) channels encoded by Kv1.4 and Kv4.2 regulate neuronal firing in the suprachiasmatic nucleus and circadian rhythms in locomotor activity.

PubMed

Granados-Fuentes, Daniel; Norris, Aaron J; Carrasquillo, Yarimar; Nerbonne, Jeanne M; Herzog, Erik D

2012-07-18

Neurons in the suprachiasmatic nucleus (SCN) display coordinated circadian changes in electrical activity that are critical for daily rhythms in physiology, metabolism, and behavior. SCN neurons depolarize spontaneously and fire repetitively during the day and hyperpolarize, drastically reducing firing rates, at night. To explore the hypothesis that rapidly activating and inactivating A-type (I(A)) voltage-gated K(+) (Kv) channels, which are also active at subthreshold membrane potentials, are critical regulators of the excitability of SCN neurons, we examined locomotor activity and SCN firing in mice lacking Kv1.4 (Kv1.4(-/-)), Kv4.2 (Kv4.2(-/-)), or Kv4.3 (Kv4.3(-/-)), the pore-forming (α) subunits of I(A) channels. Mice lacking either Kv1.4 or Kv4.2 α subunits have markedly shorter (0.5 h) periods of locomotor activity than wild-type (WT) mice. In vitro extracellular multi-electrode recordings revealed that Kv1.4(-/-) and Kv4.2(-/-) SCN neurons display circadian rhythms in repetitive firing, but with shorter periods (0.5 h) than WT cells. In contrast, the periods of wheel-running activity in Kv4.3(-/-) mice and firing in Kv4.3(-/-) SCN neurons were indistinguishable from WT animals and neurons. Quantitative real-time PCR revealed that the transcripts encoding all three Kv channel α subunits, Kv1.4, Kv4.2, and Kv4.3, are expressed constitutively throughout the day and night in the SCN. Together, these results demonstrate that Kv1.4- and Kv4.2-encoded I(A) channels regulate the intrinsic excitability of SCN neurons during the day and night and determine the period and amplitude of circadian rhythms in SCN neuron firing and locomotor behavior.

Inverter ratio failure detector

NASA Technical Reports Server (NTRS)

Wagner, A. P.; Ebersole, T. J.; Andrews, R. E. (Inventor)

1974-01-01

A failure detector which detects the failure of a dc to ac inverter is disclosed. The inverter under failureless conditions is characterized by a known linear relationship of its input and output voltages and by a known linear relationship of its input and output currents. The detector includes circuitry which is responsive to the detector's input and output voltages and which provides a failure-indicating signal only when the monitored output voltage is less by a selected factor, than the expected output voltage for the monitored input voltage, based on the known voltages' relationship. Similarly, the detector includes circuitry which is responsive to the input and output currents and provides a failure-indicating signal only when the input current exceeds by a selected factor the expected input current for the monitored output current based on the known currents' relationship.

Molecular Expression and Pharmacological Evidence for a Functional Role of Kv7 Channel Subtypes in Guinea Pig Urinary Bladder Smooth Muscle

PubMed Central

Afeli, Serge A. Y.; Malysz, John; Petkov, Georgi V.

2013-01-01

Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction. PMID:24073284

Characteristics and molecular basis of celecoxib modulation on Kv7 potassium channels

PubMed Central

Du, XN; Zhang, X; Qi, JL; An, HL; Li, JW; Wan, YM; Fu, Y; Gao, HX; Gao, ZB; Zhan, Y; Zhang, HL

2011-01-01

BACKGROUND AND PURPOSE Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used for the treatment of pain and inflammation. Emerging and accumulating evidence suggests that celecoxib can affect cellular targets other than COX, such as ion channels. In this study, we characterized the effects of celecoxib on Kv7 K+ channels and compared its effects with the well-established Kv7 channel opener retigabine. EXPERIMENTAL APPROACH A perforated whole-cell patch technique was used to record Kv7currents expressed in HEK 293 cells and M-type currents from rat superior cervical ganglion neurons. KEY RESULTS Celecoxib enhanced Kv7.2–7.4, Kv7.2/7.3 and Kv7.3/7.5 currents but inhibited Kv7.1 and Kv7.1/KCNE1 currents and these effects were concentration dependent. The IC50 value for inhibition of Kv7.1 channels was approximately 4 µM and the EC50 values for activation of Kv7.2–7.4, Kv7.2/Kv7.3 and Kv7.3/Kv7.5 channels were approximately 2–5 µM. The effects of celecoxib were manifested by increasing current amplitudes, shifting the voltage-dependent activation curve in a more negative direction and slowing the deactivation of Kv7 currents. 2,5-Dimethyl-celecoxib, a celecoxib analogue devoid of COX inhibition activity, has similar but greater effects on Kv7currents. Kv7.2(A235T) and Kv7.2(W236L) mutant channels, which have greatly attenuated responses to retigabine, showed a reversed response to celecoxib, from activation to inhibition. CONCLUSIONS AND IMPLICATIONS These results suggest that Kv7 channels are targets of celecoxib action and provide new mechanistic evidence for understanding the effects of celecoxib. They also provide a new approach to developing Kv7 modulators and for studying the structure–function relationship of Kv7 channels. PMID:21564087

Expression of A-type K channel alpha subunits Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory interneurons and colocalization with pain-modulating molecules.

PubMed

Huang, Hsin-Yi; Cheng, Jen-Kun; Shih, Yang-Hsin; Chen, Pei-Hsuan; Wang, Chin-Lin; Tsaur, Meei-Ling

2005-09-01

Voltage-gated K(+) channel alpha subunits Kv 4.2 and Kv 4.3 are the major contributors of somatodendritic A-type K(+) currents in many CNS neurons. A recent hypothesis suggests that Kv 4 subunits may be involved in pain modulation in dorsal horn neurons. However, whether Kv 4 subunits are expressed in dorsal horn neurons remains unknown. Using immunohistochemistry, we found that Kv 4.2 and Kv 4.3 immunoreactivity was concentrated in the superficial dorsal horn, mainly in lamina II. Both Kv 4.2 and Kv 4.3 appeared on many rostrocaudally orientated dendrites, whereas Kv 4.3 could be also detected from certain neuronal somata. Kv 4.3(+) neurons were a subset of excitatory inerneurons with calretinin(+)/calbindin(-)/PKCgamma(-) markers, and a fraction of them expressed micro-opioid receptors. Kv 4.3(+) neurons also expressed ERK 2 and mGluR 5, which are molecules related to the induction of central sensitization, a mechanism mediating nociceptive plasticity. Together with the expression of Kv 4.3 in VR 1(+) DRG neurons, our data suggest that Kv C4 subunits could be involved in pain modulation.

Preferential expression and function of voltage-gated, O2-sensitive K+ channels in resistance pulmonary arteries explains regional heterogeneity in hypoxic pulmonary vasoconstriction: ionic diversity in smooth muscle cells.

PubMed

Archer, Stephen L; Wu, Xi-Chen; Thébaud, Bernard; Nsair, Ali; Bonnet, Sebastien; Tyrrell, Ben; McMurtry, M Sean; Hashimoto, Kyoko; Harry, Gwyneth; Michelakis, Evangelos D

2004-08-06

Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O2-sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (E(M)), thereby activating Ca2+ influx via voltage-gated Ca2+ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O2-sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kv-inhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K+ current (I(K)) and a more hyperpolarized E(M) and were uniquely O2- and correolide-sensitive. The O2-sensitive current (active at -65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited I(K) 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide's effects. The hypoxia-sensitive, correolide-insensitive I(K) (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5>Kv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O2- and correolide-sensitive I(K) like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O2-sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O2-sensitive Kv-channels.

Selective activation of vascular Kv7.4/Kv7.5 K+ channels by fasudil contributes to its vasorelaxant effect

PubMed Central

Zhang, Xuan; An, Hailong; Li, Junwei; Zhang, Yuanyuan; Liu, Yang; Jia, Zhanfeng; Zhang, Wei

2016-01-01

Background and Purpose Kv7 (Kv7.1–7.5) channels play an important role in the regulation of neuronal excitability and the cardiac action potential. Growing evidence suggests Kv7.4/Kv7.5 channels play a crucial role in regulating vascular smooth muscle contractility. Most of the reported Kv7 openers have shown poor selectivity across these five subtypes. In this study, fasudil – a drug used for cerebral vasospasm – has been found to be a selective opener of Kv7.4/Kv7.5 channels. Experimental Approach A perforated whole‐cell patch technique was used to record the currents and membrane potential. Homology modelling and a docking technique were used to investigate the interaction between fasudil and the Kv7.4 channel. An isometric tension recording technique was used to assess the vascular tension. Key Results Fasudil selectively and potently enhanced Kv7.4 and Kv7.4/Kv7.5 currents expressed in HEK293 cells, and shifted the voltage‐dependent activation curve in a more negative direction. Fasudil did not affect either Kv7.2 and Kv7.2/Kv7.3 currents expressed in HEK293 cells, the native neuronal M‐type K+ currents, or the resting membrane potential in small rat dorsal root ganglia neurons. The Val248 in S5 and Ile308 in S6 segment of Kv7.4 were critical for this activating effect of fasudil. Fasudil relaxed precontracted rat small arteries in a concentration‐dependent fashion; this effect was antagonized by the Kv7 channel blocker XE991. Conclusions and Implications These results suggest that fasudil is a selective Kv7.4/Kv7.5 channel opener and provide a new dimension for developing selective Kv7 modulators and a new prospective for the use, action and mechanism of fasudil. PMID:27677924

Unanticipated region- and cell-specific downregulation of individual KChIP auxiliary subunit isotypes in Kv4.2 knock-out mouse brain.

PubMed

Menegola, Milena; Trimmer, James S

2006-11-22

Kv4 family voltage-gated potassium channel alpha subunits and Kv channel-interacting protein (KChIP) and dipeptidyl aminopeptidase-like protein subunits comprise somatodendritic A-type channels in mammalian neurons. Recently, a mouse was generated with a targeted deletion of Kv4.2, a Kv4 alpha subunit expressed in many but not all mammalian brain neurons. Kv4.2-/- mice are grossly indistinguishable from wild-type (WT) littermates. Here we used immunohistochemistry to analyze expression of component Kv4 and KChIP subunits of A-type channels in WT and Kv4.2-/- brains. We found that the expression level, and cellular and subcellular distribution of the other prominent brain Kv4 family member Kv4.3, was indistinguishable between WT and Kv4.2-/- samples. However, we found unanticipated regional and cell-specific decreases in expression of KChIPs. The degree of altered expression of individual KChIP isoforms in different regions and neurons precisely follows the level of Kv4.2 normally found at those sites and presumably their extent of association of these KChIPs with Kv4.2. The dramatic effects of Kv4.2 deletion on KChIP expression suggest that, in addition to previously characterized effects of KChIPs on the functional properties, trafficking, and turnover rate of Kv4 channels, Kv4:KChIP association may confer reciprocal Kv4.2-dependent effects on KChIPs. The impact of Kv4.2 deletion on KChIP expression also supports the major role of KChIPs as auxiliary subunits of Kv4 channels.

Biochemical and Electrophysiological Characterization of Two Sea Anemone Type 1 Potassium Toxins from a Geographically Distant Population of Bunodosoma caissarum

PubMed Central

Orts, Diego J. B.; Peigneur, Steve; Madio, Bruno; Cassoli, Juliana S.; Montandon, Gabriela G.; Pimenta, Adriano M. C.; Bicudo, José E. P. W.; Freitas, José C.; Zaharenko, André J.; Tytgat, Jan

2013-01-01

Sea anemone (Cnidaria, Anthozoa) venom is an important source of bioactive compounds used as tools to study the pharmacology and structure-function of voltage-gated K+ channels (KV). These neurotoxins can be divided into four different types, according to their structure and mode of action. In this work, for the first time, two toxins were purified from the venom of Bunodosoma caissarum population from Saint Peter and Saint Paul Archipelago, Brazil. Sequence alignment and phylogenetic analysis reveals that BcsTx1 and BcsTx2 are the newest members of the sea anemone type 1 potassium channel toxins. Their functional characterization was performed by means of a wide electrophysiological screening on 12 different subtypes of KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; hERG and Shaker IR). BcsTx1 shows a high affinity for rKv1.2 over rKv1.6, hKv1.3, Shaker IR and rKv1.1, while Bcstx2 potently blocked rKv1.6 over hKv1.3, rKv1.1, Shaker IR and rKv1.2. Furthermore, we also report for the first time a venom composition and biological activity comparison between two geographically distant populations of sea anemones. PMID:23466933

KV1 and KV3 Potassium Channels Identified at Presynaptic Terminals of the Corticostriatal Synapses in Rat

PubMed Central

Meneses, David; Vega, Ana V.; Torres-Cruz, Francisco Miguel; Barral, Jaime

2016-01-01

In the last years it has been increasingly clear that KV-channel activity modulates neurotransmitter release. The subcellular localization and composition of potassium channels are crucial to understanding its influence on neurotransmitter release. To investigate the role of KV in corticostriatal synapses modulation, we combined extracellular recording of population-spike and pharmacological blockage with specific and nonspecific blockers to identify several families of KV channels. We induced paired-pulse facilitation (PPF) and studied the changes in paired-pulse ratio (PPR) before and after the addition of specific KV blockers to determine whether particular KV subtypes were located pre- or postsynaptically. Initially, the presence of KV channels was tested by exposing brain slices to tetraethylammonium or 4-aminopyridine; in both cases we observed a decrease in PPR that was dose dependent. Further experiments with tityustoxin, margatoxin, hongotoxin, agitoxin, dendrotoxin, and BDS-I toxins all rendered a reduction in PPR. In contrast heteropodatoxin and phrixotoxin had no effect. Our results reveal that corticostriatal presynaptic KV channels have a complex stoichiometry, including heterologous combinations KV1.1, KV1.2, KV1.3, and KV1.6 isoforms, as well as KV3.4, but not KV4 channels. The variety of KV channels offers a wide spectrum of possibilities to regulate neurotransmitter release, providing fine-tuning mechanisms to modulate synaptic strength. PMID:27379187

The design and construction of a module to demonstrate a method for transmission of data from a medical implant

NASA Astrophysics Data System (ADS)

Morgan, I.; Benjamin, J. D.

1985-08-01

Methods of powering devices to which only ac contact can be made and receiving data transmitted back from them are described. Such devices include medical implants which communicate with the external environment via ultrasound or rf links. Two breadboard systems were built to demonstrate the techniques. In both the device is powered by picking up an ac input and rectifying it. A signal voltage detected by the device is encoded as a frequency, transmitted and decoded. In one case this is performed on a separate channel from that used to power the device. In the other only one channel is used for both signals, and data is transmitted by modulating the impedance presented by the device. The resulting modulation of the input signal is picked up by the external circuit and decoded.

Quantum design rules for single molecule logic gates.

PubMed

Renaud, N; Hliwa, M; Joachim, C

2011-08-28

Recent publications have demonstrated how to implement a NOR logic gate with a single molecule using its interaction with two surface atoms as logical inputs [W. Soe et al., ACS Nano, 2011, 5, 1436]. We demonstrate here how this NOR logic gate belongs to the general family of quantum logic gates where the Boolean truth table results from a full control of the quantum trajectory of the electron transfer process through the molecule by very local and classical inputs practiced on the molecule. A new molecule OR gate is proposed for the logical inputs to be also single metal atoms, one per logical input.

E3 ligase CHIP and Hsc70 regulate Kv1.5 protein expression and function in mammalian cells.

PubMed

Li, Peili; Kurata, Yasutaka; Maharani, Nani; Mahati, Endang; Higaki, Katsumi; Hasegawa, Akira; Shirayoshi, Yasuaki; Yoshida, Akio; Kondo, Tatehito; Kurozawa, Youichi; Yamamoto, Kazuhiro; Ninomiya, Haruaki; Hisatome, Ichiro

2015-09-01

Kv1.5 confers ultra-rapid delayed-rectifier potassium channel current (IKur) which contributes to repolarization of the atrial action potential. Kv1.5 proteins, degraded via the ubiquitin-proteasome pathway, decreased in some atrial fibrillation patients. Carboxyl-terminus heat shock cognate 70-interacting protein (CHIP), an E3 ubiquitin ligase, is known to ubiquitinate short-lived proteins. Here, we investigated the roles of CHIP in Kv1.5 degradation to provide insights into the mechanisms of Kv1.5 decreases and treatments targeting Kv1.5 for atrial fibrillation. Coexpression of CHIP with Kv1.5 in HEK293 cells increased Kv1.5 protein ubiquitination and decreased the protein level. Immunofluorescence revealed decreases of Kv1.5 proteins in the endoplasmic reticulum and on the cell membrane. A siRNA against CHIP suppressed Kv1.5 protein ubiquitination and increased its protein level. CHIP mutants, lacking either the N-terminal tetratricopeptide region domain or the C-terminal U-box domain, failed to exert these effects on Kv1.5 proteins. Immunoprecipitation showed that CHIP formed complexes with Kv1.5 proteins and heat shock cognate protein 70 (Hsc70). Effects of Hsc70 on Kv1.5 were similar to CHIP by altering interaction of CHIP with Kv1.5 protein. Coexpression of CHIP and Hsc70 with Kv1.5 additionally enhanced Kv1.5 ubiquitination. Kv1.5 currents were decreased by overexpression of CHIP or Hsc70 but were increased by knockdown of CHIP or Hsc70 in HEK 293 cells stably expressing Kv1.5. These effects of CHIP and Hsc70 were also observed on endogenous Kv1.5 in HL-1 mouse cardiomyocytes, decreasing IKur and prolonging action potential duration. These results indicate that CHIP decreases the Kv1.5 protein level and functional channel by facilitating its degradation in concert with chaperone Hsc70. Copyright © 2015 Elsevier Ltd. All rights reserved.

Electrical remodelling maintains firing properties in cortical pyramidal neurons lacking KCND2-encoded A-type K+ currents.

PubMed

Nerbonne, Jeanne M; Gerber, Benjamin R; Norris, Aaron; Burkhalter, Andreas

2008-03-15

Considerable experimental evidence has accumulated demonstrating a role for voltage-gated K(+) (Kv) channel pore-forming (alpha) subunits of the Kv4 subfamily in the generation of fast transient outward K(+), I(A), channels. Immunohistochemical data suggest that I(A) channels in hippocampal and cortical pyramidal neurons reflect the expression of homomeric Kv4.2 channels. The experiments here were designed to define directly the role of Kv4.2 in the generation of I(A) in cortical pyramidal neurons and to determine the functional consequences of the targeted deletion of Kv4.2 on the resting and active membrane properties of these cells. Whole-cell voltage-clamp recordings, obtained from visual cortical pyramidal neurons isolated from mice in which the KCND2 (Kv4.2) locus was disrupted (Kv4.2-/- mice), revealed that I(A) is indeed eliminated. In addition, the densities of other Kv current components, specifically I(K) and I(ss), are increased significantly (P < 0.001) in most ( approximately 80%) Kv4.2-/- cells. The deletion of KCND2 (Kv4.2) and the elimination of I(A) is also accompanied by the loss of the Kv4 channel accessory protein KChIP3, suggesting that in the absence of Kv4.2, the KChIP3 protein is targeted for degradation. The expression levels of several Kv alpha subunits (Kv4.3, Kv1.4, Kv2.1, Kv2.2), however, are not measurably altered in Kv4.2-/- cortices. Although I(A) is eliminated in Kv4.2-/- pyramidal neurons, the mean +/- s.e.m. current threshold for action potential generation and the waveforms of action potentials are indistinguishable from those recorded from wild-type cells. Repetitive firing is also maintained in Kv4.2-/- cortical pyramidal neurons, suggesting that the increased densities of I(K) and I(ss) compensate for the in vivo loss of I(A).

Design of a probe for two-dimensional small angle detection

NASA Astrophysics Data System (ADS)

He, Haixia; Wang, Xuanze; Zhong, Yuning; Yang, Liangen; Cao, Hongduan

2008-10-01

A novel two-dimensional small angle probe is introduced, which is based on principle of auto-collimation and utilizes quadrant Si-photoelectric detector (QPD) as detection device. AC modulation, AC magnification and absolute value demodulation are incorporated to restrain the DC excursion caused by background light and noise etc and to improve the sensitivity and stability of angle detection. To ensure that while the laser is shining, the current signal (converted into voltage signal) of QPD also is linear to the AC modulation voltage, this paper adopted AC modulation signal (5400Hz) with a DC offset. AC magnification circuit with reasonable parameters is designed to inhibit DC drift and the impact of industrial frequency noise and to ensure good amplification to signal frequency at the same time. A piezoelectric-driven micro-angle generator is designed to demarcate the angle. The calibration data are input to single chip, and the measurement of angles can be shown in SMC1602A.

From pan-reactive KV7 channel opener to subtype selective opener/inhibitor by addition of a methyl group.

PubMed

Blom, Sigrid Marie; Rottländer, Mario; Kehler, Jan; Bundgaard, Christoffer; Schmitt, Nicole; Jensen, Henrik Sindal

2014-01-01

The voltage-gated potassium channels of the KV7 family (KV7.1-5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2-5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2-5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.

Research on MMC-SST Oriented AC/DC Distribution System

NASA Astrophysics Data System (ADS)

Xie, Xifeng; Shi, Hua; Zuo, Jianglin; Zhang, Zhigang

2018-01-01

A modular multilevel converter-solid state transformer (MMC-SST) oriented AC/DC Distribution System is designed. Firstly, the topology structure is introduced, MMC is adopted in the input stage, multiple DC-DC converters are adopted in the isolation stage, and a Three-Phase Four-Leg inverter is adopted in the output stage. Then, the control strategy is analysed. Finally, simulation model and an experimental prototype of MMC-SST are built, simulation and experimental results show that topology and control strategy of MMC-SST are feasible.

A fully integrated neural recording amplifier with DC input stabilization.

PubMed

Mohseni, Pedram; Najafi, Khalil

2004-05-01

This paper presents a low-power low-noise fully integrated bandpass operational amplifier for a variety of biomedical neural recording applications. A standard two-stage CMOS amplifier in a closed-loop resistive feedback configuration provides a stable ac gain of 39.3 dB at 1 kHz. A subthreshold PMOS input transistor is utilized to clamp the large and random dc open circuit potentials that normally exist at the electrode-electrolyte interface. The low cutoff frequency of the amplifier is programmable up to 50 Hz, while its high cutoff frequency is measured to be 9.1 kHz. The tolerable dc input range is measured to be at least +/- 0.25 V with a dc rejection factor of at least 29 dB. The amplifier occupies 0.107 mm2 in die area, and dissipates 115 microW from a 3 V power supply. The total measured input-referred noise voltage in the frequency range of 0.1-10 kHz is 7.8 microVrms. It is fabricated using AMI 1.5 microm double-poly double-metal n-well CMOS process. This paper presents full characterization of the dc, ac, and noise performance of this amplifier through in vitro measurements in saline using two different neural recording electrodes.

Kv1.5 in the immune system: the good, the bad, or the ugly?

PubMed

Felipe, Antonio; Soler, Concepció; Comes, Núria

2010-01-01

For the last 20 years, knowledge of the physiological role of voltage-dependent potassium channels (Kv) in the immune system has grown exponentially. Leukocytes express a limited repertoire of Kv channels, which contribute to the membrane potential. These proteins are involved in the immune response and are therefore considered good pharmacological targets. Although there is a clear consensus about the physiological relevance of Kv1.3, the expression and the role of Kv1.5 are controversial. However, recent reports indicate that certain heteromeric Kv1.3/Kv1.5 associations may provide insight on Kv1.5. Here, we summarize what is known about this issue and highlight the role of Kv1.5 partnership interactions that could be responsible for this debate. The Kv1.3/Kv1.5 heterotetrameric composition of the channel and their possible differential associations with accessory regulatory proteins warrant further investigation.

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels.

PubMed

Matschke, Veronika; Piccini, Ilaria; Schubert, Janina; Wrobel, Eva; Lang, Florian; Matschke, Johann; Amedonu, Elsie; Meuth, Sven G; Strünker, Timo; Strutz-Seebohm, Nathalie; Greber, Boris; Scherkenbeck, Jürgen; Seebohm, Guiscard

2016-01-01

Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1. Rottlerin or an optimized derivative holds a potential as QT interval correcting drug. © 2016 The Author(s) Published by S. Karger AG, Basel.

Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.

PubMed

Chadha, Preet S; Jepps, Thomas A; Carr, Georgina; Stott, Jennifer B; Zhu, Hei-Lei; Cole, William C; Greenwood, Iain A

2014-04-01

Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine (P<0.01) and after transfection of arteries with siRNA against KCNQ4 (P<0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20-80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.

Modulation of Kv7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58

PubMed Central

Zhang, F; Mi, Y; Qi, JL; Li, JW; Si, M; Guan, BC; Du, XN; An, HL; Zhang, HL

2013-01-01

Background and Purpose Modulation of Kv7/M channel function represents a relatively new strategy to treat neuronal excitability disorders such as epilepsy and neuropathic pain. We designed and synthesized a novel series of pyrazolo[1,5-a] pyrimidin-7(4H)-one compounds, which activate Kv7 channels. Here, we characterized the effects of the lead compound, QO-58, on Kv7 channels and investigated its mechanism of action. Experimental Approach A perforated whole-cell patch technique was used to record Kv7 currents expressed in mammalian cell lines and M-type currents from rat dorsal root ganglion neurons. The effects of QO-58 in a rat model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve, were also examined. Key Results QO-58 increased the current amplitudes, shifted the voltage-dependent activation curve in a more negative direction and slowed the deactivation of Kv7.2/Kv7.3 currents. QO-58 activated Kv7.1, Kv7.2, Kv7.4 and Kv7.3/Kv7.5 channels with a more selective effect on Kv7.2 and Kv7.4, but little effect on Kv7.3. The mechanism of QO-58's activation of Kv7 channels was clearly distinct from that used by retigabine. A chain of amino acids, Val224Val225Tyr226, in Kv7.2 was important for QO-58 activation of this channel. QO-58 enhanced native neuronal M currents, resulting in depression of evoked action potentials. QO-58 also elevated the pain threshold of neuropathic pain in the sciatic nerve CCI model. Conclusions and Implications The results indicate that QO-58 is a potent modulator of Kv7 channels with a mechanism of action different from those of known Kv7 openers. Hence, QO-58 shows potential as a treatment for diseases associated with neuronal hyperexcitability. PMID:23013484

Skeletal muscle Kv7 (KCNQ) channels in myoblast differentiation and proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roura-Ferrer, Meritxell; Sole, Laura; Martinez-Marmol, Ramon

Voltage-dependent K{sup +} channels (Kv) are involved in myocyte proliferation and differentiation by triggering changes in membrane potential and regulating cell volume. Since Kv7 channels may participate in these events, the purpose of this study was to investigate whether skeletal muscle Kv7.1 and Kv7.5 were involved during proliferation and myogenesis. Here we report that, while myotube formation did not regulate Kv7 channels, Kv7.5 was up-regulated during cell cycle progression. Although, Kv7.1 mRNA also increased during the G{sub 1}-phase, pharmacological evidence mainly involves Kv7.5 in myoblast growth. Our results indicate that the cell cycle-dependent expression of Kv7.5 is involved in skeletalmore » muscle cell proliferation.« less

Localization of A-type K+ channel subunit Kv4.2 in rat brain.

PubMed

Tsaur, M L; Wu, Y L; Huang, F L; Shih, Y H

2001-09-30

Kv4.2, a voltage-gated K+ (Kv) channel subunit, has been suggested to be the key component of the subthreshold A-type K+ currents (I(SA)s) recorded from the specific subcellular compartments of certain CNS neurons. To correlate Kv4.2 localization with the I(SA)s detected, immunohistochemistry will be useful. Although the Kv4.2 immunostaining pattern in the hippocampus and cerebellum has been reported, the Kv4.2 antibody used was not specific. Furthermore, Kv4.2 localization in other brain regions remains unclear. In this report, we first demonstrated the specificity of a new Kv4.2 antibody, and then used it to examine Kv4.2 localization throughout adult rat brain by immunohistochemistry. At the cellular level, Kv4.2 was found in neurons but not glias. At the subcellular level, Kv4.2 was localized in the somatodendritic compartment of most neurons examined. Nevertheless, our preliminary data indicated that Kv4.2 might be also present in the axon/terminal compartment. At the functional level, our data indicates that Kv4.2 localization and I(SA) correlate quite well in some CNS neurons, supporting that Kv4.2 is the key component of some I(SA)s recorded in vivo.

Contribution of Kv2.1 channels to the delayed rectifier current in freshly dispersed smooth muscle cells from rabbit urethra.

PubMed

Kyle, B; Bradley, E; Ohya, S; Sergeant, G P; McHale, N G; Thornbury, K D; Hollywood, M A

2011-11-01

We have characterized the native voltage-dependent K(+) (K(v)) current in rabbit urethral smooth muscle cells (RUSMC) and compared its pharmacological and biophysical properties with K(v)2.1 and K(v)2.2 channels cloned from the rabbit urethra and stably expressed in human embryonic kidney (HEK)-293 cells (HEK(Kv2.1) and HEK(Kv2.2)). RUSMC were perfused with Hanks' solution at 37°C and studied using the patch-clamp technique with K(+)-rich pipette solutions. Cells were bathed in 100 nM Penitrem A (Pen A) to block large-conductance Ca(2+)-activated K(+) (BK) currents and depolarized to +40 mV for 500 ms to evoke K(v) currents. These were unaffected by margatoxin, κ-dendrotoxin, or α-dendrotoxin (100 nM, n = 3-5) but were blocked by stromatoxin-1 (ScTx, IC(50) ∼130 nM), consistent with the idea that the currents were carried through K(v)2 channels. RNA was detected for K(v)2.1, K(v)2.2, and the silent subunit K(v)9.3 in urethral smooth muscle. Immunocytochemistry showed membrane staining for both K(v)2 subtypes and K(v)9.3 in isolated RUSMC. HEK(Kv2.1) and HEK(Kv2.2) currents were blocked in a concentration-dependent manner by ScTx, with estimated IC(50) values of ∼150 nM (K(v)2.1, n = 5) and 70 nM (K(v)2.2, n = 6). The mean half-maximal voltage (V(1/2)) of inactivation of the USMC K(v) current was -56 ± 3 mV (n = 9). This was similar to the HEK(Kv2.1) current (-55 ± 3 mV, n = 13) but significantly different from the HEK(Kv2.2) currents (-30 ± 3 mV, n = 11). Action potentials (AP) evoked from RUSMC studied under current-clamp mode were unaffected by ScTx. However, when ScTx was applied in the presence of Pen A, the AP duration was significantly prolonged. Similarly, ScTx increased the amplitude of spontaneous contractions threefold, but only after Pen A application. These data suggest that K(v)2.1 channels contribute significantly to the K(v) current in RUSMC.

Lower KV7.5 Potassium Channel Subunit Expression in an Animal Model of Paroxysmal Dystonia.

PubMed

Sander, Svenja E; Diwan, Mustansir; Raymond, Roger; Nobrega, José N; Richter, Angelika

2016-01-01

Dystonia is a hyperkinetic disabling movement disorder. In the dt(sz) hamster, a model of paroxysmal dystonia, pronounced antidystonic effects of the KV7.2-5 potassium channel opener retigabine and aggravation of dystonia by a selective KV7.2-5 blocker indicated a pathophysiological role of an abnormal expression of KV7 channels. We therefore investigated the expression of KV7 subunits in brains of dystonic hamsters. While KV7.2 and KV7.3 subunits were unaltered, lower KV7.5 mRNA levels became evident in motor areas and in limbic structures of dystonic hamsters. The KV7.2/3 subunit-preferring channel opener N-(6-chloropyridin-3-yl)-3,4- difluorobenzamide (ICA 27243; 10-30 mg/kg i.p.) failed to reduce the severity of dystonia in mutant hamsters, suggesting that the previously observed antidystonic action of retigabine is mediated by the activation of KV7.5 channels. The experiments indicate a functional relevance for KV7.5 channels in paroxysmal dystonia. We suggest that compounds highly selective for subtypes of KV7 channels, i.e. for KV7.5, may provide new therapeutic approaches.

Comparison of Voltage Gated K+ Currents in Arterial Myocytes with Heterologously Expressed K v Subunits.

PubMed

Cox, Robert H; Fromme, Samantha

2016-12-01

We have shown that three components contribute to functional voltage gated K + (K v ) currents in rat small mesenteric artery myocytes: (1) Kv1.2 plus Kv1.5 with Kvβ1.2 subunits, (2) Kv2.1 probably associated with Kv9.3 subunits, and (3) Kv7.4 subunits. To confirm and address subunit stoichiometry of the first two, we have compared the biophysical properties of K v currents in small mesenteric artery myocytes with those of K v subunits heterologously expressed in HEK293 cells using whole cell voltage clamp methods. Selective inhibitors of Kv1 (correolide, COR) and Kv2 (stromatoxin, ScTx) channels were used to separate these K v current components. Conductance-voltage and steady state inactivation data along with time constants of activation, inactivation, and deactivation of native K v components were generally well represented by those of Kv1.2-1.5-β1.2 and Kv2.1-9.3 channels. The slope of the steady state inactivation-voltage curve (availability slope) proved to be the most sensitive measure of accessory subunit presence. The availability slope curves exhibited a single peak for both native K v components. Availability slope curves for Kv1.2-1.5-β1.2 and Kv2.1-9.3 channels expressed in human embryonic kidney cells also exhibited a single peak that shifted to more depolarized voltages with increasing accessory to α subunit transfection ratio. Availability slope curves for SxTc-insensitive currents were similar to those of Kv1.2-1.5 expressed with Kvβ1.2 at a 1:5 molar ratio while curves for COR-insensitive currents closely resembled those of Kv2.1 expressed with Kv9.3 at a 1:1 molar ratio. These results support the suggested K v subunit combinations in small mesenteric artery, and further suggest that Kv1 α and Kvβ1.2 but not Kv2.1 and Kv9.3 subunits are present in a saturated (4:4) stoichiometry.

SU-E-I-29: Care KV: Dose It Influence Radiation Dose in Non-Contrast Examination of CT Abdomen/pelvis?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, J; Ganesh, H; Weir, V

Purpose: CARE kV is a tool that automatically recommends optimal kV setting for individual patient for specific CT examination. The use of CARE kV depends on topogram and the user-selected contrast behavior. CARE kV is expected to reduce radiation dose while improving image quality. However, this may work only for certain groups of patients and/or certain CT examinations. This study is to investigate the effects of CARE kV on radiation dose of non-contrast examination of CT abdomen/pelvis. Methods: Radiation dose (CTDIvol and DLP) from patients who underwent abdomen/pelvis non-contrast examination with and without CARE kV were retrospectively reviewed. All patientsmore » were scanned in the same scanner (Siemens Somatom AS64). To mitigate any possible influences due to technologists’ unfamiliarity with the CARE kV, the data with CARE kV were retrieved 1.5 years after the start of CARE kV usage. T-test was used for significant difference in radiation dose. Results: Volume CTDIs and DLPs from 18 patients before and 24 patients after the use of CARE kV were obtained in a duration of one month. There is a slight increase in both average CTDIvol and average DLP with CARE kV compared to those without CARE kV (25.52 mGy vs. 22.65 mGy for CTDIvol; 1265.81 mGy-cm vs. 1199.19 mGy-cm). Statistically there was no significant difference. Without CARE kV, 140 kV was used in 9 of 18 patients, while with CARE KV, 140 kV was used in 15 of 24 patients. 80kV was not used in either group. Conclusion: The use of CARE kV may save time for protocol optimization and minimize variability among technologists. Radiation dose reduction was not observed in non-contrast examinations of CT abdomen/pelvis. This was partially because our CT protocols were tailored according to patient size before CARE kV and partially because of large size patients.« less

Early augmented language intervention for children with developmental delays: potential secondary motor outcomes.

PubMed

Whitmore, Ani S; Romski, Mary Ann; Sevcik, Rose A

2014-09-01

This exploratory study examined the potential secondary outcome of an early augmented language intervention that incorporates speech-generating devices (SGD) on motor skill use for children with developmental delays. The data presented are from a longitudinal study by Romski and colleagues. Toddlers in the augmented language interventions were either required (Augmented Communication-Output; AC-O) or not required (Augmented Communication-Input; AC-I) to use the SGD to produce an augmented word. Three standardized assessments and five event-based coding schemes measured the participants' language abilities and motor skills. Toddlers in the AC-O intervention used more developmentally appropriate motor movements and became more accurate when using the SGD to communicate than toddlers in the AC-I intervention. AAC strategies, interventionist/parent support, motor learning opportunities, and physical feedback may all contribute to this secondary benefit of AAC interventions that use devices.

Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability

PubMed Central

Speca, David J.; Ogata, Genki; Mandikian, Danielle; Bishop, Hannah I.; Wiler, Steve W.; Eum, Kenneth; Wenzel, H. Jürgen; Doisy, Emily T.; Matt, Lucas; Campi, Katharine L.; Golub, Mari S.; Nerbonne, Jeanne M.; Hell, Johannes W.; Trainor, Brian C.; Sack, Jon T.; Schwartzkroin, Philip A.; Trimmer, James S.

2014-01-01

The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1−/−) mice lacking this channel. Kv2.1−/− mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1−/− mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1−/− mice appears unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1−/− animals. Field recordings from hippocampal slices of Kv2.1−/− mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1−/− mice, long-term potentiation at the Schaffer collateral – CA1 synapse is decreased. Kv2.1−/− mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1−/− mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1−/− mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function. PMID:24494598

Open channel block of A-type, kv4.3, and delayed rectifier K+ channels, Kv1.3 and Kv3.1, by sibutramine.

PubMed

Kim, Sung Eun; Ahn, Hye Sook; Choi, Bok Hee; Jang, Hyun-Jong; Kim, Myung-Jun; Rhie, Duck-Joo; Yoon, Shin-Hee; Jo, Yang-Hyeok; Kim, Myung-Suk; Sung, Ki-Wug; Hahn, Sang June

2007-05-01

The effects of sibutramine on voltage-gated K+ channel (Kv)4.3, Kv1.3, and Kv3.1, stably expressed in Chinese hamster ovary cells, were investigated using the whole-cell patch-clamp technique. Sibutramine did not significantly decrease the peak Kv4.3 currents, but it accelerated the rate of decay of current inactivation in a concentration-dependent manner. This phenomenon was effectively characterized by integrating the total current over the duration of a depolarizing pulse to +40 mV. The IC50 value for the sibutramine block of Kv4.3 was 17.3 microM. Under control conditions, the inactivation of Kv4.3 currents could be fit to a biexponential function, and the time constants for the fast and slow components were significantly decreased after the application of sibutramine. The association (k+1) and dissociation (k-1) rate constants for the sibutramine block of Kv 4.3 were 1.51 microM-1s-1 and 27.35 s-1, respectively. The theoretical KD value, derived from k-1/k+1, yielded a value of 18.11 microM. The block of Kv4.3 by sibutramine displayed a weak voltage dependence, increasing at more positive potentials, and it was use-dependent at 2 Hz. Sibutramine did not affect the time course for the deactivating tail currents. Neither steady-state activation and inactivation nor the recovery from inactivation was affected by sibutramine. Sibutramine caused the concentration-dependent block of the Kv1.3 and Kv3.1 currents with an IC50 value of 3.7 and 32.7 microM, respectively. In addition, sibutramine reduced the tail current amplitude and slowed the deactivation of the tail currents of Kv1.3 and Kv3.1, resulting in a crossover phenomenon. These results indicate that sibutramine acts on Kv4.3, Kv1.3, and Kv3.1 as an open channel blocker.

Modulation of Kv4.2 channels by a peptide isolated from the venom of the giant bird-eating tarantula Theraphosa leblondi.

PubMed

Ebbinghaus, Jan; Legros, Christian; Nolting, Andreas; Guette, Catherine; Celerier, Marie-Louise; Pongs, Olaf; Bähring, Robert

2004-06-15

In order to find new peptide inhibitors for voltage-dependent potassium (Kv) channels, we examined the effects of venom from Theraphosa leblondi on Kv channel-mediated currents with the whole-cell patch-clamp technique. Both A-type currents in cultured hippocampal neurons and A-type currents recorded from HEK 293 cells transiently expressing recombinant Kv4.2 channels were selectively inhibited by T. leblondi venom. No venom activity was observed on recombinant Kv1.3, Kv1.4, Kv2.1 or Kv3.4 channels. We purified and sequenced three novel homologous peptides from this venom, which are related to previously identified Kv4 channel-specific peptide inhibitors and were named T. leblondi toxin (TLTx) 1, 2 and 3. The mode of action of TLTx1 on recombinant Kv4.2 channels was studied in more detail. TLTx1 inhibited Kv4.2-mediated currents with an IC50 of approximately 200 nM, and macroscopic current inactivation was slowed in the presence of TLTx1. Notably, TLTx1 also caused a shallower voltage dependence of Kv4.2 peak conductance and a shift of the activation midpoint to more positive potentials (DeltaV1/2 = +35 mV). TLTx1 caused a noticable slowing of Kv4.2 activation kinetics, and Kv4.2 deactivation kinetics were accelerated by TLTx1 as infered from Rb+ tail current measurements. Chimeric Kv2.1(4.2L3-4) channels, in which the linker region between S3 and S4 of the TLTx1-insensitive Kv2.1 channel was replaced by the corresponding Kv4.2 domain, were sensitive to TLTx1. Apparently, TLTx1 can act as a gating modifier of Kv4.2 channels. Copyright 2004 Elsevier Ltd.

γ-Fe2O3 nanoparticles filled polyvinyl alcohol as potential biomaterial for tissue engineering scaffold.

PubMed

Ngadiman, Nor Hasrul Akhmal; Idris, Ani; Irfan, Muhammad; Kurniawan, Denni; Yusof, Noordin Mohd; Nasiri, Rozita

2015-09-01

Maghemite (γ-Fe2O3) nanoparticle with its unique magnetic properties is recently known to enhance the cell growth rate. In this study, γ-Fe2O3 is mixed into polyvinyl alcohol (PVA) matrix and then electrospun to form nanofibers. Design of experiments was used to determine the optimum parameter settings for the electrospinning process so as to produce elctrospun mats with the preferred characteristics such as good morphology, Young's modulus and porosity. The input factors of the electrospinnning process were nanoparticles content (1-5%), voltage (25-35 kV), and flow rate (1-3 ml/h) while the responses considered were Young's modulus and porosity. Empirical models for both responses as a function of the input factors were developed and the optimum input factors setting were determined, and found to be at 5% nanoparticle content, 35 kV voltage, and 1 ml/h volume flow rate. The characteristics and performance of the optimum PVA/γ-Fe2O3 nanofiber mats were compared with those of neat PVA nanofiber mats in terms of morphology, thermal properties, and hydrophilicity. The PVA/γ-Fe2O3 nanofiber mats exhibited higher fiber diameter and surface roughness yet similar thermal properties and hydrophilicity compared to neat PVA PVA/γ-Fe2O3 nanofiber mats. Biocompatibility test by exposing the nanofiber mats with human blood cells was performed. In terms of clotting time, the PVA/γ-Fe2O3 nanofibers exhibited similar behavior with neat PVA. The PVA/γ-Fe2O3 nanofibers also showed higher cells proliferation rate when MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was done using human skin fibroblast cells. Thus, the PVA/γ-Fe2O3 electrospun nanofibers can be a promising biomaterial for tissue engineering scaffolds. Copyright © 2015 Elsevier Ltd. All rights reserved.

WE-AB-303-06: Combining DAO with MV + KV Optimization to Improve Skin Dose Sparing with Real-Time Fluoroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grelewicz, Z; Wiersma, R

Purpose: Real-time fluoroscopy may allow for improved patient positioning and tumor tracking, particularly in the treatment of lung tumors. In order to mitigate the effects of the imaging dose, previous studies have demonstrated the effect of including both imaging dose and imaging constraints into the inverse treatment planning object function. That method of combined MV+kV optimization may Result in plans with treatment beams chosen to allow for more gentle imaging beam-on times. Direct-aperture optimization (DAO) is also known to produce treatment plans with fluence maps more conducive to lower beam-on times. Therefore, in this work we demonstrate the feasibility ofmore » a combination of DAO and MV+kV optimization for further optimized real-time kV imaging. Methods: Therapeutic and imaging beams were modeled in the EGSnrc Monte Carlo environment, and applied to a patient model for a previously treated lung patient to provide dose influence matrices from DOSXYZnrc. An MV + kV IMRT DAO treatment planning system was developed to compare DAO treatment plans with and without MV+kV optimization. The objective function was optimized using simulated annealing. In order to allow for comparisons between different cases of the stochastically optimized plans, the optimization was repeated twenty times. Results: Across twenty optimizations, combined MV+kV IMRT resulted in an average of 12.8% reduction in peak skin dose. Both non-optimized and MV+kV optimized imaging beams delivered, on average, mean dose of approximately 1 cGy per fraction to the target, with peak doses to target of approximately 6 cGy per fraction. Conclusion: When using DAO, MV+kV optimization is shown to Result in improvements to plan quality in terms of skin dose, when compared to the case of MV optimization with non-optimized kV imaging. The combination of DAO and MV+kV optimization may allow for real-time imaging without excessive imaging dose. Financial support for the work has been provided in part by NIH Grant T32 EB002103, ACS RSG-13-313-01-CCE, and NIH S10 RR021039 and P30 CA14599 grants. The contents of this submission do not necessarily represent the official views of any of the supporting organizations.« less

Method and system for an on-chip AC self-test controller

DOEpatents

Flanagan, John D [Rhinebeck, NY; Herring, Jay R [Poughkeepsie, NY; Lo, Tin-Chee [Fishkill, NY

2008-09-30

A method and system for performing AC self-test on an integrated circuit that includes a system clock for use during normal operation are provided. The method includes applying a long data capture pulse to a first test register in response to the system clock, applying an at speed data launch pulse to the first test register in response to the system clock, inputting the data from the first register to a logic path in response to applying the at speed data launch pulse to the first test register, applying an at speed data capture pulse to a second test register in response to the system clock, inputting the logic path output to the second test register in response to applying the at speed data capture pulse to the second test register, and applying a long data launch pulse to the second test register in response to the system clock.

Method and system for an on-chip AC self-test controller

DOEpatents

Flanagan, John D.; Herring, Jay R.; Lo, Tin-Chee

2006-06-06

A method for performing AC self-test on an integrated circuit, including a system clock for use during normal operation. The method includes applying a long data capture pulse to a first test register in response to the system clock, and further applying at an speed data launch pulse to the first test register in response to the system clock. Inputting the data from the first register to a logic path in response to applying the at speed data launch pulse to the first test register. Applying at speed data capture pulse to a second test register in response to the system clock. Inputting the output from the logic path to the second test register in response to applying the at speed data capture pulse to the second register. Applying a long data launch pulse to the second test register in response to the system clock.

Power inverter implementing phase skipping control

DOEpatents

Somani, Utsav; Amirahmadi, Ahmadreza; Jourdan, Charles; Batarseh, Issa

2016-10-18

A power inverter includes a DC/AC inverter having first, second and third phase circuitry coupled to receive power from a power source. A controller is coupled to a driver for each of the first, second and third phase circuitry (control input drivers). The controller includes an associated memory storing a phase skipping control algorithm, wherein the controller is coupled to receive updating information including a power level generated by the power source. The drivers are coupled to control inputs of the first, second and third phase circuitry, where the drivers are configured for receiving phase skipping control signals from the controller and outputting mode selection signals configured to dynamically select an operating mode for the DC/AC inverter from a Normal Control operation and a Phase Skipping Control operation which have different power injection patterns through the first, second and third phase circuitry depending upon the power level.

Solid state light source driver establishing buck or boost operation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palmer, Fred

A solid state light source driver circuit that operates in either a buck convertor or a boost convertor configuration is provided. The driver circuit includes a controller, a boost switch circuit and a buck switch circuit, each coupled to the controller, and a feedback circuit, coupled to the light source. The feedback circuit provides feedback to the controller, representing a DC output of the driver circuit. The controller controls the boost switch circuit and the buck switch circuit in response to the feedback signal, to regulate current to the light source. The controller places the driver circuit in its boostmore » converter configuration when the DC output is less than a rectified AC voltage coupled to the driver circuit at an input node. The controller places the driver circuit in its buck converter configuration when the DC output is greater than the rectified AC voltage at the input node.« less

Kv7 (KCNQ) channel openers induce hypothermia in the mouse.

PubMed

Kristensen, Line V; Sandager-Nielsen, Karin; Hansen, Henrik H

2011-01-20

Kv7 channels, encoded by corresponding kcnq genes, are expressed both centrally and peripherally where they serve to dampen neuronal activity. While Kv7 channel openers have shown efficacy in neurological and neuropsychiatric disease models, the impact of Kv7 channel activation on physiological endpoint markers have not been addressed in detail. In this study we assessed the effect of a range of Kv7 channel openers with different affinity for neuronal Kv7.2-5 channel subunits on body temperature regulation in mice. Female NMRI mice were acutely exposed to vehicle (10% Tween-80, i.p.), retigabine (3-30 mg/kg, i.p., pan-Kv7 channel opener), (S)BMS-204352 (60-240 mg/kg, i.p., Kv7.4/5 channel-preferring opener), ICA-27243 (1-10mg/kg, i.p., Kv7.2/3 channel-preferring opener), or S-(1) (10-60 mg/kg, i.p., Kv7.2/3 channel-preferring opener), and rectal body temperature was measured 15-120 min post-injection. Retigabine (>10mg/kg), ICA-27243 (≥ 10 mg/kg), and S-(1) (≥ 30 mg/kg) dose-dependently lowered rectal body temperature with maximal doses of each Kv7 channel opener inducing a marked drop (>4°C) in rectal temperature. The Kv7 channel openers showed differential temporal pharmacodynamics, which likely reflects their different pharmacokinetic profiles. Pretreatment with the pan-Kv7 channel blocker XE-991 (1.0mg/kg, i.p.) completely reversed the hypothermic effect of the pan-Kv7 opener, retigabine (15 mg/kg), whereas ICA-27243-induced hypothermia (10mg/kg) could only be partially prevented by XE-991. Because ICA-27743 and S-(1) are Kv7.2/3 channel subunit-preferring compounds, this suggests that the Kv7.2/3 channel isoform is the predominant substrate for Kv7 channel opener-evoked hypothermia. These data indicate the physiological relevance of Kv7 channel function on body temperature regulation which may potentially reside from central inhibitory Kv7 channel activity. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Catalytic reduction of carbonyl groups in oxidized PAPC by Kvβ2 (AKR6)

PubMed Central

Xie, Zhengzhi; Barski, Oleg A.; Cai, Jian; Bhatnagar, Aruni; Tipparaju, Srinivas M.

2011-01-01

The β-subunits of the voltage-gated potassium channel (Kvβ) belong to the aldo-keto reductase superfamily. The Kvβ-subunits dock with the pore-forming Kv α-subunits and impart or accelerate the rate of inactivation in Kv channels. Inactivation of Kv currents by Kvβ is differentially regulated by oxidized and reduced pyridine nucleotides. In mammals, AKR6 family is comprised of 3 different genes Kvβ1-3. We have shown previously that Kvβ2 catalyzes the reduction of a broad range of carbonyls including aromatic carbonyls, electrophilic aldehydes and prostaglandins. However, the endogenous substrates for Kvβ have not been identified. To determine whether products of lipid oxidation are substrates of Kvβs, we tested the enzymatic activity of Kvβ2 with oxidized phospholipids generated during the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). Electrospray ionization mass spectrometric analysis showed that Kvβ2 catalyzed the NADPH-dependent reduction of several products of oxPAPC, including 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC), 1-palmitoyl-2-(epoxycyclopentenone)-sn-glycero-3-phosphorylcholine (PECPC), 1-palmitoyl-2-(5,6)- epoxyisoprostane E2-sn-glycero-3-phosphocholine (PEIPC). These results were validated using high resolution mass spectrometric analysis. Time course analysis revealed that the reduced products reached significant levels for ions at m/z 594/596 (POVPC/PHVPC), 810/812 (PECPC/2H-PECPC) and 828/830 (PEIPC/2H-PEIPC) in the oxPAPC + Kvβ2 mixture (p < 0.01). These results suggest that Kvβ could serve as a sensor of lipid oxidation via its catalytic activity and thereby alter Kv currents under conditions of oxidative stress. PMID:21296056

Novel semi-automated kidney volume measurements in autosomal dominant polycystic kidney disease.

PubMed

Muto, Satoru; Kawano, Haruna; Isotani, Shuji; Ide, Hisamitsu; Horie, Shigeo

2018-06-01

We assessed the effectiveness and convenience of a novel semi-automatic kidney volume (KV) measuring high-speed 3D-image analysis system SYNAPSE VINCENT ® (Fuji Medical Systems, Tokyo, Japan) for autosomal dominant polycystic kidney disease (ADPKD) patients. We developed a novel semi-automated KV measurement software for patients with ADPKD to be included in the imaging analysis software SYNAPSE VINCENT ® . The software extracts renal regions using image recognition software and measures KV (VINCENT KV). The algorithm was designed to work with the manual designation of a long axis of a kidney including cysts. After using the software to assess the predictive accuracy of the VINCENT method, we performed an external validation study and compared accurate KV and ellipsoid KV based on geometric modeling by linear regression analysis and Bland-Altman analysis. Median eGFR was 46.9 ml/min/1.73 m 2 . Median accurate KV, Vincent KV and ellipsoid KV were 627.7, 619.4 ml (IQR 431.5-947.0) and 694.0 ml (IQR 488.1-1107.4), respectively. Compared with ellipsoid KV (r = 0.9504), Vincent KV correlated strongly with accurate KV (r = 0.9968), without systematic underestimation or overestimation (ellipsoid KV; 14.2 ± 22.0%, Vincent KV; - 0.6 ± 6.0%). There were no significant slice thickness-specific differences (p = 0.2980). The VINCENT method is an accurate and convenient semi-automatic method to measure KV in patients with ADPKD compared with the conventional ellipsoid method.

The importance of immunohistochemical analyses in evaluating the phenotype of Kv channel knockout mice.

PubMed

Menegola, Milena; Clark, Eliana; Trimmer, James S

2012-06-01

To gain insights into the phenotype of voltage-gated potassium (Kv)1.1 and Kv4.2 knockout mice, we used immunohistochemistry to analyze the expression of component principal or α subunits and auxiliary subunits of neuronal Kv channels in knockout mouse brains. Genetic ablation of the Kv1.1 α subunit did not result in compensatory changes in the expression levels or subcellular distribution of related ion channel subunits in hippocampal medial perforant path and mossy fiber nerve terminals, where high levels of Kv1.1 are normally expressed. Genetic ablation of the Kv4.2 α subunit did not result in altered neuronal cytoarchitecture of the hippocampus. Although Kv4.2 knockout mice did not exhibit compensatory changes in the expression levels or subcellular distribution of the related Kv4.3 α subunit, we found dramatic decreases in the cellular and subcellular expression of specific Kv channel interacting proteins (KChIPs) that reflected their degree of association and colocalization with Kv4.2 in wild-type mouse and rat brains. These studies highlight the insights that can be gained by performing detailed immunohistochemical analyses of Kv channel knockout mouse brains. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Unattended Multiplicity Shift Register

DOE Office of Scientific and Technical Information (OSTI.GOV)

Newell, Matt; Jones, David C.

2017-01-16

The Unattended Multiplicity Shift Register (UMSR) is a specialized pulse counter used primarily to count neutron events originating in neutron detection instruments. While the counter can be used to count any TTL input pulses, its unique ability to record time correlated events and the multiplicity distributions of these events makes it an ideal instrument for counting neutron events in the nuclear fields of material safeguards, waste assay and process monitoring and control. The UMSR combines the Los Alamos National Laboratory (LANL) simple and robust shift register design with a Commercial-Off-The-Shelf (COTS) processor and Ethernet communications. The UMSR is fully compatiblemore » with existing International Atomic Energy Agency (IAEA) neutron data acquisition instruments such as the Advance Multiplicity Shift Register (AMSR) and JSR-15. The UMSR has three input channels: a multiplicity shift register input and two auxiliary inputs. The UMSR provides 0V to 2kV of programmable High Voltage (HV) bias and both a 12V and a 5V detector power supply output. A serial over USB communication line to the UMSR allows the use of existing versions of INCC or MIC software while the Ethernet port is compatible with the new IAEA RAINSTORM communication protocol.« less

Molecular basis for the toxin insensitivity of scorpion voltage-gated potassium channel MmKv1.

PubMed

Zhang, Chuangeng; Xie, Zili; Li, Xinxin; Chen, Jing; Feng, Jing; Lang, Yange; Yang, Weishan; Li, Wenxin; Chen, Zongyun; Yao, Jing; Cao, Zhijian; Wu, Yingliang

2016-05-01

Scorpions are insensitive to their own venoms, which contain various neurotoxins specific for mammalian or insect ion channels, whose molecular mechanism remains unsolved. Using MmKv1, a potassium channel identified from the genome of the scorpion Mesobuthus martensii, channel kinetic experiments showed that MmKv1 was a classical voltage-gated potassium channel with a voltage-dependent fast activation and slow inactivation. Compared with the human Kv1.3 channel (hKv1.3), the MmKv1 channel exhibited a remarkable insensitivity to both scorpion venom and toxin. The chimaeric channels of MmKv1 and hKv1.3 revealed that both turret and filter regions of the MmKv1 channel were critical for the toxin insensitivity of MmKv1. Furthermore, mutagenesis of the chimaeric channel indicated that two basic residues (Arg(399) and Lys(403)) in the MmKv1 turret region and Arg(425) in the MmKv1 filter region significantly affected its toxin insensitivity. Moreover, when these three basic residues of MmKv1 were simultaneously substituted with the corresponding residues from hKv1.3, the MmKv1-R399T/K403S/R425H mutant channels exhibited similar sensitivity to both scorpion venom and toxin to hKv1.3, which revealed the determining role of these three basic residues in the toxin insensitivity of the MmKv1 channel. More strikingly, a similar triad sequence structure is present in all Shaker-like channels from venomous invertebrates, which suggested a possible convergent functional evolution of these channels to enable them to resist their own venoms. Together, these findings first illustrate the mechanism by which scorpions are insensitive to their own venoms at the ion channel receptor level and enrich our knowledge of the insensitivity of scorpions and other venomous animals to their own venoms. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Study of digital charge coupled devices

NASA Technical Reports Server (NTRS)

Wilson, D. D.; Young, V. F.

1980-01-01

Charge coupled devices represent unique usage of the metal oxide semiconductor concept. These devices can sample an AC signal at the input, transfer charge proportional to this signal through the CCD shift register and then provide an output of the same frequency and shape as the input. The delay time between input and output is controlled by the CCD operating frequency and the number of stages in the shift resistor. This work is a reliability evaluation of the buried channel and surface channel CCD technologies. The constructions are analyzed, failure modes are described, and test results are reported.

Effects of haloperidol on Kv4.3 potassium channels.

PubMed

Lee, Hong Joon; Sung, Ki-Wug; Hahn, Sang June

2014-10-05

Haloperidol is commonly used in clinical practice to treat acute and chronic psychosis, but it also has been associated with adverse cardiovascular events. We investigated the effects of haloperidol on Kv4.3 currents stably expressed in CHO cells using a whole-cell patch-clamp technique. Haloperidol did not significantly inhibit the peak amplitude of Kv4.3, but accelerated the decay rate of inactivation of Kv4.3 in a concentration-dependent manner. Thus, the effects of haloperidol on Kv4.3 were estimated from the integral of the Kv4.3 currents during the depolarization pulse. The Kv4.3 was decreased by haloperidol in a concentration-dependent manner with an IC50 value of 3.6 μM. Haloperidol accelerated the decay rate of Kv4.3 inactivation and activation kinetics in a concentration-dependent manner, thereby decreasing the time-to-peak. Haloperidol shifted the voltage dependence of the steady-state activation and inactivation of Kv4.3 in a hyperpolarizing direction. Haloperidol also caused an acceleration of the closed-state inactivation of Kv4.3. Haloperidol produced a use-dependent block of Kv4.3, which was accompanied by a slowing of recovery from the inactivation of Kv4.3. These results suggest that haloperidol blocks Kv4.3 by both interacting with the open state of Kv4.3 channels during depolarization and accelerating the closed-state inactivation at subthreshold membrane potentials. Copyright © 2014 Elsevier B.V. All rights reserved.

A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels.

PubMed

Abidi, Affef; Devaux, Jérôme J; Molinari, Florence; Alcaraz, Gisèle; Michon, François-Xavier; Sutera-Sardo, Julie; Becq, Hélène; Lacoste, Caroline; Altuzarra, Cécilia; Afenjar, Alexandra; Mignot, Cyril; Doummar, Diane; Isidor, Bertrand; Guyen, Sylvie N; Colin, Estelle; De La Vaissière, Sabine; Haye, Damien; Trauffler, Adeline; Badens, Catherine; Prieur, Fabienne; Lesca, Gaetan; Villard, Laurent; Milh, Mathieu; Aniksztejn, Laurent

2015-08-01

Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the disease severity rests on the inhibitory impact of mutations on M current density. Here, we have analyzed the phenotype of 7 patients carrying the p.A294V mutation located on the S6 segment of the Kv7.2 pore domain (Kv7.2(A294V)). We investigated the functional and subcellular consequences of this mutation and compared it to another mutation (Kv7.2(A294G)) associated with a benign epilepsy and affecting the same residue. We report that all the patients carrying the p.A294V mutation presented the clinical and EEG characteristics of EOEE. In CHO cells, the total expression of Kv7.2(A294V) alone, assessed by western blotting, was only 20% compared to wild-type. No measurable current was recorded in CHO cells expressing Kv7.2(A294V) channel alone. Although the total Kv7.2(A294V) expression was rescued to wild-type levels in cells co-expressing the Kv7.3 subunit, the global current density was still reduced by 83% compared to wild-type heteromeric channel. In a configuration mimicking the patients' heterozygous genotype i.e., Kv7.2(A294V)/Kv7.2/Kv7.3, the global current density was reduced by 30%. In contrast to Kv7.2(A294V), the current density of homomeric Kv7.2(A294G) was not significantly changed compared to wild-type Kv7.2. However, the current density of Kv7.2(A294G)/Kv7.2/Kv7.3 and Kv7.2(A294G)/Kv7.3 channels were reduced by 30% and 50% respectively, compared to wild-type Kv7.2/Kv7.3. In neurons, the p.A294V mutation induced a mislocalization of heteromeric mutant channels to the somato-dendritic compartment, while the p.A294G mutation did not affect the localization of the heteromeric channels to the axon initial segment. We conclude that this position is a hotspot of mutation that can give rise to a severe or a benign epilepsy. The p.A294V mutation does not exert a dominant-negative effect on wild-type subunits but alters the preferential axonal targeting of heteromeric Kv7 channels. Our data suggest that the disease severity is not necessarily a consequence of a strong inhibition of M current and that additional mechanisms such as abnormal subcellular distribution of Kv7 channels could be determinant. Copyright © 2015 Elsevier Inc. All rights reserved.

Atmospheric correction at AERONET locations: A new science and validation data set

USGS Publications Warehouse

Wang, Y.; Lyapustin, A.I.; Privette, J.L.; Morisette, J.T.; Holben, B.

2009-01-01

This paper describes an Aerosol Robotic Network (AERONET)-based Surface Reflectance Validation Network (ASRVN) and its data set of spectral surface bidirectional reflectance and albedo based on Moderate Resolution Imaging Spectroradiometer (MODIS) TERRA and AQUA data. The ASRVN is an operational data collection and processing system. It receives 50 ?? 50 km2; subsets of MODIS level 1B (L1B) data from MODIS adaptive processing system and AERONET aerosol and water-vapor information. Then, it performs an atmospheric correction (AC) for about 100 AERONET sites based on accurate radiative-transfer theory with complex quality control of the input data. The ASRVN processing software consists of an L1B data gridding algorithm, a new cloud-mask (CM) algorithm based on a time-series analysis, and an AC algorithm using ancillary AERONET aerosol and water-vapor data. The AC is achieved by fitting the MODIS top-of-atmosphere measurements, accumulated for a 16-day interval, with theoretical reflectance parameterized in terms of the coefficients of the Li SparseRoss Thick (LSRT) model of the bidirectional reflectance factor (BRF). The ASRVN takes several steps to ensure high quality of results: 1) the filtering of opaque clouds by a CM algorithm; 2) the development of an aerosol filter to filter residual semitransparent and subpixel clouds, as well as cases with high inhomogeneity of aerosols in the processing area; 3) imposing the requirement of the consistency of the new solution with previously retrieved BRF and albedo; 4) rapid adjustment of the 16-day retrieval to the surface changes using the last day of measurements; and 5) development of a seasonal backup spectral BRF database to increase data coverage. The ASRVN provides a gapless or near-gapless coverage for the processing area. The gaps, caused by clouds, are filled most naturally with the latest solution for a given pixel. The ASRVN products include three parameters of the LSRT model (kL, kG, and kV), surface albedo, normalized BRF (computed for a standard viewing geometry, VZA = 0, SZA = 45??), and instantaneous BRF (or one-angle BRF value derived from the last day of MODIS measurement for specific viewing geometry) for the MODIS 500-m bands 17. The results are produced daily at a resolution of 1 km in gridded format. We also provide a cloud mask, a quality flag, and a browse bitmap image. The ASRVN data set, including 6 years of MODIS TERRA and 1.5 years of MODIS AQUA data, is available now as a standard MODIS product (MODASRVN) which can be accessed through the Level 1 and Atmosphere Archive and Distribution System website ( http://ladsweb.nascom.nasa.gov/data/search.html). It can be used for a wide range of applications including validation analysis and science research. ?? 2006 IEEE.

Cortisone Dissociates the Shaker Family K Channels from their Beta Subunit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pan, Y.; Weng, J; Kabaleeswaran, V

2008-01-01

The Shaker family voltage-dependent potassium channels (Kv1) are expressed in a wide variety of cells and are essential for cellular excitability. In humans, loss-of-function mutations of Kv1 channels lead to hyperexcitability and are directly linked to episodic ataxia and atrial fibrillation. All Kv1 channels assemble with {Beta} subunits (Kv{Beta}s), and certain Kv{Beta}s, for example Kv{Beta}1, have an N-terminal segment that closes the channel by the N-type inactivation mechanism. In principle, dissociation of Kv{Beta}1, although never reported, should eliminate inactivation and thus potentiate Kv1 current. We found that cortisone increases rat Kv1 channel activity by binding to Kv{Beta}1. A crystal structuremore » of the K{Beta}v-cortisone complex was solved to 1.82-{angstrom}resolution and revealed novel cortisone binding sites. Further studies demonstrated that cortisone promotes dissociation of Kv{Beta}. The new mode of channel modulation may be explored by native or synthetic ligands to fine-tune cellular excitability.« less

Serum starvation-induced voltage-gated potassium channel Kv7.5 expression and its regulation by Sp1 in canine osteosarcoma cells.

PubMed

Lee, Bo Hyung; Ryu, Pan Dong; Lee, So Yeong

2014-01-10

The KCNQ gene family, whose members encode Kv7 channels, belongs to the voltage-gated potassium (Kv) channel group. The roles of this gene family have been widely investigated in nerve and muscle cells. In the present study, we investigated several characteristics of Kv7.5, which is strongly expressed in the canine osteosarcoma cell line, CCL-183. Serum starvation upregulated Kv7.5 expression, and the Kv7 channel opener, flupirtine, attenuated cell proliferation by arresting cells in the G0/G1 phase. We also showed that Kv7.5 knockdown helps CCL-183 cells to proliferate. In an effort to find an endogenous regulator of Kv7.5, we used mithramycin A to reduce the level of the transcription factor Sp1, and it strongly inhibited the induction of Kv7.5 in CCL-183 cells. These results suggest that the activation of Kv7.5 by flupirtine may exert an anti-proliferative effect in canine osteosarcoma. Therefore, Kv7.5 is a possible molecular target for canine osteosarcoma therapy.

Kvβ1.1 (AKR6A8) senses pyridine nucleotide changes in the mouse heart and modulates cardiac electrical activity.

PubMed

Tur, Jared; Chapalamadugu, Kalyan C; Katnik, Christopher; Cuevas, Javier; Bhatnagar, Aruni; Tipparaju, Srinivas M

2017-03-01

The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvβ1.1 knockout (KO) or wild-type (WT) mice and established that Kvβ1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvβ1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvβ1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvβ1.1 is required in the mediated inactivation of Kv4.2 currents, when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in wild-type mice; regardless of the approach, our data show that Kvβ1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart. NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvβ1.1 subunit. In the present study, we identify Kvβ1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart. Copyright © 2017 the American Physiological Society.

Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+ Channel Gating.

PubMed

Ambrosino, Paolo; Freri, Elena; Castellotti, Barbara; Soldovieri, Maria Virginia; Mosca, Ilaria; Manocchio, Laura; Gellera, Cinzia; Canafoglia, Laura; Franceschetti, Silvana; Salis, Barbara; Iraci, Nunzio; Miceli, Francesco; Ragona, Francesca; Granata, Tiziana; DiFrancesco, Jacopo C; Taglialatela, Maurizio

2018-01-30

Over one hundred mutations in the Kv7.2 (KCNQ2) gene encoding for phosphatidylinositol 4,5-bisphosphate (PIP 2 )-sensitive voltage-gated K + channel subunits have been identified in early-onset epilepsies with wide phenotypic variability. By contrast, only few mutations in the closely related Kv7.3 (KCNQ3) gene have been reported, mostly associated with typical benign familial neonatal seizures (BFNS). We herein describe a patient affected by early onset epileptic encephalopathy (EOEE) carrying two Kv7.3 missense mutations (p.Val359Leu/V359L and p.Asp542Asn/D542N) in compound heterozygosis, each inherited from an asymptomatic parent. Patch-clamp recordings from transiently transfected CHO cells showed that, when incorporated in physiologically relevant Kv7.2 + Kv7.3 heteromeric channels, expression of Kv7.3 V359L or Kv7.3 D542N subunits failed to affect current density, whereas a significant decrease was instead observed when these mutant subunits were both simultaneously present. Modeling and functional experiments revealed that each variant decreased PIP 2 -dependent current regulation, with additive effects when the two were co-expressed. Moreover, expression of Kv7.2 subunits carrying the D535N variant previously described in three sporadic EOEE cases prompted functional changes more dramatic when compared to those of the corresponding D542N variant in Kv7.3, but similar to those observed when both Kv7.3 V359L and Kv7.3 D542N subunits were expressed together. Finally, the Kv7 activator retigabine restored channel dysfunction induced by each Kv7.2 or Kv7.3 variant(s). These results provide a plausible molecular explanation for the apparent recessive inheritance of the phenotype in the family investigated, and a rational basis for personalized therapy with Kv7 channel activators in EOEE patients carrying loss-of-function mutations in Kv7.2 or Kv7.3.

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility

PubMed Central

Provence, Aaron; Malysz, John

2015-01-01

The physiologic roles of voltage-gated KV7 channel subtypes (KV7.1–KV7.5) in detrusor smooth muscle (DSM) are poorly understood. Here, we sought to elucidate the functional roles of KV7.2/KV7.3 channels in guinea pig DSM excitability and contractility using the novel KV7.2/KV7.3 channel activator ICA-069673 [N-(2-chloro-5-pyrimidinyl)-3,4-difluorobenzamide]. We employed a multilevel experimental approach using Western blot analysis, immunocytochemistry, isometric DSM tension recordings, fluorescence Ca2+ imaging, and perforated whole-cell patch-clamp electrophysiology. Western blot experiments revealed the protein expression of KV7.2 and KV7.3 channel subunits in DSM tissue. In isolated DSM cells, immunocytochemistry with confocal microscopy further confirmed protein expression for KV7.2 and KV7.3 channel subunits, where they localize within the vicinity of the cell membrane. ICA-069673 inhibited spontaneous phasic, pharmacologically induced, and nerve-evoked contractions in DSM isolated strips in a concentration-dependent manner. The inhibitory effects of ICA-069673 on DSM spontaneous phasic and tonic contractions were abolished in the presence of the KV7 channel inhibitor XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride]. Under conditions of elevated extracellular K+ (60 mM), the effects of ICA-069673 on DSM tonic contractions were significantly attenuated. ICA-069673 decreased the global intracellular Ca2+ concentration in DSM cells, an effect blocked by the L-type Ca2+ channel inhibitor nifedipine. ICA-069673 hyperpolarized the membrane potential and inhibited spontaneous action potentials of isolated DSM cells, effects that were blocked in the presence of XE991. In conclusion, using the novel KV7.2/KV7.3 channel activator ICA-069673, this study provides strong evidence for a critical role for the KV7.2- and KV7.3-containing channels in DSM function at both cellular and tissue levels. PMID:26087697

The Novel KV7.2/KV7.3 Channel Opener ICA-069673 Reveals Subtype-Specific Functional Roles in Guinea Pig Detrusor Smooth Muscle Excitability and Contractility.

PubMed

Provence, Aaron; Malysz, John; Petkov, Georgi V

2015-09-01

The physiologic roles of voltage-gated KV7 channel subtypes (KV7.1-KV7.5) in detrusor smooth muscle (DSM) are poorly understood. Here, we sought to elucidate the functional roles of KV7.2/KV7.3 channels in guinea pig DSM excitability and contractility using the novel KV7.2/KV7.3 channel activator ICA-069673 [N-(2-chloro-5-pyrimidinyl)-3,4-difluorobenzamide]. We employed a multilevel experimental approach using Western blot analysis, immunocytochemistry, isometric DSM tension recordings, fluorescence Ca(2+) imaging, and perforated whole-cell patch-clamp electrophysiology. Western blot experiments revealed the protein expression of KV7.2 and KV7.3 channel subunits in DSM tissue. In isolated DSM cells, immunocytochemistry with confocal microscopy further confirmed protein expression for KV7.2 and KV7.3 channel subunits, where they localize within the vicinity of the cell membrane. ICA-069673 inhibited spontaneous phasic, pharmacologically induced, and nerve-evoked contractions in DSM isolated strips in a concentration-dependent manner. The inhibitory effects of ICA-069673 on DSM spontaneous phasic and tonic contractions were abolished in the presence of the KV7 channel inhibitor XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride]. Under conditions of elevated extracellular K(+) (60 mM), the effects of ICA-069673 on DSM tonic contractions were significantly attenuated. ICA-069673 decreased the global intracellular Ca(2+) concentration in DSM cells, an effect blocked by the L-type Ca(2+) channel inhibitor nifedipine. ICA-069673 hyperpolarized the membrane potential and inhibited spontaneous action potentials of isolated DSM cells, effects that were blocked in the presence of XE991. In conclusion, using the novel KV7.2/KV7.3 channel activator ICA-069673, this study provides strong evidence for a critical role for the KV7.2- and KV7.3-containing channels in DSM function at both cellular and tissue levels. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants

PubMed Central

Abbott, Geoffrey W.

2017-01-01

The human ventricular cardiomyocyte transient outward K+ current (Ito) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac Ito is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology. PMID:28228734

β Subunits Functionally Differentiate Human Kv4.3 Potassium Channel Splice Variants.

PubMed

Abbott, Geoffrey W

2017-01-01

The human ventricular cardiomyocyte transient outward K + current ( I to ) mediates the initial phase of myocyte repolarization and its disruption is implicated in Brugada Syndrome and heart failure (HF). Human cardiac I to is generated primarily by two Kv4.3 splice variants (Kv4.3L and Kv4.3S, diverging only by a C-terminal, S6-proximal, 19-residue stretch unique to Kv4.3L), which are differentially remodeled in HF, but considered functionally alike at baseline. Kv4.3 is regulated in human heart by β subunits including KChIP2b and KCNEs, but their effects were previously assumed to be Kv4.3 isoform-independent. Here, this assumption was tested experimentally using two-electrode voltage-clamp analysis of human subunits co-expressed in Xenopus laevis oocytes. Unexpectedly, Kv4.3L-KChIP2b channels exhibited up to 8-fold lower current augmentation, 40% slower inactivation, and 5 mV-shifted steady-state inactivation compared to Kv4.3S-KChIP2b. A synthetic peptide mimicking the 19-residue stretch diminished these differences, reinforcing the importance of this segment in mediating Kv4.3 regulation by KChIP2b. KCNE subunits induced further functional divergence, including a 7-fold increase in Kv4.3S-KCNE4-KChIP2b current compared to Kv4.3L-KCNE4-KChIP2b. The discovery of β-subunit-dependent functional divergence in human Kv4.3 splice variants suggests a C-terminal signaling hub is crucial to governing β-subunit effects upon Kv4.3, and demonstrates the potential significance of differential Kv4.3 gene-splicing and β subunit expression in myocyte physiology and pathobiology.

Regulation of Kv2.1 K+ conductance by cell surface channel density

PubMed Central

Fox, Philip D.; Loftus, Rob J.; Tamkun, Michael M.

2013-01-01

The Kv2.1 voltage-gated K+ channel is found both freely diffusing over the plasma membrane and concentrated in micron-sized clusters localized to the soma, proximal dendrites and axon initial segment of hippocampal neurons. In transfected HEK cells, Kv2.1 channels within cluster microdomains are non-conducting. Using TIRF microscopy the number of GFP-tagged Kv2.1 channels on the HEK cell surface was compared to K+ channel conductance measured by whole-cell voltage-clamp of the same cell. This approach indicated that as channel density increases non-clustered channels cease conducting. At the highest density observed, only 4% of all channels were conducting. Mutant Kv2.1 channels that fail to cluster also possessed the non-conducting state with 17% conducting K+ at higher surface densities. The non-conducting state was specific to Kv2.1 as Kv1.4 was always conducting regardless of the cell-surface expression level. Anti-Kv2.1 immuno-fluorescence intensity, standardized to Kv2.1 surface density in transfected HEK cells, was used to determine the expression levels of endogenous Kv2.1 in cultured rat hippocampal neurons. Endogenous Kv2.1 levels were compared to the number of conducting channels determined by whole-cell voltage clamp. Only 13 and 27% of the endogenous Kv2.1 was conducting in neurons cultured for 14 and 20 days, respectively. Together these data indicate that the non-conducting state depends primarily on surface density as opposed to cluster location and that this non-conducting state also exists for native Kv2.1 found in cultured hippocampal neurons. This excess of Kv2.1 protein relative to K+ conductance further supports a non-conducting role for Kv2.1 in excitable tissues. PMID:23325261

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury.

PubMed

Hedegaard, Elise R; Johnsen, Jacob; Povlsen, Jonas A; Jespersen, Nichlas R; Shanmuganathan, Jeffrey A; Laursen, Mia R; Kristiansen, Steen B; Simonsen, Ulf; Bøtker, Hans Erik

2016-04-01

The voltage-gated KV7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of KV7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of KV7.1, KV7.4, and KV7.5 in the left anterior descending rat coronary artery and all KV7 subtypes (KV7.1-KV7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of KV7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 µM) and linopirdine (10 µM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of KV7 channels, flupirtine (10 µM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 µM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. KV7 channels are expressed in rat coronary arteries and myocardium. Inhibition of KV7 channels exerts cardioprotection and opening of KV7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for KV7 blockers in the treatment of ischemia-reperfusion injury. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Effect of tyrphostin AG879 on Kv4.2 and Kv4.3 potassium channels

PubMed Central

Yu, Haibo; Zou, Beiyan; Wang, Xiaoliang; Li, Min

2015-01-01

Background and Purpose A-type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv4.2 inhibitor from. In the present study we characterized the effect of AG879 on cloned Kv4.2/Kv channel-interacting protein 2 (KChIP2) channels. Experimental Approach To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK-293 cells transiently-transfected with Kv4.2 cDNA using the Maxcyte transfection system. The effects of AG879 were further examined on CHO-K1 cells expressing Kv4.2/KChIP2 channels using a whole-cell patch-clamp technique. Key Results Tyrphostin AG879 selectively and dose-dependently inhibited Kv4.2 and Kv4.3 channels. In Kv4.2/KChIP2 channels, AG879 induced prominent acceleration of the inactivation rate, use-dependent block and slowed the recovery from inactivation. AG879 induced a hyperpolarizing shift in the voltage-dependence of the steady-state inactivation of Kv4.2 channels without apparent effect on the V1/2 of the voltage-dependent activation. The blocking effect of AG879 was enhanced as channel inactivation increased. Furthermore, AG879 significantly inhibited the A-type potassium currents in the cultured hippocampus neurons. Conclusion and Implications AG879 was identified as a selective and potent inhibitor the Kv4.2 channel. AG879 inhibited Kv4.2 channels by preferentially interacting with the open state and further accelerating their inactivation. PMID:25752739

Effect of tyrphostin AG879 on Kv 4.2 and Kv 4.3 potassium channels.

PubMed

Yu, Haibo; Zou, Beiyan; Wang, Xiaoliang; Li, Min

2015-07-01

A-type potassium channels (IA) are important proteins for modulating neuronal membrane excitability. The expression and activity of Kv 4.2 channels are critical for neurological functions and pharmacological inhibitors of Kv 4.2 channels may have therapeutic potential for Fragile X syndrome. While screening various compounds, we identified tyrphostin AG879, a tyrosine kinase inhibitor, as a Kv 4.2 inhibitor from. In the present study we characterized the effect of AG879 on cloned Kv 4.2/Kv channel-interacting protein 2 (KChIP2) channels. To screen the library of pharmacologically active compounds, the thallium flux assay was performed on HEK-293 cells transiently-transfected with Kv 4.2 cDNA using the Maxcyte transfection system. The effects of AG879 were further examined on CHO-K1 cells expressing Kv 4.2/KChIP2 channels using a whole-cell patch-clamp technique. Tyrphostin AG879 selectively and dose-dependently inhibited Kv 4.2 and Kv 4.3 channels. In Kv 4.2/KChIP2 channels, AG879 induced prominent acceleration of the inactivation rate, use-dependent block and slowed the recovery from inactivation. AG879 induced a hyperpolarizing shift in the voltage-dependence of the steady-state inactivation of Kv 4.2 channels without apparent effect on the V1/2 of the voltage-dependent activation. The blocking effect of AG879 was enhanced as channel inactivation increased. Furthermore, AG879 significantly inhibited the A-type potassium currents in the cultured hippocampus neurons. AG879 was identified as a selective and potent inhibitor the Kv 4.2 channel. AG879 inhibited Kv 4.2 channels by preferentially interacting with the open state and further accelerating their inactivation. © 2015 The British Pharmacological Society.

Single cell analysis of voltage-gated potassium channels that determines neuronal types of rat hypothalamic paraventricular nucleus neurons.

PubMed

Lee, S K; Lee, S; Shin, S Y; Ryu, P D; Lee, S Y

2012-03-15

The hypothalamic paraventricular nucleus (PVN), a site for the integration of both the neuroendocrine and autonomic systems, has heterogeneous cell composition. These neurons are classified into type I and type II neurons based on their electrophysiological properties. In the present study, we investigated the molecular identification of voltage-gated K+ (Kv) channels, which determines a distinctive characteristic of type I PVN neurons, by means of single-cell reverse transcription-polymerase chain reaction (RT-PCR) along with slice patch clamp recordings. In order to determine the mRNA expression profiles, firstly, the PVN neurons of male rats were classified into type I and type II neurons, and then, single-cell RT-PCR and single-cell real-time RT-PCR analysis were performed using the identical cell. The single-cell RT-PCR analysis revealed that Kv1.2, Kv1.3, Kv1.4, Kv4.1, Kv4.2, and Kv4.3 were expressed both in type I and in type II neurons, and several Kv channels were co-expressed in a single PVN neuron. However, we found that the expression densities of Kv4.2 and Kv4.3 were significantly higher in type I neurons than in type II neurons. Taken together, several Kv channels encoding A-type K+ currents are present both in type I and in type II neurons, and among those, Kv4.2 and Kv4.3 are the major Kv subunits responsible for determining the distinct electrophysiological properties. Thus these 2 Kv subunits may play important roles in determining PVN cell types and regulating PVN neuronal excitability. This study further provides key molecular mechanisms for differentiating type I and type II PVN neurons. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.

PubMed

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin

2010-09-01

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus.

PubMed

Granados-Fuentes, Daniel; Hermanstyne, Tracey O; Carrasquillo, Yarimar; Nerbonne, Jeanne M; Herzog, Erik D

2015-10-01

Neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, display daily rhythms in electrical activity with more depolarized resting potentials and higher firing rates during the day than at night. Although these daily variations in the electrical properties of SCN neurons are required for circadian rhythms in physiology and behavior, the mechanisms linking changes in neuronal excitability to the molecular clock are not known. Recently, we reported that mice deficient for either Kcna4 (Kv1.4(-/-)) or Kcnd2 (Kv4.2(-/-); but not Kcnd3, Kv4.3(-/-)), voltage-gated K(+) (Kv) channel pore-forming subunits that encode subthreshold, rapidly activating, and inactivating K(+) currents (IA), have shortened (0.5 h) circadian periods in SCN firing and in locomotor activity compared with wild-type (WT) mice. In the experiments here, we used a mouse (Per2(Luc)) line engineered with a bioluminescent reporter construct, PERIOD2::LUCIFERASE (PER2::LUC), replacing the endogenous Per2 locus, to test the hypothesis that the loss of Kv1.4- or Kv4.2-encoded IA channels also modifies circadian rhythms in the expression of the clock protein PERIOD2 (PER2). We found that SCN explants from Kv1.4(-/-)Per2(Luc) and Kv4.2(-/-) Per2(Luc), but not Kv4.3(-/-)Per2(Luc), mice have significantly shorter (by approximately 0.5 h) circadian periods in PER2 rhythms, compared with explants from Per2(Luc) mice, revealing that the membrane properties of SCN neurons feedback to regulate clock (PER2) expression. The combined loss of both Kv1.4- and Kv4.2-encoded IA channels in Kv1.4(-/-)/Kv4.2(-/-)Per2(Luc) SCN explants did not result in any further alterations in PER2 rhythms. Interestingly, however, mice lacking both Kv1.4 and Kv4.2 show a striking (approximately 1.8 h) advance in their daily activity onset in a light cycle compared with WT mice, suggesting additional roles for Kv1.4- and Kv4.2-encoded IA channels in controlling the light-dependent responses of neurons within and/or outside of the SCN to regulate circadian phase of daily activity. © 2015 The Author(s).

Voltage-Gated K+ Channel, Kv3.3 Is Involved in Hemin-Induced K562 Differentiation

PubMed Central

Song, Min Seok; Choi, Seon Young; Ryu, Pan Dong; Lee, So Yeong

2016-01-01

Voltage-gated K+ (Kv) channels are well known to be involved in cell proliferation. However, even though cell proliferation is closely related to cell differentiation, the relationship between Kv channels and cell differentiation remains poorly investigated. This study demonstrates that Kv3.3 is involved in K562 cell erythroid differentiation. Down-regulation of Kv3.3 using siRNA-Kv3.3 increased hemin-induced K562 erythroid differentiation through decreased activation of signal molecules such as p38, cAMP response element-binding protein, and c-fos. Down-regulation of Kv3.3 also enhanced cell adhesion by increasing integrin β3 and this effect was amplified when the cells were cultured with fibronectin. The Kv channels, or at least Kv3.3, appear to be associated with cell differentiation; therefore, understanding the mechanisms of Kv channel regulation of cell differentiation would provide important information regarding vital cellular processes. PMID:26849432

Kv3.4 is modulated by HIF-1α to protect SH-SY5Y cells against oxidative stress-induced neural cell death.

PubMed

Song, Min Seok; Ryu, Pan Dong; Lee, So Yeong

2017-05-18

The Kv3.4 channel is characterized by fast inactivation and sensitivity to oxidation. However, the physiological role of Kv3.4 as an oxidation-sensitive channel has yet to be investigated. Here, we demonstrate that Kv3.4 plays a pivotal role in oxidative stress-related neural cell damage as an oxidation-sensitive channel and that HIF-1α down-regulates Kv3.4 function, providing neuroprotection. MPP + and CoCl 2 are reactive oxygen species (ROS)-generating reagents that induce oxidative stress. However, only CoCl 2 decreases the expression and function of Kv3.4. HIF-1α, which accumulates in response to CoCl 2 treatment, is a key factor in Kv3.4 regulation. In particular, mitochondrial Kv3.4 was more sensitive to CoCl 2 . Blocking Kv3.4 function using BDS-II, a Kv3.4-specific inhibitor, protected SH-SY5Y cells against MPP + -induced neural cell death. Kv3.4 inhibition blocked MPP + -induced cytochrome c release from the mitochondrial intermembrane space to the cytosol and mitochondrial membrane potential depolarization, which are characteristic features of apoptosis. Our results highlight Kv3.4 as a possible new therapeutic paradigm for oxidative stress-related diseases, including Parkinson's disease.

Claudin5a is required for proper inflation of Kupffer's vesicle lumen and organ laterality.

PubMed

Kim, Jeong-Gyun; Bae, Sung-Jin; Lee, Hye Shin; Park, Ji-Hyeon; Kim, Kyu-Won

2017-01-01

Left-right asymmetric organ development is critical to establish a proper body plan of vertebrates. In zebrafish, the Kupffer's vesicle (KV) is a fluid-filled sac which controls asymmetric organ development, and a properly inflated KV lumen by means of fluid influx is a prerequisite for the asymmetric signal transmission. However, little is known about the components that support the paracellular tightness between the KV luminal epithelial cells to sustain hydrostatic pressure during KV lumen expansion. Here, we identified that the claudin5a (cldn5a) is highly expressed at the apical surface of KV epithelial cells and tightly seals the KV lumen. Downregulation of cldn5a in zebrafish showed a failure in organ laterality that resulted from malformed KV. In addition, accelerated fluid influx into KV by combined treatment of forskolin and 3-isobutyl-1-methylxanthine failed to expand the partially-formed KV lumen in cldn5a morphants. However, malformed KV lumen and defective heart laterality in cldn5a morphants were significantly rescued by exogenous cldn5a mRNA, suggesting that the tightness between the luminal epithelial cells is important for KV lumen formation. Taken together, these findings suggest that cldn5a is required for KV lumen inflation and left-right asymmetric organ development.

Claudin5a is required for proper inflation of Kupffer's vesicle lumen and organ laterality

PubMed Central

Kim, Jeong-gyun; Bae, Sung-Jin; Lee, Hye Shin; Park, Ji-Hyeon

2017-01-01

Left-right asymmetric organ development is critical to establish a proper body plan of vertebrates. In zebrafish, the Kupffer’s vesicle (KV) is a fluid-filled sac which controls asymmetric organ development, and a properly inflated KV lumen by means of fluid influx is a prerequisite for the asymmetric signal transmission. However, little is known about the components that support the paracellular tightness between the KV luminal epithelial cells to sustain hydrostatic pressure during KV lumen expansion. Here, we identified that the claudin5a (cldn5a) is highly expressed at the apical surface of KV epithelial cells and tightly seals the KV lumen. Downregulation of cldn5a in zebrafish showed a failure in organ laterality that resulted from malformed KV. In addition, accelerated fluid influx into KV by combined treatment of forskolin and 3-isobutyl-1-methylxanthine failed to expand the partially-formed KV lumen in cldn5a morphants. However, malformed KV lumen and defective heart laterality in cldn5a morphants were significantly rescued by exogenous cldn5a mRNA, suggesting that the tightness between the luminal epithelial cells is important for KV lumen formation. Taken together, these findings suggest that cldn5a is required for KV lumen inflation and left-right asymmetric organ development. PMID:28771527

The episodic ataxia type 1 mutation I262T alters voltage-dependent gating and disrupts protein biosynthesis of human Kv1.1 potassium channels.

PubMed

Chen, Szu-Han; Fu, Ssu-Ju; Huang, Jing-Jia; Tang, Chih-Yung

2016-01-18

Voltage-gated potassium (Kv) channels are essential for setting neuronal membrane excitability. Mutations in human Kv1.1 channels are linked to episodic ataxia type 1 (EA1). The EA1-associated mutation I262T was identified from a patient with atypical phenotypes. Although a previous report has characterized its suppression effect, several key questions regarding the impact of the I262T mutation on Kv1.1 as well as other members of the Kv1 subfamily remain unanswered. Herein we show that the dominant-negative effect of I262T on Kv1.1 current expression is not reversed by co-expression with Kvβ1.1 or Kvβ2 subunits. Biochemical examinations indicate that I262T displays enhanced protein degradation and impedes membrane trafficking of Kv1.1 wild-type subunits. I262T appears to be the first EA1 mutation directly associated with impaired protein stability. Further functional analyses demonstrate that I262T changes the voltage-dependent activation and Kvβ1.1-mediated inactivation, uncouples inactivation from activation gating, and decelerates the kinetics of cumulative inactivation of Kv1.1 channels. I262T also exerts similar dominant effects on the gating of Kv1.2 and Kv1.4 channels. Together our data suggest that I262T confers altered channel gating and reduced functional expression of Kv1 channels, which may account for some of the phenotypes of the EA1 patient.

Regulation of human cardiac potassium channels by full-length KCNE3 and KCNE4.

PubMed

Abbott, Geoffrey W

2016-12-06

Voltage-gated potassium (Kv) channels comprise pore-forming α subunits and a multiplicity of regulatory proteins, including the cardiac-expressed and cardiac arrhythmia-linked transmembrane KCNE subunits. After recently uncovering novel, N-terminally extended (L) KCNE3 and KCNE4 isoforms and detecting their transcripts in human atrium, reported here are their functional effects on human cardiac Kv channel α subunits expressed in Xenopus laevis oocytes. As previously reported for short isoforms KCNE3S and KCNE4S, KCNE3L inhibited hERG; KCNE4L inhibited Kv1.1; neither form regulated the HCN1 pacemaker channel. Unlike KCNE4S, KCNE4L was a potent inhibitor of Kv4.2 and Kv4.3; co-expression of cytosolic β subunit KChIP2, which regulates Kv4 channels in cardiac myocytes, partially relieved Kv4.3 but not Kv4.2 inhibition. Inhibition of Kv4.2 and Kv4.3 by KCNE3L was weaker, and its inhibition of Kv4.2 abolished by KChIP2. KCNE3L and KCNE4L also exhibited subunit-specific effects on Kv4 channel complex inactivation kinetics, voltage dependence and recovery. Further supporting the potential physiological significance of the robust functional effects of KCNE4L on Kv4 channels, KCNE4L protein was detected in human atrium, where it co-localized with Kv4.3. The findings establish functional effects of novel human cardiac-expressed KCNE isoforms and further contribute to our understanding of the potential mechanisms influencing cardiomyocyte repolarization.

Somatodendritic surface expression of epitope-tagged and KChIP binding-deficient Kv4.2 channels in hippocampal neurons.

PubMed

Prechtel, Helena; Hartmann, Sven; Minge, Daniel; Bähring, Robert

2018-01-01

Kv4.2 channels mediate a subthreshold-activating somatodendritic A-type current (ISA) in hippocampal neurons. We examined the role of accessory Kv channel interacting protein (KChIP) binding in somatodendritic surface expression and activity-dependent decrease in the availability of Kv4.2 channels. For this purpose we transfected cultured hippocampal neurons with cDNA coding for Kv4.2 wild-type (wt) or KChIP binding-deficient Kv4.2 mutants. All channels were equipped with an externally accessible hemagglutinin (HA)-tag and an EGFP-tag, which was attached to the C-terminal end. Combined analyses of EGFP self-fluorescence, surface HA immunostaining and patch-clamp recordings demonstrated similar dendritic trafficking and functional surface expression for Kv4.2[wt]HA,EGFP and the KChIP binding-deficient Kv4.2[A14K]HA,EGFP. Coexpression of exogenous KChIP2 augmented the surface expression of Kv4.2[wt]HA,EGFP but not Kv4.2[A14K]HA,EGFP. Notably, activity-dependent decrease in availability was more pronounced in Kv4.2[wt]HA,EGFP + KChIP2 coexpressing than in Kv4.2[A14K]HA,EGFP + KChIP2 coexpressing neurons. Our results do not support the notion that accessory KChIP binding is a prerequisite for dendritic trafficking and functional surface expression of Kv4.2 channels, however, accessory KChIP binding may play a potential role in Kv4.2 modulation during intrinsic plasticity processes.

Acoustic input and efferent activity regulate the expression of molecules involved in cochlear micromechanics

PubMed Central

Lamas, Veronica; Arévalo, Juan C.; Juiz, José M.; Merchán, Miguel A.

2015-01-01

Electromotile activity in auditory outer hair cells (OHCs) is essential for sound amplification. It relies on the highly specialized membrane motor protein prestin, and its interactions with the cytoskeleton. It is believed that the expression of prestin and related molecules involved in OHC electromotility may be dynamically regulated by signals from the acoustic environment. However little is known about the nature of such signals and how they affect the expression of molecules involved in electromotility in OHCs. We show evidence that prestin oligomerization is regulated, both at short and relatively long term, by acoustic input and descending efferent activity originating in the cortex, likely acting in concert. Unilateral removal of the middle ear ossicular chain reduces levels of trimeric prestin, particularly in the cochlea from the side of the lesion, whereas monomeric and dimeric forms are maintained or even increased in particular in the contralateral side, as shown in Western blots. Unilateral removal of the auditory cortex (AC), which likely causes an imbalance in descending efferent activity on the cochlea, also reduces levels of trimeric and tetrameric forms of prestin in the side ipsilateral to the lesion, whereas in the contralateral side prestin remains unaffected, or even increased in the case of trimeric and tetrameric forms. As far as efferent inputs are concerned, unilateral ablation of the AC up-regulates the expression of α10 nicotinic Ach receptor (nAChR) transcripts in the cochlea, as shown by RT-Quantitative real-time PCR (qPCR). This suggests that homeostatic synaptic scaling mechanisms may be involved in dynamically regulating OHC electromotility by medial olivocochlear efferents. Limited, unbalanced efferent activity after unilateral AC removal, also affects prestin and β-actin mRNA levels. These findings support that the concerted action of acoustic and efferent inputs to the cochlea is needed to regulate the expression of major molecules involved in OHC electromotility, both at the transcriptional and posttranscriptional levels. PMID:25653600

β Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation.

PubMed

Abbott, Geoffrey W

2017-01-01

The transient outward K + current, I to , activates early in the cardiac myocyte action potential, to begin repolarization. Human I to is generated primarily by two Kv4.3 potassium channel α subunit splice variants (Kv4.3L and Kv4.3S) that diverge only by a C-terminal, membrane-proximal, 19-residue stretch unique to Kv4.3L. Protein kinase C (PKC) phosphorylation of threonine 504 within the Kv4.3L-specific 19-residues mediates α-adrenergic inhibition of I to in human heart. Kv4.3 is regulated in human heart by various β subunits, including cytosolic KChIP2b and transmembrane KCNEs, yet their impact on the functional effects of human Kv4.3 phosphorylation has not been reported. Here, this gap in knowledge was addressed using human Kv4.3 splice variants, T504 mutants, and human β subunits. Subunits were co-expressed in Xenopus laevis oocytes and analyzed by two-electrode voltage-clamp, using phorbol 12-myristate 13-acetate (PMA) to stimulate PKC. Unexpectedly, KChIP2b removed the inhibitory effect of PKC on Kv4.3L (but not Kv4.3L threonine phosphorylation by PKC per-se ), while co-expression with KCNE2, but not KCNE4, restored PKC-dependent inhibition of Kv4.3L-KChIP2b to quantitatively resemble previously reported effects of α-adrenergic modulation of human ventricular I to . In addition, PKC accelerated recovery from inactivation of Kv4.3L-KChIP2b channels and, interestingly, of both Kv4.3L and Kv4.3S alone. Thus, β subunits regulate the response of human Kv4.3 to PKC phosphorylation and provide a potential mechanism for modifying the response of I to to α-adrenergic regulation in vivo .

β Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation

PubMed Central

Abbott, Geoffrey W.

2017-01-01

The transient outward K+ current, Ito, activates early in the cardiac myocyte action potential, to begin repolarization. Human Ito is generated primarily by two Kv4.3 potassium channel α subunit splice variants (Kv4.3L and Kv4.3S) that diverge only by a C-terminal, membrane-proximal, 19-residue stretch unique to Kv4.3L. Protein kinase C (PKC) phosphorylation of threonine 504 within the Kv4.3L-specific 19-residues mediates α-adrenergic inhibition of Ito in human heart. Kv4.3 is regulated in human heart by various β subunits, including cytosolic KChIP2b and transmembrane KCNEs, yet their impact on the functional effects of human Kv4.3 phosphorylation has not been reported. Here, this gap in knowledge was addressed using human Kv4.3 splice variants, T504 mutants, and human β subunits. Subunits were co-expressed in Xenopus laevis oocytes and analyzed by two-electrode voltage-clamp, using phorbol 12-myristate 13-acetate (PMA) to stimulate PKC. Unexpectedly, KChIP2b removed the inhibitory effect of PKC on Kv4.3L (but not Kv4.3L threonine phosphorylation by PKC per-se), while co-expression with KCNE2, but not KCNE4, restored PKC-dependent inhibition of Kv4.3L-KChIP2b to quantitatively resemble previously reported effects of α-adrenergic modulation of human ventricular Ito. In addition, PKC accelerated recovery from inactivation of Kv4.3L-KChIP2b channels and, interestingly, of both Kv4.3L and Kv4.3S alone. Thus, β subunits regulate the response of human Kv4.3 to PKC phosphorylation and provide a potential mechanism for modifying the response of Ito to α-adrenergic regulation in vivo. PMID:28919864

Bladder contractility is modulated by Kv7 channels in pig detrusor.

PubMed

Svalø, Julie; Bille, Michala; Parameswaran Theepakaran, Neeraja; Sheykhzade, Majid; Nordling, Jørgen; Bouchelouche, Pierre

2013-09-05

Kv7 channels are involved in smooth muscle relaxation, and accordingly we believe that they constitute potential targets for the treatment of overactive bladder syndrome. We have therefore used myography to examine the function of Kv7 channels in detrusor, i.e. pig bladder, with a view to determining the effects of the following potassium channel activators: ML213 (Kv7.2/Kv7.4 channels) and retigabine (Kv7.2-7.5 channels). Retigabine produced a concentration-dependent relaxation of carbachol- and electric field-induced contractions. The potency was similar in magnitude to that of ML213-induced relaxation, suggesting that Kv7.2 and/or Kv7.4 channels constitute the subtypes that are relevant to bladder contractility. The effects of retigabine and ML213 were attenuated by pre-incubation with 10µM XE991 (Kv7.1-7.5 channel blocker) (P<0.05), which in turn confirmed Kv7 channel selectivity. Subtype-selective effects were further investigated by incubating the detrusor with 10µM chromanol 293B (Kv7.1 channel blocker). Regardless of the experimental protocol, this did not cause a further increase in the evoked contraction. In contrast, the addition of XE991 potentiated the KCl-induced contractions, but not those induced by carbachol or electric field, indicating the presence of a phosphatidyl-inositol-4,5-biphosphate-dependent mechanism amongst the Kv7 channels in detrusor. qRT-PCR studies of the mRNA transcript level of Kv7.3-7.5 channels displayed a higher level of Kv7.4 transcript in detrusor compared to that present in brain cortex and heart tissues. Thus, we have shown that Kv7.4 channels are expressed and functionally active in pig detrusor, and that the use of selective Kv7.4 channel modulators in the treatment of detrusor overactivity seems promising. © 2013 Elsevier B.V. All rights reserved.

Controller for controlling operation of at least one electrical load operating on an AC supply, and a method thereof

DOEpatents

Cantin, Luc; Deschenes, Mario; D'Amours, Mario

1995-08-15

A controller is provided for controlling operation of at least one electrical load operating on an AC supply having a typical frequency, the AC supply being provided via power transformers by an electrical power distribution grid. The controller is associated with the load and comprises an input interface for coupling the controller to the grid, a frequency detector for detecting the frequency of the AC supply and producing a signal indicative of the frequency, memory modules for storing preprogrammed commands, a frequency monitor for reading the signal indicative of the frequency and producing frequency data derived thereof, a selector for selecting at least one of the preprogrammed commands with respect to the frequency data, a control unit for producing at least one command signal representative of the selected preprogrammed commands, and an output interface including a device responsive to the command signal for controlling the load. Therefore, the load can be controlled by means of the controller depending on the frequency of the AC supply.

Adaptive Actor-Critic Design-Based Integral Sliding-Mode Control for Partially Unknown Nonlinear Systems With Input Disturbances.

PubMed

Fan, Quan-Yong; Yang, Guang-Hong

2016-01-01

This paper is concerned with the problem of integral sliding-mode control for a class of nonlinear systems with input disturbances and unknown nonlinear terms through the adaptive actor-critic (AC) control method. The main objective is to design a sliding-mode control methodology based on the adaptive dynamic programming (ADP) method, so that the closed-loop system with time-varying disturbances is stable and the nearly optimal performance of the sliding-mode dynamics can be guaranteed. In the first step, a neural network (NN)-based observer and a disturbance observer are designed to approximate the unknown nonlinear terms and estimate the input disturbances, respectively. Based on the NN approximations and disturbance estimations, the discontinuous part of the sliding-mode control is constructed to eliminate the effect of the disturbances and attain the expected equivalent sliding-mode dynamics. Then, the ADP method with AC structure is presented to learn the optimal control for the sliding-mode dynamics online. Reconstructed tuning laws are developed to guarantee the stability of the sliding-mode dynamics and the convergence of the weights of critic and actor NNs. Finally, the simulation results are presented to illustrate the effectiveness of the proposed method.

Inhibition of Kv7/M Channel Currents by the Local Anesthetic Chloroprocaine.

PubMed

Zhang, Fan; Cheng, Yanxin; Li, Hong; Jia, Qingzhong; Zhang, Hailin; Zhao, Senming

2015-01-01

Chloroprocaine is a local ester anesthetic, producing excellent sensory block in clinical use. The Kv7/M potassium channel plays an important role in the control of neuronal excitability. In this study, we investigated the effects of the local anesthetic chloroprocaine on Kv7/M channels as well as the effect of retigabine on chloroprocaine-induced seizures. A perforated whole-cell patch technique was used to record Kv7 currents from HEK293 cells and M-type currents from rat dorsal root ganglion (DRG) neurons. Chloroprocaine produced a number of effects on Kv7.2/Kv7.3 currents, including a lowering of current amplitudes, a rightward shift in the voltage-dependent activation curves, and a slowing of channel activation. Chloroprocaine had a more selective inhibitory effect on the homomeric Kv7.3 and heteromeric Kv7.2/Kv7.3 channels than on the homomeric Kv7.2 channel. Chloroprocaine also inhibited native M channel currents and induced a depolarization of the DRG neuron membrane potential. Taken together, the findings indicate that chloroprocaine concentration dependently inhibited Kv7/M channel currents. © 2015 S. Karger AG, Basel.

A Calmodulin C-Lobe Ca2+-Dependent Switch Governs Kv7 Channel Function.

PubMed

Chang, Aram; Abderemane-Ali, Fayal; Hura, Greg L; Rossen, Nathan D; Gate, Rachel E; Minor, Daniel L

2018-02-21

Kv7 (KCNQ) voltage-gated potassium channels control excitability in the brain, heart, and ear. Calmodulin (CaM) is crucial for Kv7 function, but how this calcium sensor affects activity has remained unclear. Here, we present X-ray crystallographic analysis of CaM:Kv7.4 and CaM:Kv7.5 AB domain complexes that reveal an Apo/CaM clamp conformation and calcium binding preferences. These structures, combined with small-angle X-ray scattering, biochemical, and functional studies, establish a regulatory mechanism for Kv7 CaM modulation based on a common architecture in which a CaM C-lobe calcium-dependent switch releases a shared Apo/CaM clamp conformation. This C-lobe switch inhibits voltage-dependent activation of Kv7.4 and Kv7.5 but facilitates Kv7.1, demonstrating that mechanism is shared by Kv7 isoforms despite the different directions of CaM modulation. Our findings provide a unified framework for understanding how CaM controls different Kv7 isoforms and highlight the role of membrane proximal domains for controlling voltage-gated channel function. VIDEO ABSTRACT. Copyright © 2018 Elsevier Inc. All rights reserved.

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine.

PubMed

Syeda, Ruhma; Santos, Jose S; Montal, Mauricio

2016-02-05

KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine*

PubMed Central

Syeda, Ruhma; Santos, Jose S.; Montal, Mauricio

2016-01-01

KCNQ (voltage-gated K+ channel family 7 (Kv7)) channels control cellular excitability and underlie the K+ current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K+ current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. PMID:26627826

Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

PubMed

Hristov, Kiril L; Chen, Muyan; Afeli, Serge A Y; Cheng, Qiuping; Rovner, Eric S; Petkov, Georgi V

2012-06-01

The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction.

Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries

PubMed Central

Chen, Xingjuan; Li, Wennan; Hiett, S. Christopher; Obukhov, Alexander G.

2016-01-01

Voltage-gated Kv7 channels are inhibited by agonists of Gq-protein-coupled receptors, such as histamine. Recent works have provided evidence that inhibition of vascular Kv7 channels may trigger vessel contractions. In this study, we investigated how Kv7 activity modulates the histamine-induced contractions in “healthy” and metabolic syndrome (MetS) pig right coronary arteries (CAs). We performed isometric tension and immunohistochemical studies with domestic, lean Ossabaw, and MetS Ossabaw pig CAs. We found that neither the Kv7.2/Kv7.4/Kv7.5 activator ML213 nor the general Kv7 inhibitor XE991 altered the tension of CA rings under preload, indicating that vascular Kv7 channels are likely inactive in the preloaded rings. Conversely, ML213 potently dilated histamine-pre-contracted CAs, suggesting that Kv7 channels are activated during histamine applications and yet partially inhibited by histamine. Immunohistochemistry analysis revealed strong Kv7.4 immunostaining in the medial and intimal layers of the CA wall, whereas Kv7.5 immunostaining intensity was strong in the intimal but weak in the medial layers. The medial Kv7 immunostaining was significantly weaker in MetS Ossabaw CAs as compared to lean Ossabaw or domestic CAs. Consistently, histamine-pre-contracted MetS Ossabaw CAs exhibited attenuated ML213-dependent dilations. In domestic pig CAs, where medial Kv7 immunostaining intensity was stronger, histamine-induced contractions spontaneously decayed to ~31% of the peak amplitude within 4 minutes. Oppositely, in Ossabaw CAs, where Kv7 immunostaining intensity was weaker, the histamine-induced contractions were more sustained. XE991 pretreatment significantly slowed the decay rate of histamine-induced contractions in domestic CAs, supporting the hypothesis that increased Kv7 activity correlates with a faster rate of histamine-induced contraction decay. Alternatively, XE991 significantly decreased the amplitude of bradykinin-dependent dilations in pre-contracted CAs. We propose that in CAs, a decreased expression or a loss of function of Kv7 channels may lead to sustained histamine-induced contractions and reduced endothelium-dependent relaxation, both risk factors for coronary spasm. PMID:26844882

Functional ion channels in human pulmonary artery smooth muscle cells: Voltage-dependent cation channels

PubMed Central

Firth, Amy L.; Remillard, Carmelle V.; Platoshyn, Oleksandr; Fantozzi, Ivana; Ko, Eun A.; Yuan, Jason X.-J.

2011-01-01

The activity of voltage-gated ion channels is critical for the maintenance of cellular membrane potential and generation of action potentials. In turn, membrane potential regulates cellular ion homeostasis, triggering the opening and closing of ion channels in the plasma membrane and, thus, enabling ion transport across the membrane. Such transmembrane ion fluxes are important for excitation–contraction coupling in pulmonary artery smooth muscle cells (PASMC). Families of voltage-dependent cation channels known to be present in PASMC include voltage-gated K+ (Kv) channels, voltage-dependent Ca2+-activated K+ (Kca) channels, L- and T- type voltage-dependent Ca2+ channels, voltage-gated Na+ channels and voltage-gated proton channels. When cells are dialyzed with Ca2+-free K+- solutions, depolarization elicits four components of 4-aminopyridine (4-AP)-sensitive Kvcurrents based on the kinetics of current activation and inactivation. In cell-attached membrane patches, depolarization elicits a wide range of single-channel K+ currents, with conductances ranging between 6 and 290 pS. Macroscopic 4-AP-sensitive Kv currents and iberiotoxin-sensitive Kca currents are also observed. Transcripts of (a) two Na+ channel α-subunit genes (SCN5A and SCN6A), (b) six Ca2+ channel α–subunit genes (α1A, α1B, α1X, α1D, α1Eand α1G) and many regulatory subunits (α2δ1, β1-4, and γ6), (c) 22 Kv channel α–subunit genes (Kv1.1 - Kv1.7, Kv1.10, Kv2.1, Kv3.1, Kv3.3, Kv3.4, Kv4.1, Kv4.2, Kv5.1, Kv 6.1-Kv6.3, Kv9.1, Kv9.3, Kv10.1 and Kv11.1) and three Kv channel β-subunit genes (Kvβ1-3) and (d) four Kca channel α–subunit genes (Sloα1 and SK2-SK4) and four Kca channel β-subunit genes (Kcaβ1-4) have been detected in PASMC. Tetrodotoxin-sensitive and rapidly inactivating Na+ currents have been recorded with properties similar to those in cardiac myocytes. In the presence of 20 mM external Ca2+, membrane depolarization from a holding potential of -100 mV elicits a rapidly inactivating T-type Ca2+ current, while depolarization from a holding potential of -70 mV elicits a slowly inactivating dihydropyridine-sensitive L-type Ca2+ current. This review will focus on describing the electrophysiological properties and molecular identities of these voltage-dependent cation channels in PASMC and their contribution to the regulation of pulmonary vascular function and its potential role in the pathogenesis of pulmonary vascular disease. PMID:21927714

Improving Constraints on Climate System Properties withAdditional Data and New Statistical and Sampling Methods

NASA Astrophysics Data System (ADS)

Forest, C. E.; Libardoni, A. G.; Sokolov, A. P.; Monier, E.

2017-12-01

We use the updated MIT Earth System Model (MESM) to derive the joint probability distribution function for Equilibrium Climate sensitivity (S), an effective heat diffusivity (Kv), and the net aerosol forcing (Faer). Using a new 1800-member ensemble of MESM runs, we derive PDFs by comparing model outputs against historical observations of surface temperature and global mean ocean heat content. We focus on how changes in (i) the MESM model, (ii) recent surface temperature and ocean heat content observations, and (iii) estimates of internal climate variability will all contribute to uncertainties. We show that estimates of S increase and Faer is less negative. These shifts result partly from new model forcing inputs but also from including recent temperature records that lead to higher values of S and Kv. We show that the parameter distributions are sensitive to the internal variability in the climate system. When considering these factors, we derive our best estimate for the joint probability distribution for the climate system properties. We estimate the 90-percent confidence intervals for climate sensitivity as 2.7-5.4 oC with a mode of 3.5 oC, for Kv as 1.9-23.0 cm2 s-1 with a mode of 4.41 cm2 s-1, and for Faer as -0.4 - -0.04 Wm-2 with a mode of -0.25 Wm-2. Lastly, we estimate TCR to be between 1.4 and 2.1 oC with a mode of 1.8 oC.

An all-solid-state CO2 laser driver

NASA Astrophysics Data System (ADS)

Birx, Daniel

1991-03-01

New, all-solid-state pulse generators are described which meet military requirements for an efficient, reliable pulsed power source to drive a space based CO2 laser. These SCR-commutated, nonlinear magnetic pulse compressors are fully-compatible with the present Spectra Technologies laser head design planned for use on LOWKATER. By employing SCRs rather than thyratron commutators, these pulsers should provide a significant increase in reliability over the current generation of pulsed power drivers. The first pulser which was designed and constructed was denoted COLD-I. COLD-I was designed to meet the original LOWKATER specifications and delivered at 150 joule, 20 kV pulse into a laser load at 10 to 20 Hz repetition rate. The second pulser, denoted COLD-II, was designed to provide a 45 joule, 500 nsec duration pulse at a voltage of 20 kV and a repetition rate of 1 kHz peak and 50 to 100 Hz average. The electrical efficiency was measured to be 80 percent with an input drive of 500 VDC. This pulse served as a design verification testbed for a third pulser, presently designed but not constructed and denoted COLD-III. COLD-III would be capable of producing 36 joules at the same pulse length and repetition rate at voltages of 20 kV. The Phase-II effort was a high risk, high payoff effort aimed at developing a light weight, high reliability RF power source for advanced RF CO2 laser heads under development. COLD-IV a Branched Magnetic RF Nonlinear Magnetic Pulse Compressor was built as a bread

Seeded Fault Bearing Experiments: Methodology and Data Acquisition

DTIC Science & Technology

2011-06-01

electronics piezoelectric ( IEPE ) transducer. Constant current biased transducers require AC coupling for the output signal. The ICP-Type Signal...the outer race I/O input/output IEPE integral electronics piezoelectric LCD liquid crystal display P&D Prognostics and Diagnostics RMS root

Fractional Modeling of the AC Large-Signal Frequency Response in Magnetoresistive Current Sensors

PubMed Central

Arias, Sergio Iván Ravello; Muñoz, Diego Ramírez; Moreno, Jaime Sánchez; Cardoso, Susana; Ferreira, Ricardo; de Freitas, Paulo Jorge Peixeiro

2013-01-01

Fractional calculus is considered when derivatives and integrals of non-integer order are applied over a specific function. In the electrical and electronic domain, the transfer function dependence of a fractional filter not only by the filter order n, but additionally, of the fractional order α is an example of a great number of systems where its input-output behavior could be more exactly modeled by a fractional behavior. Following this aim, the present work shows the experimental ac large-signal frequency response of a family of electrical current sensors based in different spintronic conduction mechanisms. Using an ac characterization set-up the sensor transimpedance function Zt(if) is obtained considering it as the relationship between sensor output voltage and input sensing current, Zt(jf)=Vo,sensor(jf)/Isensor(jf). The study has been extended to various magnetoresistance sensors based in different technologies like anisotropic magnetoresistance (AMR), giant magnetoresistance (GMR), spin-valve (GMR-SV) and tunnel magnetoresistance (TMR). The resulting modeling shows two predominant behaviors, the low-pass and the inverse low-pass with fractional index different from the classical integer response. The TMR technology with internal magnetization offers the best dynamic and sensitivity properties opening the way to develop actual industrial applications. PMID:24351648

OLEM Performance Assessment Information

EPA Pesticide Factsheets

This asset includes a variety of data sets that measure the performance of Office of Land and Emergency Management (OLEM) programs in support of the Office of the Chief Financial Officer's Annual Commitment System (ACS) and Performance Evaluation Reporting System (PERS). Information is drawn from OLEM's ACRES, RCRAInfo, CERCLIS/SEMS, ICIS, and LUST4 systems, as well as input manually by authorized individuals in OLEM's program offices. Information is reviewed by OLEM program staff prior to being pushed to ACS and entered into PERS. This data asset also pulls in certain performance information input directly by Regional Office staff into ACS. Information is managed by the Performance Assessment Tool (PAT) and displayed in the PAT Dashboard.Information in this asset include:--Government Performance and Results Act (GPRA) of 1993: Measures reported for Innovations, Partnerships and Communications Office (IPCO), the Office of Brownfields and Land Revitalization (OBLR), the Office of Emergency Management (OEM), the Office of Resource Conservation and Recovery (ORCR), the Office of Superfund Remediation and Technology Innovation (OSRTI), and the Office of Underground Storage Tanks (OUST).-- Performance and Environmental Results System (PERS): Includes OLEM's information on performance results and baselines for the EPA Annual Plan and Budget.--Key Performance Indicators: OLEM has identified five KPIs that are tracked annually.--Integrated Cleanup Initiative: A pilot pe

Functional and Molecular Evidence for Kv7 Channel Subtypes in Human Detrusor from Patients with and without Bladder Outflow Obstruction

PubMed Central

Svalø, Julie; Sheykhzade, Majid; Nordling, Jørgen; Matras, Christina; Bouchelouche, Pierre

2015-01-01

The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7) and in patients with bladder outflow obstruction (n = 3). Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 μM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM), reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1–7.5 channels, 10 μM) had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and β-adrenoceptors. Using cumulative additions of isoprenaline (β-adrenoceptor agonist) and forskolin (adenylyl cyclase activator) in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome. PMID:25692982

A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity.

PubMed

Devaux, Jérôme; Abidi, Affef; Roubertie, Agathe; Molinari, Florence; Becq, Hélène; Lacoste, Caroline; Villard, Laurent; Milh, Mathieu; Aniksztejn, Laurent

2016-05-01

Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2(V175L) ) found in a patient presenting EOEE. We observed that the mutation produced a 25-40 mV hyperpolarizing shift of the conductance-voltage relationship of both the homomeric Kv7.2(V175L) and heteromeric Kv7.2(V175L) /Kv7.3 channels compared to wild-type channels and a 10 mV hyperpolarizing shift of Kv7.2(V175L) /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 μm linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain-of-function variants. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Peripheral KV7 channels regulate visceral sensory function in mouse and human colon

PubMed Central

Hockley, James RF; Reed, David E; Smith, Ewan St. John; Bulmer, David C; Blackshaw, L Ashley

2017-01-01

Background Chronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1–KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception. Results Immunohistochemical staining of mouse colon revealed labelling of KV7 subtypes (KV7.3 and KV7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the KV7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B2 bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0–80 mmHg) in a concentration-dependent manner, whereas the KV7 blocker XE991 potentiated such responses. In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon. Conclusions We show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies. PMID:28566000

PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells.

PubMed

Haick, Jennifer M; Brueggemann, Lioubov I; Cribbs, Leanne L; Denning, Mitchell F; Schwartz, Jeffrey; Byron, Kenneth L

2017-06-01

Kv7 potassium channels have recently been found to be expressed and functionally important for relaxation of airway smooth muscle. Previous research suggests that native Kv7 currents are inhibited following treatment of freshly isolated airway smooth muscle cells with bronchoconstrictor agonists, and in intact airways inhibition of Kv7 channels is sufficient to induce bronchiolar constriction. However, the mechanism by which Kv7 currents are inhibited by bronchoconstrictor agonists has yet to be elucidated. In the present study, native Kv7 currents in cultured human trachealis smooth muscle cells (HTSMCs) were observed to be inhibited upon treatment with histamine; inhibition of Kv7 currents was associated with membrane depolarization and an increase in cytosolic Ca 2+ ([Ca 2+ ] cyt ). The latter response was inhibited by verapamil, a blocker of L-type voltage-sensitive Ca 2+ channels (VSCCs). Protein kinase C (PKC) has been implicated as a mediator of bronchoconstrictor actions, although the targets of PKC are not clearly established. We found that histamine treatment significantly and dose-dependently suppressed currents through overexpressed wild-type human Kv7.5 (hKv7.5) channels in cultured HTSMCs, and this effect was inhibited by the PKC inhibitor Ro-31-8220 (3 µM). The PKC-dependent suppression of hKv7.5 currents corresponded with a PKC-dependent increase in hKv7.5 channel phosphorylation. Knocking down or inhibiting PKCα, or mutating hKv7.5 serine 441 to alanine, abolished the inhibitory effects of histamine on hKv7.5 currents. These findings provide the first evidence linking PKC activation to suppression of Kv7 currents, membrane depolarization, and Ca 2+ influx via L-type VSCCs as a mechanism for histamine-induced bronchoconstriction. Copyright © 2017 the American Physiological Society.

Functional and molecular evidence for Kv7 channel subtypes in human detrusor from patients with and without bladder outflow obstruction.

PubMed

Svalø, Julie; Sheykhzade, Majid; Nordling, Jørgen; Matras, Christina; Bouchelouche, Pierre

2015-01-01

The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7) and in patients with bladder outflow obstruction (n = 3). Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 μM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM), reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1-7.5 channels, 10 μM) had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and β-adrenoceptors. Using cumulative additions of isoprenaline (β-adrenoceptor agonist) and forskolin (adenylyl cyclase activator) in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome.

KChIPs and Kv4 alpha subunits as integral components of A-type potassium channels in mammalian brain.

PubMed

Rhodes, Kenneth J; Carroll, Karen I; Sung, M Amy; Doliveira, Lisa C; Monaghan, Michael M; Burke, Sharon L; Strassle, Brian W; Buchwalder, Lynn; Menegola, Milena; Cao, Jie; An, W Frank; Trimmer, James S

2004-09-08

Voltage-gated potassium (Kv) channels from the Kv4, or Shal-related, gene family underlie a major component of the A-type potassium current in mammalian central neurons. We recently identified a family of calcium-binding proteins, termed KChIPs (Kv channel interacting proteins), that bind to the cytoplasmic N termini of Kv4 family alpha subunits and modulate their surface density, inactivation kinetics, and rate of recovery from inactivation (An et al., 2000). Here, we used single and double-label immunohistochemistry, together with circumscribed lesions and coimmunoprecipitation analyses, to examine the regional and subcellular distribution of KChIPs1-4 and Kv4 family alpha subunits in adult rat brain. Immunohistochemical staining using KChIP-specific monoclonal antibodies revealed that the KChIP polypeptides are concentrated in neuronal somata and dendrites where their cellular and subcellular distribution overlaps, in an isoform-specific manner, with that of Kv4.2 and Kv4.3. For example, immunoreactivity for KChIP1 and Kv4.3 is concentrated in the somata and dendrites of hippocampal, striatal, and neocortical interneurons. Immunoreactivity for KChIP2, KChIP4, and Kv4.2 is concentrated in the apical and basal dendrites of hippocampal and neocortical pyramidal cells. Double-label immunofluorescence labeling revealed that throughout the forebrain, KChIP2 and KChIP4 are frequently colocalized with Kv4.2, whereas in cortical, hippocampal, and striatal interneurons, KChIP1 is frequently colocalized with Kv4.3. Coimmunoprecipitation analyses confirmed that all KChIPs coassociate with Kv4 alpha subunits in brain membranes, indicating that KChIPs 1-4 are integral components of native A-type Kv channel complexes and are likely to play a major role as modulators of somatodendritic excitability.

Conserved Kv4 N-terminal domain critical for effects of Kv channel-interacting protein 2.2 on channel expression and gating.

PubMed

Bähring, R; Dannenberg, J; Peters, H C; Leicher, T; Pongs, O; Isbrandt, D

2001-06-29

Association of Kv channel-interacting proteins (KChIPs) with Kv4 channels leads to modulation of these A-type potassium channels (An, W. F., Bowlby, M. R., Betty, M., Cao, J., Ling, H. P., Mendoza, G., Hinson, J. W., Mattsson, K. I., Strassle, B. W., Trimmer, J. S., and Rhodes, K. J. (2000) Nature 403, 553-556). We cloned a KChIP2 splice variant (KChIP2.2) from human ventricle. In comparison with KChIP2.1, coexpression of KChIP2.2 with human Kv4 channels in mammalian cells slowed the onset of Kv4 current inactivation (2-3-fold), accelerated the recovery from inactivation (5-7-fold), and shifted Kv4 steady-state inactivation curves by 8-29 mV to more positive potentials. The features of Kv4.2/KChIP2.2 currents closely resemble those of cardiac rapidly inactivating transient outward currents. KChIP2.2 stimulated the Kv4 current density in Chinese hamster ovary cells by approximately 55-fold. This correlated with a redistribution of immunoreactivity from perinuclear areas to the plasma membrane. Increased Kv4 cell-surface expression and current density were also obtained in the absence of KChIP2.2 when the highly conserved proximal Kv4 N terminus was deleted. The same domain is required for association of KChIP2.2 with Kv4 alpha-subunits. We propose that an efficient transport of Kv4 channels to the cell surface depends on KChIP binding to the Kv4 N-terminal domain. Our data suggest that the binding is necessary, but not sufficient, for the functional activity of KChIPs.

A Survey of State-of-the-Art LORAN-C Receivers.

DTIC Science & Technology

1984-06-01

urvey/monitor, (T)ining, (Land, (O)therl h(inches). 7.6i N(inches). 7.5 D(inches). 12.6 VOLUM(cu.in.) 667 WEIGHT (lb): 18.1 TENP RANGE ( dog F): -67.170...Iaches): 2.8- W~inches): 12 VOLUM kv.ia.): 369 MuIGTY (2b): 6 TRW RANGS ( dog P): 3.*12z INPU VOLTACE: 4.5-50 OE RWQIRUNT (watts): g-12 DISPLAY TYPE: 2...Dinches). v4L0N(cu.in.)• WRIGHT (lb): 4.8 TEMP RANGE ( dog F): -4,+130 INPUT VOLTAGE: 10-45 POWER RRQUIRBNBNT (Watts): DISPLAY TYPE: A-N. LED, DOT

The LTX- β Research Program

NASA Astrophysics Data System (ADS)

Majeski, R.; Bell, R. E.; Boyle, D. P.; Hughes, P. E.; Kaita, R.; Kozub, T.; Merino, E.; Zhang, X.; Biewer, T. M.; Canik, J. M.; Elliott, D. B.; Reinke, M. L.; Bialek, J.; Hansen, C.; Jarboe, T.; Kubota, S.; Rhodes, T.; Dorf, M. A.; Rognlien, T.; Scotti, F.; Soukhanovskii, V. A.; Koel, B. E.; Donovan, D.; Maan, A.

2017-10-01

LTX- β, the upgrade to the Lithium Tokamak Experiment, approximately doubles the toroidal field (to 3.4 kG) and plasma current (to 150 - 175 kA) of LTX. Neutral beam injection at 20 kV, 30 A will be added in February 2018, with systems provided by Tri-Alpha Energy. A 9.3 GHz, 100 kW, short-pulse (5-10 msec) source will be available in summer 2018 for electron Bernstein wave heating. New lithium evaporation sources will allow between-shots recoating of the walls. Upgrades to the diagnostic set are intended to strengthen the research program in the critical areas of equilibrium, core transport, scrape-off layer physics, and plasma-material interactions. The LTX- β research program will combine the capability for gradient-free temperature profiles, to stabilize ion and electron temperature gradient-driven modes, with approaches to stabilization of ∇n-driven modes, such as the trapped electron mode (TEM). Candidate stabilization mechanisms for the TEM include sheared flow stabilization, which can be tested on LTX- β. The goal will be to minimize anomalous transport in a low aspect ratio tokamak, which would lead to a very compact, tokamak-based fusion core. This work supported by US DOE contracts DE-AC02-09CH11466 and DE-AC05-00OR22725.

A joint swarm intelligence algorithm for multi-user detection in MIMO-OFDM system

NASA Astrophysics Data System (ADS)

Hu, Fengye; Du, Dakun; Zhang, Peng; Wang, Zhijun

2014-11-01

In the multi-input multi-output orthogonal frequency division multiplexing (MIMO-OFDM) system, traditional multi-user detection (MUD) algorithms that usually used to suppress multiple access interference are difficult to balance system detection performance and the complexity of the algorithm. To solve this problem, this paper proposes a joint swarm intelligence algorithm called Ant Colony and Particle Swarm Optimisation (AC-PSO) by integrating particle swarm optimisation (PSO) and ant colony optimisation (ACO) algorithms. According to simulation results, it has been shown that, with low computational complexity, the MUD for the MIMO-OFDM system based on AC-PSO algorithm gains comparable MUD performance with maximum likelihood algorithm. Thus, the proposed AC-PSO algorithm provides a satisfactory trade-off between computational complexity and detection performance.

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

PubMed Central

Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan; Mulkey, Daniel K.; Shi, Yingtang; Wagner, Paul G.; Pivaroff-Ward, Kendra; Sassic, Jessica K.; Bayliss, Douglas A.

2013-01-01

The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance–voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo. PMID:23712551

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor.

PubMed

Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan; Mulkey, Daniel K; Shi, Yingtang; Wagner, Paul G; Pivaroff-Ward, Kendra; Sassic, Jessica K; Bayliss, Douglas A; Jegla, Timothy

2013-06-01

The Ether-a-go-go (EAG) superfamily of voltage-gated K(+) channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K(+) currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K(+) channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance-voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn(2+). Low pH similarly reduces Mg(2+) sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca(2+). Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K(+) currents observed in vivo.

Expression and function of Kv7.4 channels in rat cardiac mitochondria: possible targets for cardioprotection.

PubMed

Testai, Lara; Barrese, Vincenzo; Soldovieri, Maria Virginia; Ambrosino, Paolo; Martelli, Alma; Vinciguerra, Iolanda; Miceli, Francesco; Greenwood, Iain Andrew; Curtis, Michael John; Breschi, Maria Cristina; Sisalli, Maria Josè; Scorziello, Antonella; Canduela, Miren Josune; Grandes, Pedro; Calderone, Vincenzo; Taglialatela, Maurizio

2016-05-01

Plasmalemmal Kv7.1 (KCNQ1) channels are critical players in cardiac excitability; however, little is known on the functional role of additional Kv7 family members (Kv7.2-5) in cardiac cells. In this work, the expression, function, cellular and subcellular localization, and potential cardioprotective role against anoxic-ischaemic cardiac injury of Kv7.4 channels have been investigated. Expression of Kv7.1 and Kv7.4 transcripts was found in rat heart tissue by quantitative polymerase chain reaction. Western blots detected Kv7.4 subunits in mitochondria from Kv7.4-transfected cells, H9c2 cardiomyoblasts, freshly isolated adult cardiomyocytes, and whole hearts. Immunofluorescence experiments revealed that Kv7.4 subunits co-localized with mitochondrial markers in cardiac cells, with ∼ 30-40% of cardiac mitochondria being labelled by Kv7.4 antibodies, a result also confirmed by immunogold electron microscopy experiments. In isolated cardiac (but not liver) mitochondria, retigabine (1-30 µM) and flupirtine (30 µM), two selective Kv7 activators, increased Tl(+) influx, depolarized the membrane potential, and inhibited calcium uptake; all these effects were antagonized by the Kv7 blocker XE991. In intact H9c2 cells, reducing Kv7.4 expression by RNA interference blunted retigabine-induced mitochondrial membrane depolarization; in these cells, retigabine decreased mitochondrial Ca(2+) levels and increased radical oxygen species production, both effects prevented by XE991. Finally, retigabine reduced cellular damage in H9c2 cells exposed to anoxia/re-oxygenation and largely prevented the functional and morphological changes triggered by global ischaemia/reperfusion (I/R) in Langendorff-perfused rat hearts. Kv7.4 channels are present and functional in cardiac mitochondria; their activation exerts a significant cardioprotective role, making them potential therapeutic targets against I/R-induced cardiac injury. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons.

PubMed

Yunoki, Takakazu; Takimoto, Koichi; Kita, Kaori; Funahashi, Yasuhito; Takahashi, Ryosuke; Matsuyoshi, Hiroko; Naito, Seiji; Yoshimura, Naoki

2014-11-15

Little is known about electrophysiological differences of A-type transient K(+) (KA) currents in nociceptive afferent neurons that innervate somatic and visceral tissues. Staining with isolectin B4 (IB4)-FITC classifies L6-S1 dorsal root ganglion (DRG) neurons into three populations with distinct staining intensities: negative to weak, moderate, and intense fluorescence signals. All IB4 intensely stained cells are negative for a fluorescent dye, Fast Blue (FB), injected into the bladder wall, whereas a fraction of somatic neurons labeled by FB, injected to the external urethral dermis, is intensely stained with IB4. In whole-cell, patch-clamp recordings, phrixotoxin 2 (PaTx2), a voltage-gated K(+) (Kv)4 channel blocker, exhibits voltage-independent inhibition of the KA current in IB4 intensely stained cells but not the one in bladder-innervating cells. The toxin also shows voltage-independent inhibition of heterologously expressed Kv4.1 current, whereas its inhibition of Kv4.2 and Kv4.3 currents is voltage dependent. The swapping of four amino acids at the carboxyl portion of the S3 region between Kv4.1 and Kv4.2 transfers this characteristic. RT-PCRs detected Kv4.1 and the long isoform of Kv4.3 mRNAs without significant Kv4.2 mRNA in L6-S1 DRGs. Kv4.1 and Kv4.3 mRNA levels were higher in laser-captured, IB4-stained neurons than in bladder afferent neurons. These results indicate that PaTx2 acts differently on channels in the Kv4 family and that Kv4.1 and possibly Kv4.3 subunits functionally participate in the formation of KA channels in a subpopulation of somatic C-fiber neurons but not in visceral C-fiber neurons innervating the bladder. Copyright © 2014 the American Physiological Society.

Differential contribution of Kv4-containing channels to A-type, voltage-gated potassium currents in somatic and visceral dorsal root ganglion neurons

PubMed Central

Yunoki, Takakazu; Takimoto, Koichi; Kita, Kaori; Funahashi, Yasuhito; Takahashi, Ryosuke; Matsuyoshi, Hiroko; Naito, Seiji

2014-01-01

Little is known about electrophysiological differences of A-type transient K+ (KA) currents in nociceptive afferent neurons that innervate somatic and visceral tissues. Staining with isolectin B4 (IB4)-FITC classifies L6-S1 dorsal root ganglion (DRG) neurons into three populations with distinct staining intensities: negative to weak, moderate, and intense fluorescence signals. All IB4 intensely stained cells are negative for a fluorescent dye, Fast Blue (FB), injected into the bladder wall, whereas a fraction of somatic neurons labeled by FB, injected to the external urethral dermis, is intensely stained with IB4. In whole-cell, patch-clamp recordings, phrixotoxin 2 (PaTx2), a voltage-gated K+ (Kv)4 channel blocker, exhibits voltage-independent inhibition of the KA current in IB4 intensely stained cells but not the one in bladder-innervating cells. The toxin also shows voltage-independent inhibition of heterologously expressed Kv4.1 current, whereas its inhibition of Kv4.2 and Kv4.3 currents is voltage dependent. The swapping of four amino acids at the carboxyl portion of the S3 region between Kv4.1 and Kv4.2 transfers this characteristic. RT-PCRs detected Kv4.1 and the long isoform of Kv4.3 mRNAs without significant Kv4.2 mRNA in L6-S1 DRGs. Kv4.1 and Kv4.3 mRNA levels were higher in laser-captured, IB4-stained neurons than in bladder afferent neurons. These results indicate that PaTx2 acts differently on channels in the Kv4 family and that Kv4.1 and possibly Kv4.3 subunits functionally participate in the formation of KA channels in a subpopulation of somatic C-fiber neurons but not in visceral C-fiber neurons innervating the bladder. PMID:25143545

Preparation and electrical properties of oil-based magnetic fluids

NASA Astrophysics Data System (ADS)

Sartoratto, P. P. C.; Neto, A. V. S.; Lima, E. C. D.; Rodrigues de Sá, A. L. C.; Morais, P. C.

2005-05-01

This paper describes an improvement in the preparation of magnetic fluids for electrical transformers. The samples are based on surface-coated maghemite nanoparticles dispersed in transformer insulating oil. Colloidal stability at 90°C was higher for oleate-grafted maghemite-based magnetic fluid, whereas decanoate and dodecanoate-grafted samples were very unstable. Electrical properties were evaluated for samples containing 0.80%-0.0040% maghemite volume fractions. Relative permittivity varied from 8.8 to 2.1 and the minimum value of the loss factor was 12% for the most diluted sample. The resistivity falls in the range of 0.7-2.5×1010Ωm, whereas the ac dielectric strength varied from 70to79kV. These physical characteristics reveal remarkable step forward in the properties of the magnetic fluid samples and may result in better operation of electrical transformers.

Identification of a functional interaction between Kv4.3 channels and c-Src tyrosine kinase.

PubMed

Gomes, Pedro; Saito, Tomoaki; Del Corsso, Cris; Alioua, Abderrahmane; Eghbali, Mansoureh; Toro, Ligia; Stefani, Enrico

2008-10-01

Voltage-gated K(+) (Kv) channels are key determinants of cardiac and neuronal excitability. A substantial body of evidence has accumulated in support of a role for Src family tyrosine kinases in the regulation of Kv channels. In this study, we examined the possibility that c-Src tyrosine kinase participates in the modulation of the transient voltage-dependent K(+) channel Kv4.3. Supporting a mechanistic link between Kv4.3 and c-Src, confocal microscopy analysis of HEK293 cells stably transfected with Kv4.3 showed high degree of co-localization of the two proteins at the plasma membrane. Our results further demonstrate an association between Kv4.3 and c-Src by co-immunoprecipitation and GST pull-down assays, this interaction being mediated by the SH2 and SH3 domains of c-Src. Furthermore, we show that Kv4.3 is tyrosine phosphorylated under basal conditions. The functional relevance of the observed interaction between Kv4.3 and c-Src was established in patch-clamp experiments, where application of the Src inhibitor PP2 caused a decrease in Kv4.3 peak current amplitude, but not the inactive structural analogue PP3. Conversely, intracellular application of recombinant c-Src kinase or the protein tyrosine phosphatase inhibitor bpV(phen) increased Kv4.3 peak current amplitude. In conclusion, our findings provide evidence that c-Src-induced Kv4.3 channel activation involves their association in a macromolecular complex and suggest a role for c-Src-Kv4.3 pathway in regulating cardiac and neuronal excitability.

Mapping the Interaction Anatomy of BmP02 on Kv1.3 Channel

NASA Astrophysics Data System (ADS)

Wu, B.; Wu, B. F.; Feng, Y. J.; Tao, J.; Ji, Y. H.

2016-07-01

The potassium channel Kv 1.3 plays a vital part in the activation of T lymphocytes and is an attractive pharmacological target for autoimmune diseases. BmP02, a 28-residue peptide isolated from Chinese scorpion (Buthus martensi Karsch) venom, is a potent and selective Kv1.3 channel blocker. However, the mechanism through which BmP02 recognizes and inhibits the Kv1.3 channel is still unclear. In the present study, a complex molecular model of Kv1.3-BmP02 was developed by docking analysis and molecular dynamics simulations. From these simulations, it appears the large β-turn (residues 10-16) of BmP02 might be the binding interface with Kv 1.3. These results were confirmed by scanning alanine mutagenesis of BmP02, which identified His9, Lys11 and Lys13, which lie within BmP02’s β-turn, as key residues for interacting with Kv1.3. Based on these results and molecular modeling, two negatively charged residues of Kv1.3, D421 and D422, located in turret region, were predicted to act as the binding site for BmP02. Mutation of these residues reduced sensitivity of Kv 1.3 to BmP02 inhibition, suggesting that electrostatic interactions play a crucial role in Kv1.3-BmP02 interaction. This study revealed the molecular basis of Kv 1.3 recognition by BmP02 venom, and provides a novel interaction model for Kv channel-specific blocker complex, which may help guide future drug-design for Kv1.3-related channelopathies.

A basic residue in the proximal C-terminus is necessary for efficient activation of the M-channel subunit Kv7.2 by PI(4,5)P₂.

PubMed

Telezhkin, Vsevolod; Thomas, Alison M; Harmer, Stephen C; Tinker, Andrew; Brown, David A

2013-07-01

All Kv7 potassium channels require membrane phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) for their normal function and hence can be physiologically regulated by neurotransmitters and hormones that stimulate phosphoinositide hydrolysis. Recent mutational analysis indicates that a cluster of basic residues in the proximal C-terminus (K354/K358/R360/K362) is crucial for PI(4,5)P2 activation of cardiac Kv7.1 channels. Since this cluster is largely conserved in all Kv7 subunits, we tested whether homologous residues are also required for activation of Kv7.2 (a subunit of neuronal M-channels). We found that the mutation Kv7.2 (R325A) (corresponding to R360 in Kv7.1) reduced Kv7.2 current amplitude by ∼60 % (P < 0.02) without change in voltage sensitivity and reduced the sensitivity of Kv7.2 channels to dioctanoyl-phosphatidylinositol-4,5-bisphosphate by ∼eightfold (P < 0.001). Taking into account previous experiments (Zhang et al., Neuron 37:963-75, 2003) implicating Kv7.2 (H328), and since R325 and H328 are conserved in homologous positions in all other Kv7 channels, we suggest that this proximal C-terminal domain adjacent to the last transmembrane domain that contains R325 and H328 (in Kv7.2) might play a major role in the activation of all members of the Kv7 channel family by PI(4,5)P2.

The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization

PubMed Central

Yang, Ji Eun; Song, Min Seok; Shen, Yiming; Ryu, Pan Dong; Lee, So Yeong

2016-01-01

KCNQ (KV7) channels are voltage-gated potassium (KV) channels, and the function of KV7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of KV channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that KV7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional KV7 currents were detected in MG-63 cells. Inhibition of KV7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by alkaline phosphatase, osteocalcin, and osterix in MG-63 cells, whereas the expression of Runx2 showed no significant change. The extracellular glutamate secreted by osteoblasts was also measured to investigate its effect on MG-63 osteoblast differentiation. Blockade of KV7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated upregulation of synapsin, and induced the deposition of type 1 collagen. However, activation of KV7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that KV7.3 could be a novel regulator in osteoblast differentiation. PMID:26999128

The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization.

PubMed

Yang, Ji Eun; Song, Min Seok; Shen, Yiming; Ryu, Pan Dong; Lee, So Yeong

2016-03-18

KCNQ (KV7) channels are voltage-gated potassium (KV) channels, and the function of KV7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of KV channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that KV7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional KV7 currents were detected in MG-63 cells. Inhibition of KV7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by alkaline phosphatase, osteocalcin, and osterix in MG-63 cells, whereas the expression of Runx2 showed no significant change. The extracellular glutamate secreted by osteoblasts was also measured to investigate its effect on MG-63 osteoblast differentiation. Blockade of KV7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated upregulation of synapsin, and induced the deposition of type 1 collagen. However, activation of KV7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that KV7.3 could be a novel regulator in osteoblast differentiation.

The pan-Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo.

PubMed

Hansen, Henrik H; Weikop, Pia; Mikkelsen, Maria D; Rode, Frederik; Mikkelsen, Jens D

2017-01-01

Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.

PubMed

Jerng, Henry H; Kunjilwar, Kumud; Pfaffinger, Paul J

2005-11-01

Kv4 pore-forming subunits are the principal constituents of the voltage-gated K+ channel underlying somatodendritic subthreshold A-type currents (I(SA)) in neurones. Two structurally distinct types of Kv4 channel modulators, Kv channel-interacting proteins (KChIPs) and dipeptidyl-peptidase-like proteins (DPLs: DPP6 or DPPX, DPP10 or DPPY), enhance surface expression and modify functional properties. Since KChIP and DPL distributions overlap in the brain, we investigated the potential coassembly of Kv4.2, KChIP3 and DPL proteins, and the contribution of DPLs to ternary complex properties. Immunoprecipitation results show that KChIP3 and DPP10 associate simultaneously with Kv4.2 proteins in rat brain as well as heterologously expressing Xenopus oocytes, indicating Kv4.2 + KChIP3 + DPP10 multiprotein complexes. Consistent with ternary complex formation, coexpression of Kv4.2, KChIP3 and DPP10 in oocytes and CHO cells results in current waveforms distinct from the arithmetic sum of Kv4.2 + KChIP3 and Kv4.2 + DPP10 currents. Furthermore, the Kv4.2 + KChIP3 + DPP10 channels recover from inactivation very rapidly (tau(rec) approximately 18-26 ms), closely matching that of native I(SA) and significantly faster than the recovery of Kv4.2 + KChIP3 or Kv4.2 + DPP10 channels. For comparison, identical triple coexpression experiments were performed using DPP6 variants. While most results are similar, the Kv4.2 + KChIP3 + DPP6 channels exhibit inactivation that slows with increasing membrane potential, resulting in inactivation slower than that of Kv4.2 + KChIP3 + DPP10 channels at positive voltages. In conclusion, the native neuronal subthreshold A-type channel is probably a macromolecular complex formed from Kv4 and a combination of both KChIP and DPL proteins, with the precise composition of channel alpha and auxiliary subunits underlying tissue and regional variability in I(SA) properties.

Silencing of Kv4.1 potassium channels inhibits cell proliferation of tumorigenic human mammary epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jang, Soo Hwa; Choi, Changsun; Hong, Seong-Geun

2009-06-26

Potassium channel activity has been shown to facilitate cell proliferation in cancer cells. In the present study, the role of Kv4.1 channels in immortal and tumorigenic human mammary epithelial cells was investigated. Kv4.1 protein expression was positively correlated with tumorigenicity. Moreover, transfection with siRNAs targeting Kv4.1 mRNA suppressed proliferation of tumorigenic mammary epithelial cells. Experiments using mRNA isolated from human breast cancer tissues revealed that the level of Kv4.1 mRNA expression varied depending on the stage of the tumor. Kv4.1 protein expression increased during stages T2 and T3 compared to normal tissue. These results demonstrated that Kv4.1 plays a rolemore » in proliferation of tumorigenic human mammary epithelial cells. In addition, elevated Kv4.1 expression may be useful as a diagnostic marker for staging mammary tumors and selective blockers of Kv4.1 may serve to suppress tumor cell proliferation.« less

An MRI-Compatible High Frequency AC Resistive Heating System for Homeothermic Maintenance in Small Animals

PubMed Central

Gomes, Ana L.; Kinchesh, Paul; Kersemans, Veerle; Allen, Philip D.; Smart, Sean C.

2016-01-01

Purpose To develop an MRI-compatible resistive heater, using high frequency alternating current (AC), for temperature maintenance of anaesthetised animals. Materials and Methods An MRI-compatible resistive electrical heater was formed from narrow gauge wire connected to a high frequency (10–100 kHz) AC power source. Multiple gradient echo images covering a range of echo times, and pulse-acquire spectra were acquired with the wire heater powered using high frequency AC or DC power sources and without any current flowing in order to assess the sensitivity of the MRI acquisitions to the presence of current flow through the heater wire. The efficacy of temperature maintenance using the AC heater was assessed by measuring rectal temperature immediately following induction of general anaesthesia for a period of 30 minutes in three different mice. Results Images and spectra acquired in the presence and absence of 50–100 kHz AC through the wire heater were indistinguishable, whereas DC power created field shifts and lineshape distortions. Temperature lost during induction of anaesthesia was recovered within approximately 20 minutes and a stable temperature was reached as the mouse’s temperature approached the set target. Conclusion The AC-powered wire heater maintains adequate heat input to the animal to maintain body temperature, and does not compromise image quality. PMID:27806062

Fibrillar disruption by AC electric field induced oscillation: A case study with human serum albumin.

PubMed

Sen, Shubhatam; Chakraborty, Monojit; Goley, Snigdha; Dasgupta, Swagata; DasGupta, Sunando

2017-07-01

The effect of oscillation induced by a frequency-dependent alternating current (AC) electric field to dissociate preformed amyloid fibrils has been investigated. An electrowetting-on-dielectric type setup has been used to apply the AC field of varying frequencies on preformed fibrils of human serum albumin (HSA). The disintegration potency has been monitored by a combination of spectroscopic and microscopic techniques. The experimental results suggest that the frequency of the applied AC field plays a crucial role in the disruption of preformed HSA fibrils. The extent of stress generated inside the droplet due to the application of the AC field at different frequencies has been monitored as a function of the input frequency of the applied AC voltage. This has been accomplished by assessing the morphology deformation of the oscillating HSA fibril droplets. The shape deformation of the oscillating droplets is characterized using image analysis by measuring the dynamic changes in the shape dependent parameters such as contact angle and droplet footprint radius and the amplitude. It is suggested that the cumulative effects of the stress generated inside the HSA fibril droplets due to the shape deformation induced hydrodynamic flows and the torque induced by the intrinsic electric dipoles of protein due to their continuous periodic realignment in presence of the AC electric field results in the destruction of the fibrillar species. Copyright © 2017. Published by Elsevier B.V.

De Novo Design and Experimental Characterization of Ultrashort Self-Associating Peptides

PubMed Central

Xue, Bo; Robinson, Robert C.; Hauser, Charlotte A. E.; Floudas, Christodoulos A.

2014-01-01

Self-association is a common phenomenon in biology and one that can have positive and negative impacts, from the construction of the architectural cytoskeleton of cells to the formation of fibrils in amyloid diseases. Understanding the nature and mechanisms of self-association is important for modulating these systems and in creating biologically-inspired materials. Here, we present a two-stage de novo peptide design framework that can generate novel self-associating peptide systems. The first stage uses a simulated multimeric template structure as input into the optimization-based Sequence Selection to generate low potential energy sequences. The second stage is a computational validation procedure that calculates Fold Specificity and/or Approximate Association Affinity (K*association) based on metrics that we have devised for multimeric systems. This framework was applied to the design of self-associating tripeptides using the known self-associating tripeptide, Ac-IVD, as a structural template. Six computationally predicted tripeptides (Ac-LVE, Ac-YYD, Ac-LLE, Ac-YLD, Ac-MYD, Ac-VIE) were chosen for experimental validation in order to illustrate the self-association outcomes predicted by the three metrics. Self-association and electron microscopy studies revealed that Ac-LLE formed bead-like microstructures, Ac-LVE and Ac-YYD formed fibrillar aggregates, Ac-VIE and Ac-MYD formed hydrogels, and Ac-YLD crystallized under ambient conditions. An X-ray crystallographic study was carried out on a single crystal of Ac-YLD, which revealed that each molecule adopts a β-strand conformation that stack together to form parallel β-sheets. As an additional validation of the approach, the hydrogel-forming sequences of Ac-MYD and Ac-VIE were shuffled. The shuffled sequences were computationally predicted to have lower K*association values and were experimentally verified to not form hydrogels. This illustrates the robustness of the framework in predicting self-associating tripeptides. We expect that this enhanced multimeric de novo peptide design framework will find future application in creating novel self-associating peptides based on unnatural amino acids, and inhibitor peptides of detrimental self-aggregating biological proteins. PMID:25010703

Phorbol esters alter adenylate cyclase responses to vasoactive intestinal peptide and forskolin in the GH cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Summers, S.; Florio, T.; Cronin, M.

1986-05-01

Activation of protein kinase C with phorbol ester modifies cyclic AMP production in several anterior pituitary cell systems. In the GH cell line from a rat pituitary tumor, exposure to phorbol 12-myristate 13-acetate (PMA: 100 nM) for 30 minutes significantly reduces vasoactive intestinal peptide (VIP: 100 nM) stimulated adenylate cyclase (AC) activity in subsequent membrane preparations to 62 + 4% of control (n = 6 independent studies). In contrast, these same membrane preparations respond to forskolin (1 ..mu..M) with significantly more activity, 130 +/- 6% of controls (n = 6 independent studies). Finally, phorbol ester does not block an inhibitorymore » hormone input into the AC system; somatostatin (100 nM) reduction of VIP-stimulated AC activity is not significantly different in membrane preparations from PMA treated and control cells (n = 3 independent studies). These other findings lead the authors to propose that protein kinase C can modify several sites in the AC complex in anterior pituitary cells.« less

Inactivation of the cloned potassium channel mouse Kv1.1 by the human Kv3.4 'ball' peptide and its chemical modification.

PubMed Central

Stephens, G J; Robertson, B

1995-01-01

1. This study used the whole-cell patch clamp technique to investigate the action of a 28-mer 'inactivation peptide' based on part of the N-terminal sequence of the human Kv3.4 K+ channel (hKv3.4 peptide) on the cloned mouse brain K+ channel mKv1.1 expressed in Chinese hamster ovary (CHO) cells, and compared this with the inactivation produced by Shaker B inactivation peptide (ShB peptide). 2. Inclusion of the hKv3.4 peptide in the patch electrode (320 microM) transformed non-inactivating mKv1.1 into a rapidly inactivating current. The voltage dependence of time constants of decay and steady-state inactivation induced by hKv3.4 peptide were characteristic of an 'A-type' K+ current. 3. The hKv3.4 peptide had no effect on the voltage dependence of activation of mKv1.1, with a mid-point of activation of -8 mV, and a slope factor of 15 mV. Steady-state inactivation curves had a mid-point of inactivation of -36 mV and a slope factor of -7 mV; the time constant of recovery from inactivation at -90 mV was 1.3 s. 4. The chemical modification reagents N-bromoacetamide (NBA, 100 microM) and chloramine-T (CL-T, 500 microM) had no effect on the fast inactivation of mKv1.1 induced by ShB peptide. In contrast, the inactivation caused by hKv3.4 peptide was removed by brief exposure to NBA and CL-T. 5. Chemical modification resulted in a hyperpolarizing shift of -8 mV (CL-T) and -11 mV (NBA) in the voltage dependence of activation of mKv1.1 in the presence of hKv3.4 peptide. 6. Chemical modification was critically dependent on the presence of a cysteine residue at position 6, and not position 24, of hKv3.4 peptide. 7. NBA and CL-T caused only a slight inhibition of unmodified mKv1.1 current with no significant effect on the voltage dependence of mKv1.1 activation, and also had no effect on channel deactivation at -90 mV. 8. Chemical modification experiments were consistent with a selective action on the hKv3.4 peptide itself, specifically at the cysteine residue at position 6. PMID:7602512

Multivariate logistic regression for predicting total culturable virus presence at the intake of a potable-water treatment plant: novel application of the atypical coliform/total coliform ratio.

PubMed

Black, L E; Brion, G M; Freitas, S J

2007-06-01

Predicting the presence of enteric viruses in surface waters is a complex modeling problem. Multiple water quality parameters that indicate the presence of human fecal material, the load of fecal material, and the amount of time fecal material has been in the environment are needed. This paper presents the results of a multiyear study of raw-water quality at the inlet of a potable-water plant that related 17 physical, chemical, and biological indices to the presence of enteric viruses as indicated by cytopathic changes in cell cultures. It was found that several simple, multivariate logistic regression models that could reliably identify observations of the presence or absence of total culturable virus could be fitted. The best models developed combined a fecal age indicator (the atypical coliform [AC]/total coliform [TC] ratio), the detectable presence of a human-associated sterol (epicoprostanol) to indicate the fecal source, and one of several fecal load indicators (the levels of Giardia species cysts, coliform bacteria, and coprostanol). The best fit to the data was found when the AC/TC ratio, the presence of epicoprostanol, and the density of fecal coliform bacteria were input into a simple, multivariate logistic regression equation, resulting in 84.5% and 78.6% accuracies for the identification of the presence and absence of total culturable virus, respectively. The AC/TC ratio was the most influential input variable in all of the models generated, but producing the best prediction required additional input related to the fecal source and the fecal load. The potential for replacing microbial indicators of fecal load with levels of coprostanol was proposed and evaluated by multivariate logistic regression modeling for the presence and absence of virus.

Kv4.2 Knockout Mice Have Hippocampal-Dependent Learning and Memory Deficits

ERIC Educational Resources Information Center

Lugo, Joaquin N.; Brewster, Amy L.; Spencer, Corinne M.; Anderson, Anne E.

2012-01-01

Kv4.2 channels contribute to the transient, outward K[superscript +] current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit…

A Quantitative Analysis of Neurons with Kv3 Potassium Channel Subunits–Kv3.1b and Kv3.2–in Macaque Primary Visual Cortex

PubMed Central

Constantinople, Christine M.; Disney, Anita A; Maffie, Jonathan; Rudy, Bernardo; Hawken, Michael J

2010-01-01

Voltage-gated potassium channels that are composed of Kv3 subunits exhibit distinct electrophysiological properties: activation at more depolarized potentials than other voltage-gated K+ channels and fast kinetics. These channels have been shown to contribute to the high-frequency firing of fast-spiking (FS) GABAergic interneurons in the rat and mouse brain. In the rodent neocortex, there are distinct patterns of expression for the Kv3.1b and Kv3.2 channel subunits and of co-expression of these subunits with neurochemical markers, such as the calcium-binding proteins parvalbumin (PV) and calbindin D-28K (CB). The distribution of Kv3 channels and interrelationship with calcium-binding protein expression has not been investigated in primate cortex. We used immunoperoxidase and immunofluorescent labeling and stereological counting techniques to characterize the laminar and cell-type distributions of Kv3-ir neurons in macaque V1. We found that across the cortical layers ~25% of both Kv3.1b- and Kv3.2-ir neurons are non-GABAergic. In contrast all Kv3-ir neurons in rodent cortex are GABAergic (Chow et al., 1999). The putatively excitatory Kv3-ir neurons were mostly located in layers 2, 3 and 4b. Further, the proportion of Kv3-ir neurons that express PV or CB also differs between macaque V1 and rodent cortex. These data indicate that, within the population of cortical neurons, a broader population of neurons, encompassing cells of a wider range of morphological classes may be capable of sustaining high-frequency firing in macaque V1. PMID:19634181

The role of PSD-95 in the rearrangement of Kv1.3 channels to the immunological synapse.

PubMed

Szilágyi, Orsolya; Boratkó, Anita; Panyi, György; Hajdu, Péter

2013-09-01

Establishment of the immunological synapse (IS) between T lymphocytes and antigen-presenting cells is a key step in the adaptive immune response. Several proteins accumulate in the IS, such as the Kv1.3 potassium channel; however, the mechanism of this translocation is unknown. PSD-95 and SAP97 are adaptor proteins that regulate the polarized cell surface expression and localization of Kv1 channels in neurons. We investigated whether these proteins affect the redistribution of Kv1.3 into the IS in non-excitable human T cells. We show here that PSD-95 and SAP97 are expressed in Jurkat and interact with the C terminus of Kv1.3. Disruption of the interaction between PSD-95 or SAP97 and Kv1.3 in Jurkat was realized by the expression of a C-terminal truncated Kv1.3, which lacks the binding domain for these proteins, or by the knockdown of the expression of PSD-95 or SAP97 using specific shRNA. Expression of the truncated Kv1.3 or knockdown of PSD-95, but not the knockdown of SAP97, inhibited the recruitment of Kv1.3 into the IS; the fraction of cells showing polarized Kv1.3 expression upon engagement in an IS was significantly lower than in control cells expressing the full-length Kv1.3, and the rearrangement of Kv1.3 did not show time dependence. In contrast, Jurkat cells expressing the full-length channel showed marked time dependence in the recruitment into the IS peaking at 1 min after the conjugation of the cells. These results demonstrate that PSD-95 participates in the targeting of Kv1.3 into the IS, implying its important role in human T-cell activation.

K+ channels expression in hypertension after arterial injury, and effect of selective Kv1.3 blockade with PAP-1 on intimal hyperplasia formation.

PubMed

Cidad, P; Novensà, L; Garabito, M; Batlle, M; Dantas, A P; Heras, M; López-López, J R; Pérez-García, M T; Roqué, M

2014-12-01

K(+) channels are central to vascular pathophysiology. Previous results demonstrated that phenotypic modulation associates with a change in Kv1.3 to Kv1.5 expression, and that Kv1.3 blockade inhibits proliferation of VSMCs cultures. To explore whether the Kv1.3 to Kv1.5 switch could be a marker of the increased risk of intimal hyperplasia in essential hypertension and whether systemic treatment with Kv1.3 blockers can prevent intimal hyperplasia after endoluminal lesion . Morphometric and immunohistochemical analysis were performed in arterial segments following arterial injury and constant infusion of the Kv1.3 blocker PAP-1 during 28 days. Differential expression of K(+) channel genes was studied in VSMC from hypertensive (BPH) and normotensive (BPN) mice, both in control and after endoluminal lesion. Finally, the migration and proliferation rate of BPN and BPH VSMCs was explored in vitro. Changes in mRNA expression led to an increased Kv1.3/Kv1.5 ratio in BPH VSMC. Consistent with this, arterial injury in BPH mice induced a higher degree of luminal stenosis, (84 ± 4% vs. 70 ± 5% in BPN, p < 0.01), although no differences in migration and proliferation rate were observed in cultured VSMCs. The in vivo proliferative lesions were significantly decreased upon PAP-1 systemic infusion (18 ± 6% vs. 58 ± 20% with vehicle, p < 0.05). Hypertension leads to a higher degree of luminal stenosis in our arterial injury model, that correlates with a decreased expression of Kv1.5 channels. Kv1.3 blockers decreased in vitro VSMCs proliferation, migration, and in vivo intimal hyperplasia formation, pointing to Kv1.3 channels as promising therapeutical targets against restenosis.

Elimination of fast inactivation in Kv4 A-type potassium channels by an auxiliary subunit domain.

PubMed

Holmqvist, Mats H; Cao, Jie; Hernandez-Pineda, Ricardo; Jacobson, Michael D; Carroll, Karen I; Sung, M Amy; Betty, Maria; Ge, Pei; Gilbride, Kevin J; Brown, Melissa E; Jurman, Mark E; Lawson, Deborah; Silos-Santiago, Inmaculada; Xie, Yu; Covarrubias, Manuel; Rhodes, Kenneth J; Distefano, Peter S; An, W Frank

2002-01-22

The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a). Coexpression of KChIP4a with Kv4 alpha-subunits abolishes fast inactivation of the Kv4 currents in various cell types, including cerebellar granule neurons. Kinetic analysis shows that the KIS domain delays Kv4.3 opening, but once the channel is open, it disrupts rapid inactivation and slows Kv4.3 closing. Accordingly, KChIP4a increases the open probability of single Kv4.3 channels. The net effects of KChIP4a and KChIP1-3 on Kv4 gating are quite different. When both KChIP4a and KChIP1 are present, the Kv4.3 current shows mixed inactivation profiles dependent on KChIP4a/KChIP1 ratios. The KIS domain effectively converts the A-type Kv4 current to a slowly inactivating delayed rectifier-type potassium current. This conversion is opposite to that mediated by the Kv1-specific "ball" domain of the Kv beta 1 subunit. Together, these results demonstrate that specific auxiliary subunits with distinct functions actively modulate gating of potassium channels that govern membrane excitability.

Roles of specific Kv channel types in repolarization of the action potential in genetically identified subclasses of pyramidal neurons in mouse neocortex

PubMed Central

Pathak, Dhruba; Guan, Dongxu

2016-01-01

The action potential (AP) is a fundamental feature of excitable cells that serves as the basis for long-distance signaling in the nervous system. There is considerable diversity in the appearance of APs and the underlying repolarization mechanisms in different neuronal types (reviewed in Bean BP. Nat Rev Neurosci 8: 451–465, 2007), including among pyramidal cell subtypes. In the present work, we used specific pharmacological blockers to test for contributions of Kv1, Kv2, or Kv4 channels to repolarization of single APs in two genetically defined subpopulations of pyramidal cells in layer 5 of mouse somatosensory cortex (etv1 and glt) as well as pyramidal cells from layer 2/3. These three subtypes differ in AP properties (Groh A, Meyer HS, Schmidt EF, Heintz N, Sakmann B, Krieger P. Cereb Cortex 20: 826–836, 2010; Guan D, Armstrong WE, Foehring RC. J Neurophysiol 113: 2014–2032, 2015) as well as laminar position, morphology, and projection targets. We asked what the roles of Kv1, Kv2, and Kv4 channels are in AP repolarization and whether the underlying mechanisms are pyramidal cell subtype dependent. We found that Kv4 channels are critically involved in repolarizing neocortical pyramidal cells. There are also pyramidal cell subtype-specific differences in the role for Kv1 channels. Only Kv4 channels were involved in repolarizing the narrow APs of glt cells. In contrast, in etv1 cells and layer 2/3 cells, the broader APs are partially repolarized by Kv1 channels in addition to Kv4 channels. Consistent with their activation in the subthreshold range, Kv1 channels also regulate AP voltage threshold in all pyramidal cell subtypes. PMID:26864770

Operating experience of the southwire high-temperature superconducting cable project

NASA Astrophysics Data System (ADS)

Hughey, R. L.; Lindsay, D.

2002-01-01

Southwire Company of Carrollton, Georgia in cooperation with Oak Ridge National Laboratory has designed, built, installed and is operating the world's first field installation of a High Temperature Superconducting (HTS) cable system. The cables supply power to three Southwire manufacturing facilities and part of the corporate headquarters building in Carrollton, GA. The system consists of three 30-m single phase cables rated at 12.4 kV, 1250 Amps, liquid nitrogen cooling system, and the computer-based control system. The cables are built using BSCCO-2223 powder-in-tube HTS tapes and a proprietary cryogenic dielectric material called Cryoflex™. The cables are fully shielded with a second layer of HTS tapes to eliminate any external magnetic fields. The Southwire HTS cables were first energized on january 6, 2000. Since that time they have logged over 8,500 hours of operation while supplying 100% of the required customer load. To date, the cables have worked without failure and operations are continuing. The cable design has passed requisite testing for this class of conventional cables including 10× over current to 12,500 Amps and BIL testing to 110 kV. Southwire has also successfully designed and tested a cable splice. System heat loads and AC Losses have been measured and compared to calculated values. On June 1, 2001 on-site monitoring was ceased and the system was changed to unattended operation to further prove the reliability of the HTS cable system. .

Potential environmental effects of 765-kV transmission lines: views before the New York State Public Service Commission, Cases 26529 and 26559, 1976-1978

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott-Walton, B.; Clark, K. M.; Holt, B. R.

1979-11-01

Testimony given before the New York Public Service Commission in two recent cases on the potential environmental effects of 765-kV overhead ac transmission lines is reviewed. The testimony focused on the potential effects of audible noise, on the potential biological effects of the electromagnetic fields, on the potential for electric shocks to people who touch vehicles parked under the proposed lines, on the potential effects of the electromagnetic fields on electronic cardiac pacemakers, and on potential effects of ozone produced by corona discharge from the lines. The testimony fully explored these questions; however, it did not resolve all of them.more » The testimony indicates potential impacts from the audible noise and from the electrostatic shocks that people can receive when they touch a large vehicle parked under the lines. The testimony also indicates that certain cardiac pacemaker and lead combinations may, under certain circumstances, undergo reversion to a fixed rate of pacing in the presence of the fields under the lines, but that little risk to cardiac patients results except possibly for those patients for whom competition between the heart's own rate and the pacemaker rate presents a health risk. The testimony fails to demonstrate biological hazards from the field; further research is necessary to understand better the effects of the fields on biological systems. The testimony indicates that ozone produced by the lines will not significantly affect the environment.« less

Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking.

PubMed

Andersen, Martin N; Hefting, Louise L; Steffensen, Annette B; Schmitt, Nicole; Olesen, Søren-Peter; Olsen, Jesper V; Lundby, Alicia; Rasmussen, Hanne B

2015-11-15

The potassium channel Kv7.1 plays critical physiological roles in both heart and epithelial tissues. In heart, Kv7.1 and the accessory subunit KCNE1 forms the slowly activating delayed-rectifier potassium current current, which is enhanced by protein kinase A (PKA)-mediated phosphorylation. The observed current increase requires both phosphorylation of Kv7.1 and the presence of KCNE1. However, PKA also stimulates Kv7.1 currents in epithelial tissues, such as colon, where the channel does not coassemble with KCNE1. Here, we demonstrate that PKA activity significantly impacts the subcellular localization of Kv7.1 in Madin-Darby canine kidney cells. While PKA inhibition reduced the fraction of channels at the cell surface, PKA activation increased it. We show that PKA inhibition led to intracellular accumulation of Kv7.1 in late endosomes/lysosomes. By mass spectroscopy we identified eight phosphorylated residues on Kv7.1, however, none appeared to play a role in the observed response. Instead, we found that PKA acted by regulating endocytic trafficking involving the ubiquitin ligase Nedd4-2. We show that a Nedd4-2-resistant Kv7.1-mutant displayed significantly reduced intracellular accumulation upon PKA inhibition. Similar effects were observed upon siRNA knockdown of Nedd4-2. However, although Nedd4-2 is known to regulate Kv7.1 by ubiquitylation, biochemical analyses demonstrated that PKA did not influence the amount of Nedd4-2 bound to Kv7.1 or the ubiquitylation level of the channel. This suggests that PKA influences Nedd4-2-dependent Kv7.1 transport though a different molecular mechanism. In summary, we identify a novel mechanism whereby PKA can increase Kv7.1 current levels, namely by regulating Nedd4-2-dependent Kv7.1 transport. Copyright © 2015 the American Physiological Society.

Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking

PubMed Central

Andersen, Martin N.; Hefting, Louise L.; Steffensen, Annette B.; Schmitt, Nicole; Olesen, Søren-Peter; Olsen, Jesper V.; Lundby, Alicia

2015-01-01

The potassium channel Kv7.1 plays critical physiological roles in both heart and epithelial tissues. In heart, Kv7.1 and the accessory subunit KCNE1 forms the slowly activating delayed-rectifier potassium current current, which is enhanced by protein kinase A (PKA)-mediated phosphorylation. The observed current increase requires both phosphorylation of Kv7.1 and the presence of KCNE1. However, PKA also stimulates Kv7.1 currents in epithelial tissues, such as colon, where the channel does not coassemble with KCNE1. Here, we demonstrate that PKA activity significantly impacts the subcellular localization of Kv7.1 in Madin-Darby canine kidney cells. While PKA inhibition reduced the fraction of channels at the cell surface, PKA activation increased it. We show that PKA inhibition led to intracellular accumulation of Kv7.1 in late endosomes/lysosomes. By mass spectroscopy we identified eight phosphorylated residues on Kv7.1, however, none appeared to play a role in the observed response. Instead, we found that PKA acted by regulating endocytic trafficking involving the ubiquitin ligase Nedd4-2. We show that a Nedd4-2-resistant Kv7.1-mutant displayed significantly reduced intracellular accumulation upon PKA inhibition. Similar effects were observed upon siRNA knockdown of Nedd4-2. However, although Nedd4-2 is known to regulate Kv7.1 by ubiquitylation, biochemical analyses demonstrated that PKA did not influence the amount of Nedd4-2 bound to Kv7.1 or the ubiquitylation level of the channel. This suggests that PKA influences Nedd4-2-dependent Kv7.1 transport though a different molecular mechanism. In summary, we identify a novel mechanism whereby PKA can increase Kv7.1 current levels, namely by regulating Nedd4-2-dependent Kv7.1 transport. PMID:26405101

Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels.

PubMed

Fineberg, Jeffrey D; Ritter, David M; Covarrubias, Manuel

2012-11-01

A-type voltage-gated K(+) (Kv) channels self-regulate their activity by inactivating directly from the open state (open-state inactivation [OSI]) or by inactivating before they open (closed-state inactivation [CSI]). To determine the inactivation pathways, it is often necessary to apply several pulse protocols, pore blockers, single-channel recording, and kinetic modeling. However, intrinsic hurdles may preclude the standardized application of these methods. Here, we implemented a simple method inspired by earlier studies of Na(+) channels to analyze macroscopic inactivation and conclusively deduce the pathways of inactivation of recombinant and native A-type Kv channels. We investigated two distinct A-type Kv channels expressed heterologously (Kv3.4 and Kv4.2 with accessory subunits) and their native counterparts in dorsal root ganglion and cerebellar granule neurons. This approach applies two conventional pulse protocols to examine inactivation induced by (a) a simple step (single-pulse inactivation) and (b) a conditioning step (double-pulse inactivation). Consistent with OSI, the rate of Kv3.4 inactivation (i.e., the negative first derivative of double-pulse inactivation) precisely superimposes on the profile of the Kv3.4 current evoked by a single pulse because the channels must open to inactivate. In contrast, the rate of Kv4.2 inactivation is asynchronous, already changing at earlier times relative to the profile of the Kv4.2 current evoked by a single pulse. Thus, Kv4.2 inactivation occurs uncoupled from channel opening, indicating CSI. Furthermore, the inactivation time constant versus voltage relation of Kv3.4 decreases monotonically with depolarization and levels off, whereas that of Kv4.2 exhibits a J-shape profile. We also manipulated the inactivation phenotype by changing the subunit composition and show how CSI and CSI combined with OSI might affect spiking properties in a full computational model of the hippocampal CA1 neuron. This work unambiguously elucidates contrasting inactivation pathways in neuronal A-type Kv channels and demonstrates how distinct pathways might impact neurophysiological activity.

Ternary Kv4.2 channels recapitulate voltage-dependent inactivation kinetics of A-type K+ channels in cerebellar granule neurons.

PubMed

Amarillo, Yimy; De Santiago-Castillo, Jose A; Dougherty, Kevin; Maffie, Jonathon; Kwon, Elaine; Covarrubias, Manuel; Rudy, Bernardo

2008-04-15

Kv4 channels mediate most of the somatodendritic subthreshold operating A-type current (I(SA)) in neurons. This current plays essential roles in the regulation of spike timing, repetitive firing, dendritic integration and plasticity. Neuronal Kv4 channels are thought to be ternary complexes of Kv4 pore-forming subunits and two types of accessory proteins, Kv channel interacting proteins (KChIPs) and the dipeptidyl-peptidase-like proteins (DPPLs) DPPX (DPP6) and DPP10. In heterologous cells, ternary Kv4 channels exhibit inactivation that slows down with increasing depolarization. Here, we compared the voltage dependence of the inactivation rate of channels expressed in heterologous mammalian cells by Kv4.2 proteins with that of channels containing Kv4.2 and KChIP1, Kv4.2 and DPPX-S, or Kv4.2, KChIP1 and DPPX-S, and found that the relation between inactivation rate and membrane potential is distinct for these four conditions. Moreover, recordings from native neurons showed that the inactivation kinetics of the I(SA) in cerebellar granule neurons has voltage dependence that is remarkably similar to that of ternary Kv4 channels containing KChIP1 and DPPX-S proteins in heterologous cells. The fact that this complex and unique behaviour (among A-type K(+) currents) is observed in both the native current and the current expressed in heterologous cells by the ternary complex containing Kv4, DPPX and KChIP proteins supports the hypothesis that somatically recorded native Kv4 channels in neurons include both types of accessory protein. Furthermore, quantitative global kinetic modelling showed that preferential closed-state inactivation and a weakly voltage-dependent opening step can explain the slowing of the inactivation rate with increasing depolarization. Therefore, it is likely that preferential closed-state inactivation is the physiological mechanism that regulates the activity of both ternary Kv4 channel complexes and native I(SA)-mediating channels.

[Modulation of Kv4 channels by KChIPs clamping].

PubMed

Cui, Yuan-Yuan; Wang, Ke-Wei

2009-01-01

The rapidly inactivating (A-type) potassium channels regulate membrane excitability that defines the fundamental mechanism of neuronal functions such as pain signaling. Cytosolic Kv channel-interacting proteins KChIPs co-assemble with Kv4 (Shal) alpha subunits to form a native complex. The specific binding of auxiliary KChIPs to the Kv4 N-terminus results in modulation of gating properties, surface expression and subunit assembly of Kv4 channels. Based on recent structural efforts, here we attempt to emphasize the interaction between KChIPs and Kv4 channel complex in which a single KChIP1 molecule laterally clamps two neighboring Kv4.3 N-termini in a 4:4 manner. Greater insights into molecular mechanism between KChIPs and Kv4 interaction may provide therapeutic potentials by structure-based design of chemical compounds aimed at disrupting the protein-protein interaction for treatment of membrane excitability-related disorders.

Redundant operation of counter modules

NASA Technical Reports Server (NTRS)

Nagano, S. (Inventor)

1980-01-01

A technique for the redundant operation of counter modules is described. Redundant operation is maintained by detecting the zero state of each counter and clearing the other to that state, thus periodically resynchronizing the counters, and obtaining an output from both counters through AC coupled diode-OR gates. Redundant operation of counter flip flops is maintained in a similar manner, and synchronous operation of redundant squarewave clock generators of the feedback type is effected by connecting together the feedback inputs of the squarewave generators through a coupling resistor, and obtaining an output from both generators through AC coupled diode-OR gates.

miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries.

PubMed

Mondejar-Parreño, Gema; Callejo, María; Barreira, Bianca; Morales-Cano, Daniel; Esquivel-Ruiz, Sergio; Moreno, Laura; Cogolludo, Angel; Perez-Vizcaino, Francisco

2018-05-02

■The expression of miR-1 is increased in lungs from the Hyp/Su5416 PAH rat model. ■PASMC from this animal model are more depolarised and show decreased expression and activity of Kv1.5. ■miR-1 directly targets Kv1.5 channels, reduces Kv1.5 activity and induces membrane depolarization. ■Antagomir-1 prevents Kv1.5 channel downregulation and the depolarization induced by hypoxia/Su5416 exposition. Impairment of voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to the 3'-UTR region of specific mRNAs. The aim of this study was to analyze the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of patch-clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells (PASMCs). Luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O 2 ) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces PASMC hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Visualizing Mutation-Specific Differences in the Trafficking-Deficient Phenotype of Kv11.1 Proteins Linked to Long QT Syndrome Type 2.

PubMed

Hall, Allison R; Anderson, Corey L; Smith, Jennifer L; Mirshahi, Tooraj; Elayi, Claude S; January, Craig T; Delisle, Brian P

2018-01-01

KCNH2 encodes the Kv11.1 α-subunit that underlies the rapidly activating delayed-rectifier K + current in the heart. Loss-of-function KCNH2 mutations cause long QT syndrome type 2 (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channel protein to the cell surface membrane. Several trafficking-deficient LQT2 mutations (e.g., G601S) generate Kv11.1 proteins that are sequestered in a microtubule-dependent quality control (QC) compartment in the transitional endoplasmic reticulum (ER). We tested the hypothesis that the QC mechanisms that regulate LQT2-linked Kv11.1 protein trafficking are mutation-specific. Confocal imaging analyses of HEK293 cells stably expressing the trafficking-deficient LQT2 mutation F805C showed that, unlike G601S-Kv11.1 protein, F805C-Kv11.1 protein was concentrated in several transitional ER subcompartments. The microtubule depolymerizing drug nocodazole differentially affected G601S- and F805C-Kv11.1 protein immunostaining. Nocodazole caused G601S-Kv11.1 protein to distribute into peripheral reticular structures, and it increased the diffuse immunostaining of F805C-Kv11.1 protein around the transitional ER subcompartments. Proteasome inhibition also affected the immunostaining of G601S- and F805C-Kv11.1 protein differently. Incubating cells in MG132 minimally impacted G601S-Kv11.1 immunostaining, but it dramatically increased the diffuse immunostaining of F805C-Kv11.1 protein in the transitional ER. Similar results were seen after incubating cells in the proteasome inhibitor lactacystin. Differences in the cellular distribution of G601S-Kv11.1 and F805C-Kv11.1 protein persisted in transfected human inducible pluripotent stem cell derived cardiomyocytes. These are the first data to visually demonstrate mutation-specific differences in the trafficking-deficient LQT2 phenotype, and this study has identified a novel way to categorize trafficking-deficient LQT2 mutations based on differences in intracellular retention.

Epilepsy-causing mutations in Kv7.2 C-terminus affect binding and functional modulation by calmodulin.

PubMed

Ambrosino, Paolo; Alaimo, Alessandro; Bartollino, Silvia; Manocchio, Laura; De Maria, Michela; Mosca, Ilaria; Gomis-Perez, Carolina; Alberdi, Araitz; Scambia, Giovanni; Lesca, Gaetan; Villarroel, Alvaro; Taglialatela, Maurizio; Soldovieri, Maria Virginia

2015-09-01

Mutations in the KCNQ2 gene, encoding for voltage-gated Kv7.2K(+) channel subunits, are responsible for early-onset epileptic diseases with widely-diverging phenotypic presentation, ranging from Benign Familial Neonatal Seizures (BFNS) to epileptic encephalopathy. In the present study, Kv7.2 BFNS-causing mutations (W344R, L351F, L351V, Y362C, and R553Q) have been investigated for their ability to interfere with calmodulin (CaM) binding and CaM-induced channel regulation. To this aim, semi-quantitative (Far-Western blotting) and quantitative (Surface Plasmon Resonance and dansylated CaM fluorescence) biochemical assays have been performed to investigate the interaction of CaM with wild-type or mutant Kv7.2 C-terminal fragments encompassing the CaM-binding domain; in parallel, mutation-induced changes in CaM-dependent Kv7.2 or Kv7.2/Kv7.3 current regulation were investigated by patch-clamp recordings in Chinese Hamster Ovary (CHO) cells co-expressing Kv7.2 or Kv7.2/Kv7.3 channels and CaM or CaM1234 (a CaM isoform unable to bind Ca(2+)). The results obtained suggest that each BFNS-causing mutation prompts specific biochemical and/or functional consequences; these range from slight alterations in CaM affinity which did not translate into functional changes (L351V), to a significant reduction in the affinity and functional modulation by CaM (L351F, Y362C or R553Q), to a complete functional loss without significant alteration in CaM affinity (W344R). CaM overexpression increased Kv7.2 and Kv7.2/Kv7.3 current levels, and partially (R553Q) or fully (L351F) restored normal channel function, providing a rationale pathogenetic mechanism for mutation-induced channel dysfunction in BFNS, and highlighting the potentiation of CaM-dependent Kv7.2 modulation as a potential therapeutic approach for Kv7.2-related epilepsies. Copyright © 2015 Elsevier B.V. All rights reserved.

Application of Filters for High-Altitude Electromagnetic Pulse Protection

DTIC Science & Technology

1981-04-01

The application of filters for the protection of electrical equipment from electrical transient signals induced by high-altitude electromagnetic ... pulse (HEMP) is discussed, and the application of filters to ac and dc power supplies and analog and digital signal inputs is described. The application

Quantization-Based Adaptive Actor-Critic Tracking Control With Tracking Error Constraints.

PubMed

Fan, Quan-Yong; Yang, Guang-Hong; Ye, Dan

2018-04-01

In this paper, the problem of adaptive actor-critic (AC) tracking control is investigated for a class of continuous-time nonlinear systems with unknown nonlinearities and quantized inputs. Different from the existing results based on reinforcement learning, the tracking error constraints are considered and new critic functions are constructed to improve the performance further. To ensure that the tracking errors keep within the predefined time-varying boundaries, a tracking error transformation technique is used to constitute an augmented error system. Specific critic functions, rather than the long-term cost function, are introduced to supervise the tracking performance and tune the weights of the AC neural networks (NNs). A novel adaptive controller with a special structure is designed to reduce the effect of the NN reconstruction errors, input quantization, and disturbances. Based on the Lyapunov stability theory, the boundedness of the closed-loop signals and the desired tracking performance can be guaranteed. Finally, simulations on two connected inverted pendulums are given to illustrate the effectiveness of the proposed method.

An isolated bridgeless AC-DC PFC converter using a LC resonant voltage doubler rectifier

NASA Astrophysics Data System (ADS)

Lee, Sin-woo; Do, Hyun-Lark

2016-12-01

This paper proposed an isolated bridgeless AC-DC power factor correction (PFC) converter using a LC resonant voltage doubler rectifier. The proposed converter is based on isolated conventional single-ended primary inductance converter (SEPIC) PFC converter. The conduction loss of rectification is reduced than a conventional one because the proposed converter is designed to eliminate a full-bridge rectifier at an input stage. Moreover, for zero-current switching (ZCS) operation and low voltage stresses of output diodes, the secondary of the proposed converter is designed as voltage doubler with a LC resonant tank. Additionally, an input-output electrical isolation is provided for safety standard. In conclusion, high power factor is achieved and efficiency is improved. The operational principles, steady-state analysis and design equations of the proposed converter are described in detail. Experimental results from a 60 W prototype at a constant switching frequency 100 kHz are presented to verify the performance of the proposed converter.

Acoustic Emission Characteristics of Nanocrystalline Porous Silicon Device Driven as an Ultrasonic Speaker

NASA Astrophysics Data System (ADS)

Tsubaki, Kenji; Komoda, Takuya; Koshida, Nobuyoshi

2006-04-01

It is shown that the dc-superimposed driving mode is more useful for the efficient operation of a novel thermally induced ultrasonic emitter based on nanocrystalline porous silicon (nc-PS) than the conventional simple ac-voltage driving mode. The nc-PS device is composed of a patterned heater electrode, an nc-PS layer and a single crystalline silicon (c-Si) substrate. The almost complete thermally insulating property of nc-PS as a quantum-sized system makes it possible to apply the nc-PS device as an ultrasonic generator by efficient thermo acoustic conversion without any mechanical vibrations. In the dc-superimposed driving mode, the output frequency is the same as the input frequency and a stationary temperature rise is kept constant independent of input peak-to-peak voltage. In addition, power efficiency is significantly increases compared with that in the ac-voltage driving mode without affecting on the temperature rise. The present results suggest the further possibility of the nc-PS device being used as a functional speaker.

Lower-Order Compensation Chain Threshold-Reduction Technique for Multi-Stage Voltage Multipliers.

PubMed

Dell' Anna, Francesco; Dong, Tao; Li, Ping; Wen, Yumei; Azadmehr, Mehdi; Casu, Mario; Berg, Yngvar

2018-04-17

This paper presents a novel threshold-compensation technique for multi-stage voltage multipliers employed in low power applications such as passive and autonomous wireless sensing nodes (WSNs) powered by energy harvesters. The proposed threshold-reduction technique enables a topological design methodology which, through an optimum control of the trade-off among transistor conductivity and leakage losses, is aimed at maximizing the voltage conversion efficiency (VCE) for a given ac input signal and physical chip area occupation. The conducted simulations positively assert the validity of the proposed design methodology, emphasizing the exploitable design space yielded by the transistor connection scheme in the voltage multiplier chain. An experimental validation and comparison of threshold-compensation techniques was performed, adopting 2N5247 N-channel junction field effect transistors (JFETs) for the realization of the voltage multiplier prototypes. The attained measurements clearly support the effectiveness of the proposed threshold-reduction approach, which can significantly reduce the chip area occupation for a given target output performance and ac input signal.

Study of switching transients in high frequency converters

NASA Technical Reports Server (NTRS)

Zinger, Donald S.; Elbuluk, Malik E.; Lee, Tony

1993-01-01

As the semiconductor technologies progress rapidly, the power densities and switching frequencies of many power devices are improved. With the existing technology, high frequency power systems become possible. Use of such a system is advantageous in many aspects. A high frequency ac source is used as the direct input to an ac/ac pulse-density-modulation (PDM) converter. This converter is a new concept which employs zero voltage switching techniques. However, the development of this converter is still in its infancy stage. There are problems associated with this converter such as a high on-voltage drop, switching transients, and zero-crossing detecting. Considering these problems, the switching speed and power handling capabilities of the MOS-Controlled Thyristor (MCT) makes the device the most promising candidate for this application. A complete insight of component considerations for building an ac/ac PDM converter for a high frequency power system is addressed. A power device review is first presented. The ac/ac PDM converter requires switches that can conduct bi-directional current and block bi-directional voltage. These bi-directional switches can be constructed using existing power devices. Different bi-directional switches for the converter are investigated. Detailed experimental studies of the characteristics of the MCT under hard switching and zero-voltage switching are also presented. One disadvantage of an ac/ac converter is that turn-on and turn-off of the switches has to be completed instantaneously when the ac source is at zero voltage. Otherwise shoot-through current or voltage spikes can occur which can be hazardous to the devices. In order for the devices to switch softly in the safe operating area even under non-ideal cases, a unique snubber circuit is used in each bi-directional switch. Detailed theory and experimental results for circuits using these snubbers are presented. A current regulated ac/ac PDM converter built using MCT's and IGBT's is evaluated.

Ambient-Temperature Trap/Release of Arsenic by Dielectric Barrier Discharge and Its Application to Ultratrace Arsenic Determination in Surface Water Followed by Atomic Fluorescence Spectrometry.

PubMed

Mao, Xuefei; Qi, Yuehan; Huang, Junwei; Liu, Jixin; Chen, Guoying; Na, Xing; Wang, Min; Qian, Yongzhong

2016-04-05

A novel dielectric barrier discharge reactor (DBDR) was utilized to trap/release arsenic coupled to hydride generation atomic fluorescence spectrometry (HG-AFS). On the DBD principle, the precise and accurate control of trap/release procedures was fulfilled at ambient temperature, and an analytical method was established for ultratrace arsenic in real samples. Moreover, the effects of voltage, oxygen, hydrogen, and water vapor on trapping and releasing arsenic by DBDR were investigated. For trapping, arsenic could be completely trapped in DBDR at 40 mL/min of O2 input mixed with 600 mL/min Ar carrier gas and 9.2 kV discharge potential; prior to release, the Ar carrier gas input should be changed from the upstream gas liquid separator (GLS) to the downstream GLS and kept for 180 s to eliminate possible water vapor interference; for arsenic release, O2 was replaced by 200 mL/min H2 and discharge potential was adjusted to 9.5 kV. Under optimized conditions, arsenic could be detected as low as 1.0 ng/L with an 8-fold enrichment factor; the linearity of calibration reached R(2) > 0.995 in the 0.05 μg/L-5 μg/L range. The mean spiked recoveries for tap, river, lake, and seawater samples were 98% to 103%; and the measured values of the CRMs including GSB-Z50004-200431, GBW08605, and GBW(E)080390 were in good agreement with the certified values. These findings proved the feasibility of DBDR as an arsenic preconcentration tool for atomic spectrometric instrumentation and arsenic recycling in industrial waste gas discharge.

Characteristics of a KA-band third-harmonic peniotron driven by a high-quality linear axis-encircling electron beam

NASA Astrophysics Data System (ADS)

Zhao, Xiaoyun; Tuo, Xianguo; Ge, Qing; Peng, Ying

2017-12-01

We employ a high-quality linear axis-encircling electron beam generated by a Cuccia coupler to drive a Ka-band third-harmonic peniotron and develop a self-consistent nonlinear calculation code to numerically analyze the characteristics of the designed peniotron. It is demonstrated that through a Cuccia coupler, a 6 kV, 0.5 A pencil beam and an input microwave power of 16 kW at 10 GHz can generate a 37 kV, 0.5 A linear axis-encircling beam, and it is characterized by a very low velocity spread. Moreover, the electron beam guiding center deviation can be adjusted easily. Driven by such a beam, a 30 GHz, Ka-band third-harmonic peniotron is predicted to achieve a conversion efficiency of 51.0% and a microwave output power of 9.44 kW; the results are in good agreement with the Magic3D simulation. Using this code, we studied the factors influencing the peniotron performance, and it can provide some guidelines for the design of a Ka-band third-harmonic peniotron driven by a linear electron beam and can promote the application of high-harmonic peniotrons in practice.

Low Beam Voltage, 10 MW, L-Band Cluster Klystron

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teryaev, V.; /Novosibirsk, IYF; Yakovlev, V.P.

2009-05-01

Conceptual design of a multi-beam klystron (MBK) for possible ILC and Project X applications is presented. The chief distinction between this MBK design and existing 10-MW MBK's is the low operating voltage of 60 kV. There are at least four compelling reasons that justify development at this time of a low-voltage MBK, namely (1) no pulse transformer; (2) no oil tank for high-voltage components and for the tube socket; (3) no high-voltage cables; and (4) modulator would be a compact 60-kV IGBT switching circuit. The proposed klystron consists of four clusters containing six beams each. The tube has common inputmore » and output cavities for all 24 beams, and individual gain cavities for each cluster. A closely related optional configuration, also for a 10 MW tube, would involve four totally independent cavity clusters with four independent input cavities and four 2.5 MW output ports, all within a common magnetic circuit. This option has appeal because the output waveguides would not require a controlled atmosphere, and because it would be easier to achieve phase and amplitude stability as required in individual SC accelerator cavities.« less

Behavioural and functional characterization of Kv10.1 (Eag1) knockout mice

PubMed Central

Ufartes, Roser; Schneider, Tomasz; Mortensen, Lena Sünke; de Juan Romero, Camino; Hentrich, Klaus; Knoetgen, Hendrik; Beilinson, Vadim; Moebius, Wiebke; Tarabykin, Victor; Alves, Frauke; Pardo, Luis A.; Rawlins, J. Nicholas P.; Stuehmer, Walter

2013-01-01

Kv10.1 (Eag1), member of the Kv10 family of voltage-gated potassium channels, is preferentially expressed in adult brain. The aim of the present study was to unravel the functional role of Kv10.1 in the brain by generating knockout mice, where the voltage sensor and pore region of Kv10.1 were removed to render non-functional proteins through deletion of exon 7 of the KCNH1 gene using the ‘3 Lox P strategy’. Kv10.1-deficient mice show no obvious alterations during embryogenesis and develop normally to adulthood; cortex, hippocampus and cerebellum appear anatomically normal. Other tests, including general health screen, sensorimotor functioning and gating, anxiety, social behaviour, learning and memory did not show any functional aberrations in Kv10.1 null mice. Kv10.1 null mice display mild hyperactivity and longer-lasting haloperidol-induced catalepsy, but there was no difference between genotypes in amphetamine sensitization and withdrawal, reactivity to apomorphine and haloperidol in the prepulse inhibition tests or to antidepressants in the haloperidol-induced catalepsy. Furthermore, electrical properties of Kv10.1 in cerebellar Purkinje cells did not show any difference between genotypes. Bearing in mind that Kv10.1 is overexpressed in over 70% of all human tumours and that its inhibition leads to a reduced tumour cell proliferation, the fact that deletion of Kv10.1 does not show a marked phenotype is a prerequisite for utilizing Kv10.1 blocking and/or reduction techniques, such as siRNA, to treat cancer. PMID:23424202

The Kv7.2/Kv7.3 heterotetramer assembles with a random subunit arrangement.

PubMed

Stewart, Andrew P; Gómez-Posada, Juan Camilo; McGeorge, Jessica; Rouhani, Maral J; Villarroel, Alvaro; Murrell-Lagnado, Ruth D; Edwardson, J Michael

2012-04-06

Voltage-gated K(+) channels composed of Kv7.2 and Kv7.3 are the predominant contributors to the M-current, which plays a key role in controlling neuronal activity. Various lines of evidence have indicated that Kv7.2 and Kv7.3 form a heteromeric channel. However, the subunit stoichiometry and arrangement within this putative heteromer are so far unknown. Here, we have addressed this question using atomic force microscopy imaging of complexes between isolated Kv7.2/Kv7.3 channels and antibodies to epitope tags on the two subunits, Myc on Kv7.2 and HA on Kv7.3. Initially, tsA 201 cells were transiently transfected with equal amounts of cDNA for the two subunits. The heteromer was isolated through binding of either tag to immunoaffinity beads and then decorated with antibodies to the other tag. In both cases, the distribution of angles between pairs of bound antibodies had two peaks, at around 90° and around 180°, and in both cases the 90° peak was about double the size of the 180° peak. These results indicate that the Kv7.2/Kv7.3 heteromer generated by cells expressing approximately equal amounts of the two subunits assembles as a tetramer with a predominantly 2:2 subunit stoichiometry and with a random subunit arrangement. When the DNA ratio for the two subunits was varied, copurification experiments indicated that the subunit stoichiometry was variable and not fixed at 2:2. Hence, there are no constraints on either the subunit stoichiometry or the subunit arrangement.

Tannic acid activates the Kv7.4 and Kv7.3/7.5 K(+) channels expressed in HEK293 cells and reduces tension in the rat mesenteric arteries.

PubMed

Zhang, Yuanyuan; Chu, Xi; Liu, Ling; Zhang, Nan; Guo, Hui; Yang, Fan; Liu, Zhenyi; Dong, Yongsheng; Bao, Yifan; Zhang, Xuan; Zhang, Jianping

2016-04-01

This study investigated the effect of tannic acid (TA), a plant-derived hydrolyzable polyphenol, on Kv7.4 and Kv7.5 K(+) channels and rat mesenteric artery. Whole-cell patch clamp experiments were used to record the Kv7.4 and Kv7.3/7.5 K(+) currents expressed in HEK293 cells; and the tension changes of mesenteric arteries isolated from rats were recorded using small vessel myography apparatus. Tannic acid increases the Kv7.4 and Kv7.3/7.5 K(+) currents in a concentration-dependent manner (median effective concentration (EC50 ) = 27.3 ± 3.6 μm and EC50 = 23.1 ± 3.9 μm, respectively). In addition, 30 μm TA shifts the G-V curve of Kv7.4 and Kv7.3/7.5 K(+) currents to the left by 14.18 and 25.24 mV, respectively, and prolongs the deactivation time constants by 184.44 and 154.77 ms, respectively. Moreover, TA relaxes the vascular tension of rat mesenteric arteries in a concentration-dependent manner (half inhibitory concentration (IC50 ) = 148.7 ± 13.4 μm). These results confirms the vasodilatory effects of TA on rat mesenteric artery and the activating effects on the Kv7.4 and Kv7.3/7.5 K(+) channels, which may be a mechanism to explain the vasodilatory effect and this mechanism can be used in the research of antihypertension. © 2016 Royal Pharmaceutical Society.

Contribution of Kv2.1 channels to the delayed rectifier current in freshly dispersed smooth muscle cells from rabbit urethra

PubMed Central

Kyle, B.; Bradley, E.; Ohya, S.; Sergeant, G. P.; McHale, N. G.; Thornbury, K. D.

2011-01-01

We have characterized the native voltage-dependent K+ (Kv) current in rabbit urethral smooth muscle cells (RUSMC) and compared its pharmacological and biophysical properties with Kv2.1 and Kv2.2 channels cloned from the rabbit urethra and stably expressed in human embryonic kidney (HEK)-293 cells (HEKKv2.1 and HEKKv2.2). RUSMC were perfused with Hanks′ solution at 37°C and studied using the patch-clamp technique with K+-rich pipette solutions. Cells were bathed in 100 nM Penitrem A (Pen A) to block large-conductance Ca2+-activated K+ (BK) currents and depolarized to +40 mV for 500 ms to evoke Kv currents. These were unaffected by margatoxin, κ-dendrotoxin, or α-dendrotoxin (100 nM, n = 3–5) but were blocked by stromatoxin-1 (ScTx, IC50 ∼130 nM), consistent with the idea that the currents were carried through Kv2 channels. RNA was detected for Kv2.1, Kv2.2, and the silent subunit Kv9.3 in urethral smooth muscle. Immunocytochemistry showed membrane staining for both Kv2 subtypes and Kv9.3 in isolated RUSMC. HEKKv2.1 and HEKKv2.2 currents were blocked in a concentration-dependent manner by ScTx, with estimated IC50 values of ∼150 nM (Kv2.1, n = 5) and 70 nM (Kv2.2, n = 6). The mean half-maximal voltage (V1/2) of inactivation of the USMC Kv current was −56 ± 3 mV (n = 9). This was similar to the HEKKv2.1 current (−55 ± 3 mV, n = 13) but significantly different from the HEKKv2.2 currents (−30 ± 3 mV, n = 11). Action potentials (AP) evoked from RUSMC studied under current-clamp mode were unaffected by ScTx. However, when ScTx was applied in the presence of Pen A, the AP duration was significantly prolonged. Similarly, ScTx increased the amplitude of spontaneous contractions threefold, but only after Pen A application. These data suggest that Kv2.1 channels contribute significantly to the Kv current in RUSMC. PMID:21813710

Kv10.1 potassium channel: from the brain to the tumors.

PubMed

Cázares-Ordoñez, V; Pardo, L A

2017-10-01

The KCNH1 gene encodes the Kv10.1 (Eag1) ion channel, a member of the EAG (ether-à-go-go) family of voltage-gated potassium channels. Recent studies have demonstrated that KCHN1 mutations are implicated in Temple-Baraitser and Zimmermann-Laband syndromes and other forms of developmental deficits that all present with mental retardation and epilepsy, suggesting that Kv10.1 might be important for cognitive development in humans. Although the Kv10.1 channel is mainly expressed in the mammalian brain, its ectopic expression occurs in 70% of human cancers. Cancer cells and tumors expressing Kv10.1 acquire selective advantages that favor cancer progression through molecular mechanisms that involve several cellular pathways, indicating that protein-protein interactions may be important for Kv10.1 influence in cell proliferation and tumorigenesis. Several studies on transcriptional and post-transcriptional regulation of Kv10.1 expression have shown interesting mechanistic insights about Kv10.1 role in oncogenesis, increasing the importance of identifying the cellular factors that regulate Kv10.1 expression in tumors.

Measurement of ozone production scaling in a helium plasma jet with oxygen admixture

NASA Astrophysics Data System (ADS)

Sands, Brian; Ganguly, Biswa

2012-10-01

Capillary dielectric barrier plasma jet devices that generate confined streamer-like discharges along a rare gas flow can produce significant quantities of reactive oxygen species with average input powers ranging from 100 mW to >1 W. We have measured spatially-resolved ozone production in a He plasma jet with O2 admixture concentrations up to 5% using absorption spectroscopy of the O3 Hartley band system. A 20-ns risetime, 10-13 kV positive unipolar voltage pulse train was used to power the discharge, with pulse repetition rates varied from 1-20 kHz. The discharge was operated in a transient glow mode to scale the input power by adjusting the gap width between the anode and downstream cathodic plane. Peak ozone number densities in the range of 10^16 - 10^17 cm-3 were measured. At a given voltage, the density of ozone increased monotonically up to 3% O2 admixture (6 mm gap) as the peak discharge current decreased by an order of magnitude. Ozone production increased with distance from the capillary, consistent with observations by other groups. Atomic oxygen production inferred from O-atom 777 nm emission intensity did not scale with ozone as the input power was increased. The spatial distribution of ozone and scaling with input power will be presented.

29 CFR 1926.1409 - Power line safety (over 350 kV).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 8 2012-07-01 2012-07-01 false Power line safety (over 350 kV). 1926.1409 Section 1926... Construction § 1926.1409 Power line safety (over 350 kV). The requirements of § 1926.1407 and § 1926.1408 apply to power lines over 350 kV except: (a) For power lines at or below 1000 kV, wherever the distance “20...

29 CFR 1926.1409 - Power line safety (over 350 kV).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 8 2014-07-01 2014-07-01 false Power line safety (over 350 kV). 1926.1409 Section 1926... Construction § 1926.1409 Power line safety (over 350 kV). The requirements of § 1926.1407 and § 1926.1408 apply to power lines over 350 kV except: (a) For power lines at or below 1000 kV, wherever the distance “20...

29 CFR 1926.1409 - Power line safety (over 350 kV).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 8 2013-07-01 2013-07-01 false Power line safety (over 350 kV). 1926.1409 Section 1926... Construction § 1926.1409 Power line safety (over 350 kV). The requirements of § 1926.1407 and § 1926.1408 apply to power lines over 350 kV except: (a) For power lines at or below 1000 kV, wherever the distance “20...

29 CFR 1926.1409 - Power line safety (over 350 kV).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 8 2011-07-01 2011-07-01 false Power line safety (over 350 kV). 1926.1409 Section 1926... Construction § 1926.1409 Power line safety (over 350 kV). The requirements of § 1926.1407 and § 1926.1408 apply to power lines over 350 kV except: (a) For power lines at or below 1000 kV, wherever the distance “20...

Auxiliary KChIP4a Suppresses A-type K+ Current through Endoplasmic Reticulum (ER) Retention and Promoting Closed-state Inactivation of Kv4 Channels*

PubMed Central

Tang, Yi-Quan; Liang, Ping; Zhou, Jingheng; Lu, Yanxin; Lei, Lei; Bian, Xiling; Wang, KeWei

2013-01-01

In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 α-subunits to form a native K+ channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1–4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12–17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19–21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation. PMID:23576435

Activation of KV7 channels stimulates vasodilatation of human placental chorionic plate arteries.

PubMed

Mills, T A; Greenwood, S L; Devlin, G; Shweikh, Y; Robinson, M; Cowley, E; Hayward, C E; Cottrell, E C; Tropea, T; Brereton, M F; Dalby-Brown, W; Wareing, M

2015-06-01

Potassium (K(+)) channels are key regulators of vascular smooth muscle cell (VSMC) excitability. In systemic small arteries, Kv7 channel expression/activity has been noted and a role in vascular tone regulation demonstrated. We aimed to demonstrate functional Kv7 channels in human fetoplacental small arteries. Human placental chorionic plate arteries (CPAs) were obtained at term. CPA responses to Kv7 channel modulators was determined by wire myography. Presence of Kv7 channel mRNA (encoded by KCNQ1-5) and protein expression were assessed by RT-PCR and immunohistochemistry/immunofluorescence, respectively. Kv7 channel blockade with linopirdine increased CPA basal tone and AVP-induced contraction. Pre-contracted CPAs (AVP; 80 mM K(+) depolarization solution) exhibited significant relaxation to flupirtine, retigabine, the acrylamide (S)-1, and (S) BMS-204352, differential activators of Kv7.1 - Kv7.5 channels. All CPAs assessed expressed KCNQ1 and KCNQ3-5 mRNA; KCNQ2 was expressed only in a subset of CPAs. Kv7 protein expression was confirmed in intact CPAs and isolated VSMCs. Kv7 channels are present and active in fetoplacental vessels, contributing to vascular tone regulation in normal pregnancy. Targeting these channels may represent a therapeutic intervention in pregnancies complicated by increased vascular resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

Auxiliary KChIP4a suppresses A-type K+ current through endoplasmic reticulum (ER) retention and promoting closed-state inactivation of Kv4 channels.

PubMed

Tang, Yi-Quan; Liang, Ping; Zhou, Jingheng; Lu, Yanxin; Lei, Lei; Bian, Xiling; Wang, KeWei

2013-05-24

In the brain and heart, auxiliary Kv channel-interacting proteins (KChIPs) co-assemble with pore-forming Kv4 α-subunits to form a native K(+) channel complex and regulate the expression and gating properties of Kv4 currents. Among the KChIP1-4 members, KChIP4a exhibits a unique N terminus that is known to suppress Kv4 function, but the underlying mechanism of Kv4 inhibition remains unknown. Using a combination of confocal imaging, surface biotinylation, and electrophysiological recordings, we identified a novel endoplasmic reticulum (ER) retention motif, consisting of six hydrophobic and aliphatic residues, 12-17 (LIVIVL), within the KChIP4a N-terminal KID, that functions to reduce surface expression of Kv4-KChIP complexes. This ER retention capacity is transferable and depends on its flanking location. In addition, adjacent to the ER retention motif, the residues 19-21 (VKL motif) directly promote closed-state inactivation of Kv4.3, thus leading to an inhibition of channel current. Taken together, our findings demonstrate that KChIP4a suppresses A-type Kv4 current via ER retention and enhancement of Kv4 closed-state inactivation.

Photovoltaic Inverter Controllers Seeking AC Optimal Power Flow Solutions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dall'Anese, Emiliano; Dhople, Sairaj V.; Giannakis, Georgios B.

This paper considers future distribution networks featuring inverter-interfaced photovoltaic (PV) systems, and addresses the synthesis of feedback controllers that seek real- and reactive-power inverter setpoints corresponding to AC optimal power flow (OPF) solutions. The objective is to bridge the temporal gap between long-term system optimization and real-time inverter control, and enable seamless PV-owner participation without compromising system efficiency and stability. The design of the controllers is grounded on a dual ..epsilon..-subgradient method, while semidefinite programming relaxations are advocated to bypass the non-convexity of AC OPF formulations. Global convergence of inverter output powers is analytically established for diminishing stepsize rules formore » cases where: i) computational limits dictate asynchronous updates of the controller signals, and ii) inverter reference inputs may be updated at a faster rate than the power-output settling time.« less

Developmental Expression of Kv Potassium Channels at the Axon Initial Segment of Cultured Hippocampal Neurons

PubMed Central

Sánchez-Ponce, Diana; DeFelipe, Javier; Garrido, Juan José; Muñoz, Alberto

2012-01-01

Axonal outgrowth and the formation of the axon initial segment (AIS) are early events in the acquisition of neuronal polarity. The AIS is characterized by a high concentration of voltage-dependent sodium and potassium channels. However, the specific ion channel subunits present and their precise localization in this axonal subdomain vary both during development and among the types of neurons, probably determining their firing characteristics in response to stimulation. Here, we characterize the developmental expression of different subfamilies of voltage-gated potassium channels in the AISs of cultured mouse hippocampal neurons, including subunits Kv1.2, Kv2.2 and Kv7.2. In contrast to the early appearance of voltage-gated sodium channels and the Kv7.2 subunit at the AIS, Kv1.2 and Kv2.2 subunits were tethered at the AIS only after 10 days in vitro. Interestingly, we observed different patterns of Kv1.2 and Kv2.2 subunit expression, with each confined to distinct neuronal populations. The accumulation of Kv1.2 and Kv2.2 subunits at the AIS was dependent on ankyrin G tethering, it was not affected by disruption of the actin cytoskeleton and it was resistant to detergent extraction, as described previously for other AIS proteins. This distribution of potassium channels in the AIS further emphasizes the heterogeneity of this structure in different neuronal populations, as proposed previously, and suggests corresponding differences in action potential regulation. PMID:23119056

Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders.

PubMed

Gilling, Mette; Rasmussen, Hanne B; Calloe, Kirstine; Sequeira, Ana F; Baretto, Marta; Oliveira, Guiomar; Almeida, Joana; Lauritsen, Marlene B; Ullmann, Reinhard; Boonen, Susanne E; Brondum-Nielsen, Karen; Kalscheuer, Vera M; Tümer, Zeynep; Vicente, Astrid M; Schmitt, Nicole; Tommerup, Niels

2013-01-01

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders.

Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders

PubMed Central

Gilling, Mette; Rasmussen, Hanne B.; Calloe, Kirstine; Sequeira, Ana F.; Baretto, Marta; Oliveira, Guiomar; Almeida, Joana; Lauritsen, Marlene B.; Ullmann, Reinhard; Boonen, Susanne E.; Brondum-Nielsen, Karen; Kalscheuer, Vera M.; Tümer, Zeynep; Vicente, Astrid M.; Schmitt, Nicole; Tommerup, Niels

2012-01-01

Heterozygous mutations in the KCNQ3 gene on chromosome 8q24 encoding the voltage-gated potassium channel KV7.3 subunit have previously been associated with rolandic epilepsy and idiopathic generalized epilepsy (IGE) including benign neonatal convulsions. We identified a de novo t(3;8) (q21;q24) translocation truncating KCNQ3 in a boy with childhood autism. In addition, we identified a c.1720C > T [p.P574S] nucleotide change in three unrelated individuals with childhood autism and no history of convulsions. This nucleotide change was previously reported in patients with rolandic epilepsy or IGE and has now been annotated as a very rare SNP (rs74582884) in dbSNP. The p.P574S KV7.3 variant significantly reduced potassium current amplitude in Xenopus laevis oocytes when co-expressed with KV7.5 but not with KV7.2 or KV7.4. The nucleotide change did not affect trafficking of heteromeric mutant KV7.3/2, KV7.3/4, or KV7.3/5 channels in HEK 293 cells or primary rat hippocampal neurons. Our results suggest that dysfunction of the heteromeric KV7.3/5 channel is implicated in the pathogenesis of some forms of autism spectrum disorders, epilepsy, and possibly other psychiatric disorders and therefore, KCNQ3 and KCNQ5 are suggested as candidate genes for these disorders. PMID:23596459

Activity-dependent downregulation of M-Type (Kv7) K⁺ channels surface expression requires the activation of iGluRs/Ca²⁺/PKC signaling pathway in hippocampal neuron.

PubMed

Li, Cai; Lu, Qing; Huang, Pengcheng; Fu, Tianli; Li, Changjun; Guo, Lianjun; Xu, Xulin

2015-08-01

M-type (Kv7) K(+) channels, encoded by KCNQ2-KCNQ5 genes, play a pivotal role in controlling neuronal excitability. However, precisely how neuronal activity regulates Kv7 channel translocation has not yet been fully defined. Here we reported activity-dependent changes in Kv7 channel subunits Kv7.2 and Kv7.3 surface expression by glutamate (glu). In the present study, we found that treatment with glutamate rapidly caused a specific decrease in M-current as well as Kv7 channel surface expression in primary cultured hippocampal neurons. The glutamate effects were mimicked by NMDA and AMPA. The glutamate effects on Kv7 channels were partially attenuated by pre-treatment of NMDA receptors antagonist d,l-APV or AMPA-KA receptors antagonist CNQX. The signal required Ca(2+) influx through L-type Ca(2+) channel and intracellular Ca(2+) elevations. PKC activation was involved in the glutamate-induced reduction of Kv7 channel surface expression. Moreover, a significant reduction of Kv7 channel surface expression occurred following glycine-induced "chem"-LTP in vitro and hippocampus-dependent behavioral learning training in vivo. These results demonstrated that activity-dependent reduction of Kv7 channel surface expression through activation of ionotropic glutamate receptors (iGluRs)/Ca(2+)/PKC signaling pathway might be an important molecular mechanism for regulation of neuronal excitability and synaptic plasticity. Copyright © 2015 Elsevier Ltd. All rights reserved.

FGF and BMP derived from dorsal root ganglia regulate blastema induction in limb regeneration in Ambystoma mexicanum.

PubMed

Satoh, Akira; Makanae, Aki; Nishimoto, Yurie; Mitogawa, Kazumasa

2016-09-01

Urodele amphibians have a remarkable organ regeneration ability that is regulated by neural inputs. The identification of these neural inputs has been a challenge. Recently, Fibroblast growth factor (Fgf) and Bone morphogenic protein (Bmp) were shown to substitute for nerve functions in limb and tail regeneration in urodele amphibians. However, direct evidence of Fgf and Bmp being secreted from nerve endings and regulating regeneration has not yet been shown. Thus, it remained uncertain whether they were the nerve factors responsible for successful limb regeneration. To gather experimental evidence, the technical difficulties involved in the usage of axolotls had to be overcome. We achieved this by modifying the electroporation method. When Fgf8-AcGFP or Bmp7-AcGFP was electroporated into the axolotl dorsal root ganglia (DRG), GFP signals were detectable in the regenerating limb region. This suggested that Fgf8 and Bmp7 synthesized in neural cells in the DRG were delivered to the limbs through the long axons. Further knockdown experiments with double-stranded RNA interference resulted in impaired limb regeneration ability. These results strongly suggest that Fgf and Bmp are the major neural inputs that control the organ regeneration ability. Copyright © 2016 Elsevier Inc. All rights reserved.

[Dual energy CT angiography of the carotid arteries: quality, bone subtraction, and radiation dosage using tube voltage 80/140 kV versus 100/140 kV].

PubMed

Santos Armentia, E; Tardáguila de la Fuente, G; Castellón Plaza, D; Delgado Sánchez-Gracián, C; Prada González, R; Fernández Fernández, L; Tardáguila Montero, F

2014-01-01

To study the differences in vascular image quality, bone subtraction, and dose of radiation of dual energy CT angiography of the supraaortic trunks using different tube voltages. We reviewed the CT angiograms of the supraaortic trunks in 46 patients acquired with a 128-slice dual source CT scanner using two voltage protocols (80/140 kV and 100/140 kV). The "head bone removal" tool was used for postprocessing. We divided the arteries into 15 segments. In each segment, we evaluated the image quality of the vessels and the effectiveness of bone removal in multiplanar reconstructions (MPR) and in maximum intensity projections (MIP) with each protocol, analyzing the trabecular and cortical bones separately. We also evaluated the dose of radiation received. Of the 46 patients, 13 were studied using 80/140 kV and 33 with 100/140 kV. There were no significant differences between the two groups in age or sex. Image quality in four segments was better in the group examined with 100/140 kV. Cortical bone removal in MPR and MIP and trabecular bone removal in MIP were also better in the group examined with 100/140 kV. The dose of radiation received was significantly higher in the group examined with 100/140 kV (1.16 mSv with 80/140 kV vs. 1.59 mSv with 100/140 kV). Using 100/140 kV increases the dose of radiation but improves the quality of the study of arterial segments and bone subtraction. Copyright © 2011 SERAM. Published by Elsevier Espana. All rights reserved.

Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate

PubMed Central

Soldovieri, Maria Virginia; Ambrosino, Paolo; Mosca, Ilaria; De Maria, Michela; Moretto, Edoardo; Miceli, Francesco; Alaimo, Alessandro; Iraci, Nunzio; Manocchio, Laura; Medoro, Alessandro; Passafaro, Maria; Taglialatela, Maurizio

2016-01-01

Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K+ current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP2). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP2 levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP2 is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies. PMID:27905566

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

PubMed Central

Goodwill, Adam G.; Fu, Lijuan; Noblet, Jillian N.; Casalini, Eli D.; Berwick, Zachary C.; Kassab, Ghassan S.; Tune, Johnathan D.

2016-01-01

Hydrogen peroxide (H2O2) and voltage-dependent K+ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. PMID:26825518

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity.

PubMed

Stott, Jennifer B; Povstyan, Oleksandr V; Carr, Georgina; Barrese, Vincenzo; Greenwood, Iain A

2015-05-19

Kv7.4 channels are a crucial determinant of arterial diameter both at rest and in response to endogenous vasodilators. However, nothing is known about the factors that ensure effective activity of these channels. We report that G-protein βγ subunits increase the amplitude and activation rate of whole-cell voltage-dependent K(+) currents sensitive to the Kv7 blocker linopirdine in HEK cells heterologously expressing Kv7.4, and in rat renal artery myocytes. In excised patch recordings, Gβγ subunits (2-250 ng /mL) enhanced the open probability of Kv7.4 channels without changing unitary conductance. Kv7 channel activity was also augmented by stimulation of G-protein-coupled receptors. Gallein, an inhibitor of Gβγ subunits, prevented these stimulatory effects. Moreover, gallein and two other structurally different Gβγ subunit inhibitors (GRK2i and a β-subunit antibody) abolished Kv7 channel currents in the absence of either Gβγ subunit enrichment or G-protein-coupled receptor stimulation. Proximity ligation assay revealed that Kv7.4 and Gβγ subunits colocalized in HEK cells and renal artery smooth muscle cells. Gallein disrupted this colocalization, contracted whole renal arteries to a similar degree as the Kv7 inhibitor linopirdine, and impaired isoproterenol-induced relaxations. Furthermore, mSIRK, which disassociates Gβγ subunits from α subunits without stimulating nucleotide exchange, relaxed precontracted arteries in a linopirdine-sensitive manner. These results reveal that Gβγ subunits are fundamental for Kv7.4 activation and crucial for vascular Kv7 channel activity, which has major consequences for the regulation of arterial tone.

Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate.

PubMed

Soldovieri, Maria Virginia; Ambrosino, Paolo; Mosca, Ilaria; De Maria, Michela; Moretto, Edoardo; Miceli, Francesco; Alaimo, Alessandro; Iraci, Nunzio; Manocchio, Laura; Medoro, Alessandro; Passafaro, Maria; Taglialatela, Maurizio

2016-12-01

Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K + current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP 2 levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP 2 is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies.

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

PubMed Central

Stott, Jennifer B.; Povstyan, Oleksandr V.; Carr, Georgina; Barrese, Vincenzo; Greenwood, Iain A.

2015-01-01

Kv7.4 channels are a crucial determinant of arterial diameter both at rest and in response to endogenous vasodilators. However, nothing is known about the factors that ensure effective activity of these channels. We report that G-protein βγ subunits increase the amplitude and activation rate of whole-cell voltage-dependent K+ currents sensitive to the Kv7 blocker linopirdine in HEK cells heterologously expressing Kv7.4, and in rat renal artery myocytes. In excised patch recordings, Gβγ subunits (2–250 ng /mL) enhanced the open probability of Kv7.4 channels without changing unitary conductance. Kv7 channel activity was also augmented by stimulation of G-protein–coupled receptors. Gallein, an inhibitor of Gβγ subunits, prevented these stimulatory effects. Moreover, gallein and two other structurally different Gβγ subunit inhibitors (GRK2i and a β-subunit antibody) abolished Kv7 channel currents in the absence of either Gβγ subunit enrichment or G-protein–coupled receptor stimulation. Proximity ligation assay revealed that Kv7.4 and Gβγ subunits colocalized in HEK cells and renal artery smooth muscle cells. Gallein disrupted this colocalization, contracted whole renal arteries to a similar degree as the Kv7 inhibitor linopirdine, and impaired isoproterenol-induced relaxations. Furthermore, mSIRK, which disassociates Gβγ subunits from α subunits without stimulating nucleotide exchange, relaxed precontracted arteries in a linopirdine-sensitive manner. These results reveal that Gβγ subunits are fundamental for Kv7.4 activation and crucial for vascular Kv7 channel activity, which has major consequences for the regulation of arterial tone. PMID:25941381

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine.

PubMed

Goodwill, Adam G; Fu, Lijuan; Noblet, Jillian N; Casalini, Eli D; Sassoon, Daniel; Berwick, Zachary C; Kassab, Ghassan S; Tune, Johnathan D; Dick, Gregory M

2016-03-15

Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. Copyright © 2016 the American Physiological Society.

Distinct cellular distributions of Kv4 pore-forming and auxiliary subunits in rat dorsal root ganglion neurons.

PubMed

Matsuyoshi, Hiroko; Takimoto, Koichi; Yunoki, Takakazu; Erickson, Vickie L; Tyagi, Pradeep; Hirao, Yoshihiko; Wanaka, Akio; Yoshimura, Naoki

2012-09-17

Dorsal root ganglia contain heterogeneous populations of primary afferent neurons that transmit various sensory stimuli. This functional diversity may be correlated with differential expression of voltage-gated K(+) (Kv) channels. Here, we examine cellular distributions of Kv4 pore-forming and ancillary subunits that are responsible for fast-inactivating A-type K(+) current. Expression pattern of Kv α-subunit, β-subunit and auxiliary subunit was investigated using immunohistochemistry, in situ hybridization and RT-PCR technique. The two pore-forming subunits Kv4.1 and Kv4.3 show distinct cellular distributions: Kv4.3 is predominantly in small-sized C-fiber neurons, whereas Kv4.1 is seen in DRG neurons in various sizes. Furthermore, the two classes of Kv4 channel auxiliary subunits are also distributed in different-sized cells. KChIP3 is the only significantly expressed Ca(2+)-binding cytosolic ancillary subunit in DRGs and present in medium to large-sized neurons. The membrane-spanning auxiliary subunit DPP6 is seen in a large number of DRG neurons in various sizes, whereas DPP10 is restricted in small-sized neurons. Distinct combinations of Kv4 pore-forming and auxiliary subunits may constitute A-type channels in DRG neurons with different physiological roles. Kv4.1 subunit, in combination with KChIP3 and/or DPP6, form A-type K(+) channels in medium to large-sized A-fiber DRG neurons. In contrast, Kv4.3 and DPP10 may contribute to A-type K(+) current in non-peptidergic, C-fiber somatic afferent neurons. Copyright © 2012 Elsevier Inc. All rights reserved.

New pyrimido-indole compound CD-160130 preferentially inhibits the KV11.1B isoform and produces antileukemic effects without cardiotoxicity.

PubMed

Gasparoli, Luca; D'Amico, Massimo; Masselli, Marika; Pillozzi, Serena; Caves, Rachel; Khuwaileh, Rawan; Tiedke, Wolfgang; Mugridge, Kenneth; Pratesi, Alessandro; Mitcheson, John S; Basso, Giuseppe; Becchetti, Andrea; Arcangeli, Annarosa

2015-02-01

KV11.1 (hERG1) channels are often overexpressed in human cancers. In leukemias, KV11.1 regulates pro-survival signals that promote resistance to chemotherapy, raising the possibility that inhibitors of KV11.1 could be therapeutically beneficial. However, because of the role of KV11.1 in cardiac repolarization, blocking these channels may cause cardiac arrhythmias. We show that CD-160130, a novel pyrimido-indole compound, blocks KV11.1 channels with a higher efficacy for the KV11.1 isoform B, in which the IC50 (1.8 μM) was approximately 10-fold lower than observed in KV11.1 isoform A. At this concentration, CD-160130 also had minor effects on Kir2.1, KV 1.3, Kv1.5, and KCa3.1. In vitro, CD-160130 induced leukemia cell apoptosis, and could overcome bone marrow mesenchymal stromal cell (MSC)-induced chemoresistance. This effect was caused by interference with the survival signaling pathways triggered by MSCs. In vivo, CD-160130 produced an antileukemic activity, stronger than that caused by cytarabine. Consistent with its atypical target specificity, CD-160130 did not bind to the main binding site of the arrhythmogenic KV11.1 blockers (the Phe656 pore residue). Importantly, in guinea pigs CD-160130 produced neither alteration of the cardiac action potential shape in dissociated cardiomyocytes nor any lengthening of the QT interval in vivo. Moreover, CD-160130 had no myelotoxicity on human bone marrow-derived cells. Therefore, CD-160130 is a promising first-in-class compound to attempt oncologic therapy without cardiotoxicity, based on targeting KV11.1. Because leukemia and cardiac cells tend to express different ratios of the A and B KV11.1 isoforms, the pharmacological properties of CD-160130 may depend, at least in part, on isoform specificity. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Rearrangement of potassium ions and Kv1.1/Kv1.2 potassium channels in regenerating axons following end-to-end neurorrhaphy: ionic images from TOF-SIMS.

PubMed

Liu, Chiung-Hui; Chang, Hung-Ming; Wu, Tsung-Huan; Chen, Li-You; Yang, Yin-Shuo; Tseng, To-Jung; Liao, Wen-Chieh

2017-10-01

The voltage-gated potassium channels Kv1.1 and Kv1.2 that cluster at juxtaparanodal (JXP) regions are essential in the regulation of nerve excitability and play a critical role in axonal conduction. When demyelination occurs, Kv1.1/Kv1.2 activity increases, suppressing the membrane potential nearly to the equilibrium potential of K + , which results in an axonal conduction blockade. The recovery of K + -dependent communication signals and proper clustering of Kv1.1/Kv1.2 channels at JXP regions may directly reflect nerve regeneration following peripheral nerve injury. However, little is known about potassium channel expression and its relationship with the dynamic potassium ion distribution at the node of Ranvier during the regenerative process of peripheral nerve injury (PNI). In the present study, end-to-end neurorrhaphy (EEN) was performed using an in vivo model of PNI. The distribution of K + at regenerating axons following EEN was detected by time-of-flight secondary-ion mass spectrometry. The specific localization and expression of Kv1.1/Kv1.2 channels were examined by confocal microscopy and western blotting. Our data showed that the re-establishment of K + distribution and intensity was correlated with the functional recovery of compound muscle action potential morphology in EEN rats. Furthermore, the re-clustering of Kv1.1/1.2 channels 1 and 3 months after EEN at the nodal region of the regenerating nerve corresponded to changes in the K + distribution. This study provided direct evidence of K + distribution in regenerating axons for the first time. We proposed that the Kv1.1/Kv1.2 channels re-clustered at the JXP regions of regenerating axons are essential for modulating the proper patterns of K + distribution in axons for maintaining membrane potential stability after EEN.

SU-E-J-31: Monitor Interfractional Variation of Tumor Respiratory Motion Using 4D KV Conebeam Computed Tomography for Stereotactic Body Radiation Therapy of Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai, A; Prior, P; Gore, E

Purpose: 4DCT has been widely used to generate internal tumor volume (ITV) for a lung tumor for treatment planning. However, lung tumors may show different respiratory motion on the treatment day. The purpose of this study is to evaluate 4D KV conebeam computed tomography (CBCT) for monitoring tumor interfractional motion variation between simulation and each fraction of stereotactic body radiation therapy (SBRT) for lung cancer. Methods: 4D KV CBCT was acquired with the Elekta XVI system. The accuracy of 4D KV CBCT for image-guided radiation therapy (IGRT) was tested with a dynamic thorax motion phantom (CIRS, Virginia) with a linearmore » amplitude of 2 cm. In addition, an adult anthropomorphic phantom (Alderson, Rando) with optically stimulated luminescence (OSL) dosimeters embedded at the center and periphery of a slab of solid water was used to measure the dose of 4D KV CBCT and to compare it with the dose with 3D KV CBCT. The image registration was performed by aligning\\ each phase images of 4D KV CBCT to the planning images and the final couch shifts were calculated as a mean of all these individual shifts along each direction.A workflow was established based on these quality assurance tests for lung cancer patients. Results: 4D KV CBCT does not increase imaging dose in comparison to 3D KV CBCT. Acquisition of 4D KV CBCT is 4 minutes as compared to 2 minutes for 3D KV CBCT. Most of patients showed a small daily variation of tumor respiratory motion about 2 mm. However, some patients may have more than 5 mm variations of tumor respiratory motion. Conclusion: The radiation dose does not increase with 4D KV CBCT. 4D KV CBCT is a useful tool for monitoring interfractional variations of tumor respiratory motion before SBRT of lung cancer patients.« less

Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala.

PubMed

Dabrowska, J; Rainnie, D G

2010-12-15

The Kv4 potassium channel α subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary β-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other β-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family α- and β-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 α subunits. We show that all three α-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 α subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Polarized targeting of a shaker-like (A-type) K(+)-channel in the polarized epithelial cell line MDCK.

PubMed

Le Maout, S; Sewing, S; Coudrier, E; Elalouf, J M; Pongs, O; Merot, J

1996-01-01

Functional Kv 1-4 channels were stably expressed in filter-grown MDCK cells which form a polarized epithelium with two distinct plasma membrane domains: a basolateral and an apical cell surface. The Shaker-related Kv 1-4 channels mediated in MDCK cells fast transient (A-type) voltage-activated outward currents having similar properties to the ones reported for Kv 1-4 in the Xenopus oocytes expression system. Immunoblot analysis with specific anti-Kv 1-4 antibodies showed that two Kv 1-4 protein forms are expressed in MDCK cells which most likely represent the glycosylated and non-glycosylated Kv 1-4 protein, respectively. Using immunocytochemistry and confocal microscopy we showed that the Kv 1-4 channels are specifically localized in the basolateral membranes of MDCK cells. Thus, the MDCK cells may provide an important model system to analyse the polarized transport of ion channels such as Kv 1-4, which are distinctly expressed in the mammalian central nervous system.

SU-E-I-23: A General KV Constrained Optimization of CNR for CT Abdominal Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weir, V; Zhang, J

Purpose: While Tube current modulation has been well accepted for CT dose reduction, kV adjusting in clinical settings is still at its early stage. This is mainly due to the limited kV options of most current CT scanners. kV adjusting can potentially reduce radiation dose and optimize image quality. This study is to optimize CT abdomen imaging acquisition based on the assumption of a continuous kV, with the goal to provide the best contrast to noise ratio (CNR). Methods: For a given dose (CTDIvol) level, the CNRs at different kV and pitches were measured with an ACR GAMMEX phantom. Themore » phantom was scanned in a Siemens Sensation 64 scanner and a GE VCT 64 scanner. A constrained mathematical optimization was used to find the kV which led to the highest CNR for the anatomy and pitch setting. Parametric equations were obtained from polynomial fitting of plots of kVs vs CNRs. A suitable constraint region for optimization was chosen. Subsequent optimization yielded a peak CNR at a particular kV for different collimations and pitch setting. Results: The constrained mathematical optimization approach yields kV of 114.83 and 113.46, with CNRs of 1.27 and 1.11 at the pitch of 1.2 and 1.4, respectively, for the Siemens Sensation 64 scanner with the collimation of 32 x 0.625mm. An optimized kV of 134.25 and 1.51 CNR is obtained for a GE VCT 64 slice scanner with a collimation of 32 x 0.625mm and a pitch of 0.969. At 0.516 pitch and 32 x 0.625 mm an optimized kV of 133.75 and a CNR of 1.14 was found for the GE VCT 64 slice scanner. Conclusion: CNR in CT image acquisition can be further optimized with a continuous kV option instead of current discrete or fixed kV settings. A continuous kV option is a key for individualized CT protocols.« less

Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels

PubMed Central

Fineberg, Jeffrey D.; Ritter, David M.

2012-01-01

A-type voltage-gated K+ (Kv) channels self-regulate their activity by inactivating directly from the open state (open-state inactivation [OSI]) or by inactivating before they open (closed-state inactivation [CSI]). To determine the inactivation pathways, it is often necessary to apply several pulse protocols, pore blockers, single-channel recording, and kinetic modeling. However, intrinsic hurdles may preclude the standardized application of these methods. Here, we implemented a simple method inspired by earlier studies of Na+ channels to analyze macroscopic inactivation and conclusively deduce the pathways of inactivation of recombinant and native A-type Kv channels. We investigated two distinct A-type Kv channels expressed heterologously (Kv3.4 and Kv4.2 with accessory subunits) and their native counterparts in dorsal root ganglion and cerebellar granule neurons. This approach applies two conventional pulse protocols to examine inactivation induced by (a) a simple step (single-pulse inactivation) and (b) a conditioning step (double-pulse inactivation). Consistent with OSI, the rate of Kv3.4 inactivation (i.e., the negative first derivative of double-pulse inactivation) precisely superimposes on the profile of the Kv3.4 current evoked by a single pulse because the channels must open to inactivate. In contrast, the rate of Kv4.2 inactivation is asynchronous, already changing at earlier times relative to the profile of the Kv4.2 current evoked by a single pulse. Thus, Kv4.2 inactivation occurs uncoupled from channel opening, indicating CSI. Furthermore, the inactivation time constant versus voltage relation of Kv3.4 decreases monotonically with depolarization and levels off, whereas that of Kv4.2 exhibits a J-shape profile. We also manipulated the inactivation phenotype by changing the subunit composition and show how CSI and CSI combined with OSI might affect spiking properties in a full computational model of the hippocampal CA1 neuron. This work unambiguously elucidates contrasting inactivation pathways in neuronal A-type Kv channels and demonstrates how distinct pathways might impact neurophysiological activity. PMID:23109714

802.11ac WLAN MIMO radio-over-fiber distributed antenna system for in-building networks based on multicore fiber

NASA Astrophysics Data System (ADS)

Morant, Maria; Llorente, Roberto

2017-01-01

In this work we propose and evaluate experimentally the performance of IEEE 802.11ac WLAN standard signals in radio-over-fiber (RoF) distributed-antenna systems based on multicore fiber (MCF) for in-building WLAN connectivity. The RoF performance of WLAN signals with different bandwidth is investigated considering up to IEEE 802.11ac maximum of 160 MHz per user. We evaluate experimentally the performance of WLAN signals employing different modulation and coding schemes achieving bitrates from 78 Mbps to 1404 Mbps per user in distances up to 300 m in a 4-core MCF. The performance of the wireless standard multiple-input multiple-output (MIMO) processing algorithms included in WLAN signals applied to the RoF transmission in MCF optical systems is also evaluated. The impact on the quality of the signal from one of the cores in the MIMO processing is investigated and compared with the results achieved with single-input single-output (SISO) transmission in each core. We measured the error vector magnitude (EVM) and the OFDM data burst information of the received WLAN signals after RoF transmission for different distributed-antenna systems with uni- and bi-directional MCF communication. Finally, we compare the received EVM of a single-antenna system (SISO arrangement) with WLAN systems using two antennas (2×2 MIMO) and four antennas (4×4 MIMO).

TRIAC/SCR proportional control circuit

DOEpatents

Hughes, Wallace J.

1999-01-01

A power controller device which uses a voltage-to-frequency converter in conjunction with a zero crossing detector to linearly and proportionally control AC power being supplied to a load. The output of the voltage-to frequency converter controls the "reset" input of a R-S flip flop, while an "0" crossing detector controls the "set" input. The output of the flip flop triggers a monostable multivibrator controlling the SCR or TRIAC firing circuit connected to the load. Logic gates prevent the direct triggering of the multivibrator in the rare instance where the "reset" and "set" inputs of the flip flop are in coincidence. The control circuit can be supplemented with a control loop, providing compensation for line voltage variations.

The Schizophrenia-Associated Kv11.1-3.1 Isoform Results in Reduced Current Accumulation during Repetitive Brief Depolarizations

PubMed Central

Heide, Juliane; Mann, Stefan A.; Vandenberg, Jamie I.

2012-01-01

Recent genome wide association studies identified a brain and primate specific isoform of a voltage-gated potassium channel, referred to as Kv11.1-3.1, which is significantly associated with schizophrenia. The 3.1 isoform replaces the first 102 amino acids of the most abundant isoform (referred to as Kv11.1-1A) with six unique amino acids. Here we show that the Kv11.1-3.1 isoform has faster rates of channel deactivation but a slowing of the rates of inactivation compared to the Kv11.1-1A isoform. The Kv11.1-3.1 isoform also has a significant depolarizing shift in the voltage-dependence of steady-state inactivation. The consequence of the altered gating kinetics is that there is lower current accumulation for Kv11.1-3.1 expressing cells during repetitive action potential firing compared to Kv11.1-1A expressing cells, which in turn will result in longer lasting trains of action potentials. Increased expression of Kv11.1-3.1 channels in the brain of schizophrenia patients might therefore contribute to disorganized neuronal firing. PMID:23029143

Ca2+-Calmodulin and PIP2 interactions at the proximal C-terminus of Kv7 channels.

PubMed

Tobelaim, William S; Dvir, Meidan; Lebel, Guy; Cui, Meng; Buki, Tal; Peretz, Asher; Marom, Milit; Haitin, Yoni; Logothetis, Diomedes E; Hirsch, Joel A; Attali, Bernard

2017-11-02

In the heart, co-assembly of Kv7.1 with KCNE1 produces the slow I KS potassium current, which repolarizes the cardiac action potential and mutations in human Kv7.1 and KCNE1 genes cause cardiac arrhythmias. The proximal Kv7.1 C-terminus binds calmodulin (CaM) and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) and recently we revealed the competition of PIP 2 with the calcified CaM N-lobe to a previously unidentified site in Kv7.1 helix B, also known to harbor a LQT mutation. Data indicated that PIP 2 and Ca 2+ -CaM perform the same function on I KS channel gating to stabilize the channel open state. Here we show that similar features were observed for Kv7.1 currents expressed alone. We also find that conservation of homologous residues in helix B of other Kv7 subtypes confer similar competition of Ca 2+ -CaM with PIP2 binding to their proximal C-termini and suggest that PIP2-CaM interactions converge to Kv7 helix B to modulates channel activity in a Kv7 subtype-dependent manner.

VOLTAGE-GATED POTASSIUM CHANNELS AT THE CROSSROADS OF NEURONAL FUNCTION, ISCHEMIC TOLERANCE, AND NEURODEGENERATION

PubMed Central

Shah, Niyathi Hegde; Aizenman, Elias

2013-01-01

Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system, and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death of neurons. Injury-mediated increased K+ efflux through Kv2.1 channels promotes neuronal apoptosis, contributing to widespread neuronal loss in neurodegenerative disorders such as Alzheimer’s disease and stroke. In contrast, some forms of neuronal activity can dramatically alter Kv2.1 channel phosphorylation levels and influence their localization. These changes are normally accompanied by modifications in channel voltage-dependence, which may be neuroprotective within the context of ischemic injury. Kv1 and Kv7 channel dysfunction leads to neuronal hyperexcitability that critically contributes to the pathophysiology of human clinical disorders such as episodic ataxia and epilepsy. This review summarizes the neurotoxic, neuroprotective, and neuroregulatory roles of Kv channels, and highlights the consequences of Kv channel dysfunction on neuronal physiology. The studies described in this review thus underscore the importance of normal Kv channel function in neurons, and emphasize the therapeutic potential of targeting Kv channels in the treatment of a wide range of neurological diseases. PMID:24323720

Kv7(KCNQ)-K+-Channels Influence Total Peripheral Resistance in Female but Not Male Rats, and Hamper Catecholamine Release in Hypertensive Rats of Both Sexes

PubMed Central

Berg, Torill

2018-01-01

K+-channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if they may contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1-inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine-stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy. PMID:29515459

Kv7(KCNQ)-K+-Channels Influence Total Peripheral Resistance in Female but Not Male Rats, and Hamper Catecholamine Release in Hypertensive Rats of Both Sexes.

PubMed

Berg, Torill

2018-01-01

K + -channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if they may contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1-inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine-stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy.

hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism.

PubMed

Perez-Neut, Mathew; Rao, Vidhya R; Gentile, Saverio

2016-09-13

The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers.The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21waf/cip and p16INK4A. In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators.

hERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism

PubMed Central

Perez-Neut, Mathew; Rao, Vidhya R.; Gentile, Saverio

2016-01-01

The function of Kv11.1 is emerging in breast cancer biology, as a growing body of evidence indicates that the hERG1/Kv11.1 potassium channel is aberrantly expressed in several cancer types including breast cancers. The biological effects of Kv11.1 channel blockers and their associated side effects are very well known but the potential use of Kv11.1 activators as an anticancer strategy are still unexplored. In our previous work, we have established that stimulation of the Kv11.1 potassium channel activates a senescent-like program that is characterized by a significant increase in tumor suppressor protein levels, such as p21waf/cip and p16INK4A. In this study we investigated the mechanism linking Kv11.1 stimulation to augmentation of p21waf/cip protein level. We have demonstrated that the Kv11.1 channel activator NS1643 activates a calcineurin-dependent transcription of p21waf/cip and that this event is fundamental for the inhibitory effect of NS1643 on cell proliferation. Our results reveal a novel mechanism by which stimulation of Kv11.1 channel leads to transcription of a potent tumor suppressor and suggest a potential therapeutic use for Kv11.1 channel activators. PMID:25945833

Heterogeneity in Kv7 channel function in the cerebral and coronary circulation.

PubMed

Lee, Sewon; Yang, Yan; Tanner, Miles A; Li, Min; Hill, Michael A

2015-02-01

Kv7 channels are considered important regulators of vascular smooth muscle contractility. The present study aimed to examine the hypotheses that (i) Kv7 channels are present in mouse cerebral and coronary arteries and regulate vascular reactivity and (ii) regional differences exist in the activity of these channels. PCR confirmed that basilar, Circle of Willis and LAD arteries express predominantly Kv7.1 and 7.4. Western blot analysis, however, showed greater Kv7.4 protein levels in the cerebral vessels. Relaxation to the Kv7 channel activator, retigabine (1-50 μM) was significantly greater in the basilar artery compared to the LAD artery. Similarly, the Kv7 channel inhibitor, linopirdine (10 μM) caused a stronger contraction of the basilar artery. Furthermore, pre-incubation with linopirdine reduced forskolin (cAMP activator)-induced vasorelaxation in basilar while not altering forskolin-induced vasorelaxation of the LAD, suggesting that Kv7 channels play a more prominent role in the cerebral than in the coronary circulation. Consistent with the vessel data, whole cell Kv7 currents in cerebral VSMCs were potentiated by retigabine and inhibited by linopirdine, while these responses were blunted in coronary VSMCs. This study provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing novel therapeutics for cardiovascular dysfunction. © 2014 John Wiley & Sons Ltd.

Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels.

PubMed

Sihn, Choong-Ryoul; Kim, Hyo Jeong; Woltz, Ryan L; Yarov-Yarovoy, Vladimir; Yang, Pei-Chi; Xu, Jun; Clancy, Colleen E; Zhang, Xiao-Dong; Chiamvimonvat, Nipavan; Yamoah, Ebenezer N

2016-01-29

Calmodulin (CaM), a Ca(2+)-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca(2+)-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report that CaM binds to two isoforms of the hKv7.4 channel in a Ca(2+)-independent manner but that only the long isoform (hKv7.4a) is regulated by Ca(2+)/CaM. Ca(2+)/CaM mediate reduction of the hKv7.4a channel by decreasing the channel open probability and altering activation kinetics. We took advantage of a known missense mutation (G321S) that has been linked to progressive hearing loss to further examine the inhibitory effects of Ca(2+)/CaM on the Kv7.4 channel. Using multidisciplinary techniques, we demonstrate that the G321S mutation may destabilize CaM binding, leading to a decrease in the inhibitory effects of Ca(2+) on the channels. Our study utilizes an expression system to dissect the biophysical properties of the WT and mutant Kv7.4 channels. This report provides mechanistic insights into the critical roles of Ca(2+)/CaM regulation of the Kv7.4 channel under physiological and pathological conditions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Heterogeneity in Kv7 channel function in the Cerebral and Coronary Circulation

PubMed Central

Tanner, Miles A.; Li, Min; Hill, Michael A.

2014-01-01

Kv7 channels are considered important regulators of vascular smooth muscle contractility. The present study examined the hypotheses that 1. Kv7 channels are present in mouse cerebral and coronary arteries and regulate vascular reactivity, and 2. regional differences exist in the activity of these channels. PCR confirmed that basilar, Circle of Willis and left anterior descending (LAD) arteries express predominantly Kv7.1 and 7.4. Western blot analysis, however, showed greater Kv7.4 protein levels in the cerebral vessels. Relaxation to the Kv7 channel activator, retigabine (1-50μM) was significantly greater in basilar compared to LAD. Similarly, the Kv7 channel inhibitor, linopirdine (10μM) caused stronger contraction of the basilar artery. Furthermore, pre-incubation with linopirdine reduced forskolin (cAMP activator)-induced vasorelaxation in basilar while not altering forskolin-induced vasorelaxation of the LAD, suggesting that Kv7 channels play a more prominent role in the cerebral than coronary circulation. Consistent with the vessel data, whole cell Kv7 currents in cerebral VSMCs were potentiated by retigabine and inhibited by linopirdine, while these responses were blunted in coronary VSMCs. This study provides evidence that mouse Kv7 channels may contribute differently to regulating the functional properties of cerebral and coronary arteries. Such heterogeneity has important implications for developing novel therapeutics for cardiovascular dysfunction. PMID:25476662

The notochord breaks bilateral symmetry by controlling cell shapes in the zebrafish laterality organ.

PubMed

Compagnon, Julien; Barone, Vanessa; Rajshekar, Srivarsha; Kottmeier, Rita; Pranjic-Ferscha, Kornelija; Behrndt, Martin; Heisenberg, Carl-Philipp

2014-12-22

Kupffer's vesicle (KV) is the zebrafish organ of laterality, patterning the embryo along its left-right (LR) axis. Regional differences in cell shape within the lumen-lining KV epithelium are essential for its LR patterning function. However, the processes by which KV cells acquire their characteristic shapes are largely unknown. Here, we show that the notochord induces regional differences in cell shape within KV by triggering extracellular matrix (ECM) accumulation adjacent to anterior-dorsal (AD) regions of KV. This localized ECM deposition restricts apical expansion of lumen-lining epithelial cells in AD regions of KV during lumen growth. Our study provides mechanistic insight into the processes by which KV translates global embryonic patterning into regional cell shape differences required for its LR symmetry-breaking function. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of the scheme of plasmachemical processes on the calculated characteristics of a barrier discharge in xenon

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avtaeva, S. V.; Kulumbaev, E. B.

2008-06-15

The dynamics of a repetitive barrier discharge in xenon at a pressure of 400 Torr is simulated using a one-dimensional drift-diffusion model. The thicknesses of identical barriers with a dielectric constant of 4 are 2 mm, and the gap length is 4 mm. The discharge is fed with an 8-kV ac voltage at a frequency of 25 or 50 kHz. The development of the ionization wave and the breakdown and afterglow phases of a barrier discharge are analyzed using two different kinetic schemes of elementary processes in a xenon plasma. It is shown that the calculated waveforms of the dischargemore » voltage and current, the instant of breakdown, and the number of breakdowns per voltage half-period depend substantially on the properties of the kinetic scheme of plasmachemical processes.« less

Gas chemical studies using corona discharge reactors

NASA Astrophysics Data System (ADS)

Schulze, P.; Stankiewicz, A.; Aicher, M.; Mattner, M.; Ulrich, A.

2010-12-01

Corona discharges with voltages up to 60 kV (DC) were studied with the aim to induce chemical reactions in flue gases at atmospheric pressure. Various plasma reactors with different geometries of multi-needle arrays were tested. The power input was optimised by studying the electrical parameters of the set-up systematically. Both, solid and liquid electrodes were used in combination with the needle arrays. A precise positioning of the corona needles allowed operation without a ballast resistor. Formation rates for CO and the sum of NO2 and O3 are reported and discussed. Three catalytic anode-coatings were tested for their potential to decompose carbon dioxide.

The C-terminal HRET sequence of Kv1.3 regulates gating rather than targeting of Kv1.3 to the plasma membrane.

PubMed

Voros, Orsolya; Szilagyi, Orsolya; Balajthy, András; Somodi, Sándor; Panyi, Gyorgy; Hajdu, Péter

2018-04-12

Kv1.3 channels are expressed in several cell types including immune cells, such as T lymphocytes. The targeting of Kv1.3 to the plasma membrane is essential for T cell clonal expansion and assumed to be guided by the C-terminus of the channel. Using two point mutants of Kv1.3 with remarkably different features compared to the wild-type Kv1.3 (A413V and H399K having fast inactivation kinetics and tetraethylammonium-insensitivity, respectively) we showed that both Kv1.3 channel variants target to the membrane when the C-terminus was truncated right after the conserved HRET sequence and produce currents identical to those with a full-length C-terminus. The truncation before the HRET sequence (NOHRET channels) resulted in reduced membrane-targeting but non-functional phenotypes. NOHRET channels did not display gating currents, and coexpression with wild-type Kv1.3 did not rescue the NOHRET-A413V phenotype, no heteromeric current was observed. Interestingly, mutants of wild-type Kv1.3 lacking HRET(E) (deletion) or substituted with five alanines for the HRET(E) motif expressed current indistinguishable from the wild-type. These results demonstrate that the C-terminal region of Kv1.3 immediately proximal to the S6 helix is required for the activation gating and conduction, whereas the presence of the distal region of the C-terminus is not exclusively required for trafficking of Kv1.3 to the plasma membrane.

Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

PubMed

Liu, Dong-Hai; Huang, Xu; Guo, Xin; Meng, Xiang-Min; Wu, Yi-Song; Lu, Hong-Li; Zhang, Chun-Mei; Kim, Young-chul; Xu, Wen-Xie

2014-01-01

Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV) was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV) to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

Pharmacological Targeting Of Neuronal Kv7.2/3 Channels: A Focus On Chemotypes And Receptor Sites.

PubMed

Miceli, Francesco; Soldovieri, Maria Virginia; Ambrosino, Paolo; Manocchio, Laura; Medoro, Alessandro; Mosca, Ilaria; Taglialatela, Maurizio

2017-10-12

The Kv7 (KCNQ) subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing a characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for development of new drugs for neuronal, cardiac and metabolic diseases. In the present manuscript, we focus on describing the pharmacological relevance and the potential therapeutic applications of drugs acting on neuronally-expressed Kv7.2/3 channels, placing particular emphasis on the different modulator chemotypes, and highlighting their pharmacodynamic and, whenever possible, pharmacokinetic peculiarities. The present work is based on an in-depth search of the currently available scientific literature, and on our own experience and knowledge in the field of neuronal Kv7 channel pharmacology. Space limitations impeded to describe the full pharmacological potential of Kv7 channels; thus, we have chosen to focus on neuronal channels composed of Kv7.2 and Kv7.3 subunits, and to mainly concentrate on their involvement in epilepsy. An astonishing heterogeneity in the molecular scaffolds exploitable to develop Kv7.2/3 modulators is evident, with important structural/functional peculiarities of distinct compound classes. In the present work we have attempted to show the current status and growing potential of the Kv7 pharmacology field. We anticipate a bright future for the field, and we express our hopes that the efforts herein reviewed will result in an improved treatment of hyperexcitability (or any other) diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Power supply

DOEpatents

Yakymyshyn, Christopher Paul; Hamilton, Pamela Jane; Brubaker, Michael Allen

2007-12-04

A modular, low weight impedance dropping power supply with battery backup is disclosed that can be connected to a high voltage AC source and provide electrical power at a lower voltage. The design can be scaled over a wide range of input voltages and over a wide range of output voltages and delivered power.

75 FR 16957 - Energy Conservation Program: Test Procedures for Battery Chargers and External Power Supplies

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-02

... Procedures C. Review of Single-Voltage External Power Supply Test Procedure D. Multiple-Voltage External...) Deletions of Existing Definitions (b) Revisions to Existing Definitions (c) Additions of New Definitions 4. Test Apparatus and General Instructions (a) Confidence Intervals (b) Temperature (c) AC Input Voltage...

Superpave in-situ stress/strain investigation--phase II implementing (SISSI II) : draft report, evaluating the sensitivity of MEPDG to SISSI data.

DOT National Transportation Integrated Search

2009-01-01

The objective of the sensitivity study was to evaluate the input parameters related to AC material properties, traffic, and climate that significantly or insignificantly influence the predicted performance for two specific SISSI flexible pavements: W...

75 FR 56051 - Bemidji to Grand Rapids Minnesota 230 kV Transmission Line Project

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-15

... Service Bemidji to Grand Rapids Minnesota 230 kV Transmission Line Project AGENCY: Rural Utilities Service... Environmental Impact Statement (EIS) for the proposed Bemidji to Grand Rapids, Minnesota 230 kV Transmission... Cooperative, Inc. for RUS financing to construct a 230 kilovolt (kV) transmission line between the Wilton...

Cortisone and hydrocortisone inhibit human Kv1.3 activity in a non-genomic manner.

PubMed

Yu, Jing; Park, Mi-Hyeong; Choi, Se-Young; Jo, Su-Hyun

2015-06-01

Glucocorticoids are hormones released in response to stress that are involved in various physiological processes including immune functions. One immune-modulating mechanism is achieved by the Kv1.3 voltage-dependent potassium channel, which is expressed highly in lymphocytes including effector memory T lymphocytes (TEM). Although glucocorticoids are known to inhibit Kv1.3 function, the detailed inhibitory mechanism is not yet fully understood. Here we studied the rapid non-genomic effects of cortisone and hydrocortisone on the human Kv1.3 channel expressed in Xenopus oocytes. Both cortisone and hydrocortisone reduced the amplitude of the Kv1.3 channel current in a concentration-dependent manner. Both cortisone and hydrocortisone rapidly and irreversibly inhibited Kv1.3 currents, eliminating the possibility of genomic regulation. Inhibition rate was stable relative to the degree of depolarization. Kinetically, cortisone altered the activating gate of Kv1.3 and hydrocortisone interacted with this channel in an open state. These results suggest that cortisone and hydrocortisone inhibit Kv1.3 currents via a non-genomic mechanism, providing a mechanism for the immunosuppressive effects of glucocorticoids.

Decrease of a Current Mediated by Kv1.3 Channels Causes Striatal Cholinergic Interneuron Hyperexcitability in Experimental Parkinsonism.

PubMed

Tubert, Cecilia; Taravini, Irene R E; Flores-Barrera, Eden; Sánchez, Gonzalo M; Prost, María Alejandra; Avale, María Elena; Tseng, Kuei Y; Rela, Lorena; Murer, Mario Gustavo

2016-09-06

The mechanism underlying a hypercholinergic state in Parkinson's disease (PD) remains uncertain. Here, we show that disruption of the Kv1 channel-mediated function causes hyperexcitability of striatal cholinergic interneurons in a mouse model of PD. Specifically, our data reveal that Kv1 channels containing Kv1.3 subunits contribute significantly to the orphan potassium current known as IsAHP in striatal cholinergic interneurons. Typically, this Kv1 current provides negative feedback to depolarization that limits burst firing and slows the tonic activity of cholinergic interneurons. However, such inhibitory control of cholinergic interneuron excitability by Kv1.3-mediated current is markedly diminished in the parkinsonian striatum, suggesting that targeting Kv1.3 subunits and their regulatory pathways may have therapeutic potential in PD therapy. These studies reveal unexpected roles of Kv1.3 subunit-containing channels in the regulation of firing patterns of striatal cholinergic interneurons, which were thought to be largely dependent on KCa channels. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Casper to Dave Johnston 230-kV Transmission Line Project: Environmental assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1986-01-01

Western proposes to reconstruct the existing Casper-Glendo North 115-kV Transmission Line to 230-kV between a point 1.1 miles northeast of the Pacific Power and Light (Pacific) Casper Substation and the Dave Johnston (DJ) Powerplant near Glenrock, Wyoming. As part of the proposed action, Western proposes to remove the portion of the existing Casper-Glendo South 115-kV Transmission Line between Western's Casper Substation and the intersection with the Casper-Glendo North Transmission Line, about 15 miles east of Casper. The removed portion of the Casper-Glendo North Transmission Line would be rebuilt on steel, single-shaft, structures. The section between the point northeast of themore » Pacific Substation and the intersection with the Casper-Glendo South Transmission Line would be double circuit (230-kV/115-kV). At the intersection of the north and south lines, the new 115-kV section would be tied to the remaining portion of the Casper-Glendo South Line to complete the 115-kV Casper-Glendo circuit. 52 refs.,12 figs., 14 tabs.« less

Modulation by clamping: Kv4 and KChIP interactions.

PubMed

Wang, Kewei

2008-10-01

The rapidly inactivating (A-type) potassium channels regulate membrane excitability that defines the fundamental mechanism of neuronal functions such as pain signaling. Cytosolic Kv channel-interacting proteins KChIPs that belong to neuronal calcium sensor (NCS) family of calcium binding EF-hand proteins co-assemble with Kv4 (Shal) alpha subunits to form a native complex that encodes major components of neuronal somatodendritic A-type K+ current, I(SA), in neurons and transient outward current, I(TO), in cardiac myocytes. The specific binding of auxiliary KChIPs to the Kv4 N-terminus results in modulation of gating properties, surface expression and subunit assembly of Kv4 channels. Here, I attempt to emphasize the interaction between KChIPs and Kv4 based on recent progress made in understanding the structure complex in which a single KChIP1 molecule laterally clamps two neighboring Kv4.3 N-termini in a 4:4 manner. Greater insights into molecular mechanism between KChIPs and Kv4 interaction may provide therapeutic potentials of designing compounds aimed at disrupting the protein-protein interaction for treatment of membrane excitability-related disorders.

The ITER ICRF Antenna Design with TOPICA

NASA Astrophysics Data System (ADS)

Milanesio, Daniele; Maggiora, Riccardo; Meneghini, Orso; Vecchi, Giuseppe

2007-11-01

TOPICA (Torino Polytechnic Ion Cyclotron Antenna) code is an innovative tool for the 3D/1D simulation of Ion Cyclotron Radio Frequency (ICRF), i.e. accounting for antennas in a realistic 3D geometry and with an accurate 1D plasma model [1]. The TOPICA code has been deeply parallelized and has been already proved to be a reliable tool for antennas design and performance prediction. A detailed analysis of the 24 straps ITER ICRF antenna geometry has been carried out, underlining the strong dependence and asymmetries of the antenna input parameters due to the ITER plasma response. We optimized the antenna array geometry dimensions to maximize loading, lower mutual couplings and mitigate sheath effects. The calculated antenna input impedance matrices are TOPICA results of a paramount importance for the tuning and matching system design. Electric field distributions have been also calculated and they are used as the main input for the power flux estimation tool. The designed optimized antenna is capable of coupling 20 MW of power to plasma in the 40 -- 55 MHz frequency range with a maximum voltage of 45 kV in the feeding coaxial cables. [1] V. Lancellotti et al., Nuclear Fusion, 46 (2006) S476-S499

Study of Photon Emission with the Fission Event Generator FREYA

NASA Astrophysics Data System (ADS)

Vogt, Ramona; Randrup, Jorgen

2017-09-01

The event-by-event fission model FREYA is employed to study photon observables. The model has been expanded beyond the simple statistical photon emission reported previously to include the discrete RIPL-3 lines. We update these prior results and discuss the sensitivity of the results to the FREYA input parameters sensitive to photon observables. The work of R.V. was performed under the auspices of the U.S. DOE by LLNL Contract DE-AC52-07NA27344, that of J.R. by LBNL Contract DE-AC02-05CH11231. The authors thank NNSA Defense Nuclear Nonproliferation R&D for support.

[Impact of exposure dose reduction of radiation treatment planning CT using low tube voltage technique].

PubMed

Kouno, Takuya; Kuga, Noriyuki; Enzaki, Masahiro; Yamashita, Yuuki; Kitazato, Yumiko; Shimotabira, Haruhiko; Jinnouchi, Takashi; Kusuhara, Kazuo; Kawamura, Shinji

2015-04-01

The aim of this study was to reduce the exposed dose of radiotherapy treatment planning computed tomography (CT) by using low tube voltage technique. We used tube voltages of 80 kV, 100 kV, and 120 kV, respectively. First, we evaluated exposure dose with CT dose index (CTDI) for each voltage. Second, we compared image quality indexes such as modulation transfer function (MTF), noise power spectrum (NPS), and contrast to noise ratio (CNR) of phantom images with each voltage. Third, CT to electron density tables were measured in three voltages and monitor unit value was calculated along with clinical cases. Finally, CT surface exposed dose of chest skin was measured by thermoluminescent dosimeter (TLD). In image evaluation MTF and NPS were approximately equal; CNR slightly decreased, 2.0% for 100 kV. We performed check radiation dose accuracy for each tube voltage with each model phantom. As a result, the difference of MU value was not accepted. Finally, compared with 120 kV, CTDIvol and TLD value showed markedly decreased radiation dose, 60% for 80 kV and 30% for 100 kV. Using a technique with low tube voltages, especially 100 kV, is useful in radiotherapy treatment planning to obtain 20% dose reduction without compromising 120 kV image quality.

Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis.

PubMed

Romi, Fredrik; Suzuki, Shigeaki; Suzuki, Norihiro; Petzold, Axel; Plant, Gordon T; Gilhus, Nils Erik

2012-07-01

Myasthenia gravis (MG) is an autoimmune disease characterized by skeletal muscle weakness mainly caused by acetylcholine receptor antibodies. MG can be divided into generalized and ocular, and into early-onset (<50 years of age) and late-onset (≥50 years of age). Anti-Kv1.4 antibodies targeting α-subunits (Kv1.4) of the voltage-gated potassium K(+) channel occurs frequently among patients with severe MG, accounting for 18% of a Japanese MG population. The aim of this study was to characterize the clinical features and serological associations of anti-Kv1.4 antibodies in a Caucasian MG population with mild and localized MG. Serum samples from 129 Caucasian MG patients with mainly ocular symptoms were tested for the presence of anti-Kv1.4 antibodies and compared to clinical and serological parameters. There were 22 (17%) anti-Kv1.4 antibody-positive patients, most of them women with late-onset MG, and all of them with mild MG. This contrasts to the Japanese anti-Kv1.4 antibody-positive patients who suffered from severe MG with bulbar symptoms, myasthenic crisis, thymoma, myocarditis and prolonged QT time on electrocardiography, despite equal anti-Kv1.4 antibody occurrence in both populations. No other clinical or serological parameters influenced anti-Kv1.4 antibody occurrence.

PWM Inverter control and the application thereof within electric vehicles

DOEpatents

Geppert, Steven

1982-01-01

An inverter (34) which provides power to an A.C. machine (28) is controlled by a circuit (36) employing PWM control strategy whereby A.C. power is supplied to the machine at a preselectable frequency and preselectable voltage. This is accomplished by the technique of waveform notching in which the shapes of the notches are varied to determine the average energy content of the overall waveform. Through this arrangement, the operational efficiency of the A.C. machine is optimized. The control circuit includes a micro-computer and memory element which receive various parametric inputs and calculate optimized machine control data signals therefrom. The control data is asynchronously loaded into the inverter through an intermediate buffer (38). In its preferred embodiment, the present invention is incorporated within an electric vehicle (10) employing a 144 VDC battery pack (32) and a three-phase induction motor (18).

Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

PubMed Central

Covarrubias, Anthony J; Aksoylar, Halil Ibrahim; Yu, Jiujiu; Snyder, Nathaniel W; Worth, Andrew J; Iyer, Shankar S; Wang, Jiawei; Ben-Sahra, Issam; Byles, Vanessa; Polynne-Stapornkul, Tiffany; Espinosa, Erika C; Lamming, Dudley; Manning, Brendan D; Zhang, Yijing; Blair, Ian A; Horng, Tiffany

2016-01-01

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation. DOI: http://dx.doi.org/10.7554/eLife.11612.001 PMID:26894960

EV drivetrain inverter with V/HZ optimization

DOEpatents

Gritter, David J.; O'Neil, Walter K.

1986-01-01

An inverter (34) which provides power to an A.C. machine (28) is controlled by a circuit (36) employing PWM control strategy whereby A.C. power is supplied to the machine at a preselectable frequency and preselectable voltage. This is accomplished by the technique of waveform notching in which the shapes of the notches are varied to determine the average energy content of the overall waveform. Through this arrangement, the operational efficiency of the A.C. machine is optimized. The control circuit includes a micro-computer which calculates optimized machine control data signals from various parametric inputs and during steady state load conditions, seeks a best V/HZ ratio to minimize battery current drawn (system losses) from a D.C. power source (32). In the preferred embodiment, the present invention is incorporated within an electric vehicle (10) employing a 144 VDC battery pack and a three-phase induction motor (18).

Use-dependent activation of neuronal Kv1.2 channel complexes.

PubMed

Baronas, Victoria A; McGuinness, Brandon R; Brigidi, G Stefano; Gomm Kolisko, Rachel N; Vilin, Yury Y; Kim, Robin Y; Lynn, Francis C; Bamji, Shernaz X; Yang, Runying; Kurata, Harley T

2015-02-25

In excitable cells, ion channels are frequently challenged by repetitive stimuli, and their responses shape cellular behavior by regulating the duration and termination of bursts of action potentials. We have investigated the behavior of Shaker family voltage-gated potassium (Kv) channels subjected to repetitive stimuli, with a particular focus on Kv1.2. Genetic deletion of this subunit results in complete mortality within 2 weeks of birth in mice, highlighting a critical physiological role for Kv1.2. Kv1.2 channels exhibit a unique property described previously as "prepulse potentiation," in which activation by a depolarizing step facilitates activation in a subsequent pulse. In this study, we demonstrate that this property enables Kv1.2 channels to exhibit use-dependent activation during trains of very brief depolarizations. Also, Kv subunits usually assemble into heteromeric channels in the central nervous system, generating diversity of function and sensitivity to signaling mechanisms. We demonstrate that other Kv1 channel types do not exhibit use-dependent activation, but this property is conferred in heteromeric channel complexes containing even a single Kv1.2 subunit. This regulatory mechanism is observed in mammalian cell lines as well as primary cultures of hippocampal neurons. Our findings illustrate that use-dependent activation is a unique property of Kv1.2 that persists in heteromeric channel complexes and may influence function of hippocampal neurons. Copyright © 2015 the authors 0270-6474/15/353515-10$15.00/0.

A Drosophila Model of Essential Tremor.

PubMed

Smith, Philip; Arias, Ronald; Sonti, Shilpa; Odgerel, Zagaa; Santa-Maria, Ismael; McCabe, Brian D; Tsaneva-Atanasova, Krasimira; Louis, Elan D; Hodge, James J L; Clark, Lorraine N

2018-05-16

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K + channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K + channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.

Identification of a key residue in Kv7.1 potassium channel essential for sensing external potassium ions.

PubMed

Wang, Wenying; Flores, Maria Cristina Perez; Sihn, Choong-Ryoul; Kim, Hyo Jeong; Zhang, Yinuo; Doyle, Karen J; Chiamvimonvat, Nipavan; Zhang, Xiao-Dong; Yamoah, Ebenezer N

2015-03-01

Kv7.1 voltage-gated K(+) (Kv) channels are present in the apical membranes of marginal cells of the stria vascularis of the inner ear, where they mediate K(+) efflux into the scala media (cochlear duct) of the cochlea. As such, they are exposed to the K(+)-rich (∼ 150 mM of external K(+) (K(+) e)) environment of the endolymph. Previous studies have shown that Kv7.1 currents are substantially suppressed by high K(+) e (independent of the effects of altering the electrochemical gradient). However, the molecular basis for this inhibition, which is believed to involve stabilization of an inactivated state, remains unclear. Using sequence alignment of S5-pore linkers of several Kv channels, we identified a key residue, E290, found in only a few Kv channels including Kv7.1. We used substituted cysteine accessibility methods and patch-clamp analysis to provide evidence that the ability of Kv7.1 to sense K(+) e depends on E290, and that the charge at this position is essential for Kv7.1's K(+) e sensitivity. We propose that Kv7.1 may use this feedback mechanism to maintain the magnitude of the endocochlear potential, which boosts the driving force to generate the receptor potential of hair cells. The implications of our findings transcend the auditory system; mutations at this position also result in long QT syndrome in the heart. © 2015 Wang et al.

Specification of skeletal muscle differentiation by repressor element-1 silencing transcription factor (REST)-regulated Kv7.4 potassium channels

PubMed Central

Iannotti, Fabio Arturo; Barrese, Vincenzo; Formisano, Luigi; Miceli, Francesco; Taglialatela, Maurizio

2013-01-01

Changes in the expression of potassium (K+) channels is a pivotal event during skeletal muscle differentiation. In mouse C2C12 cells, similarly to human skeletal muscle cells, myotube formation increased the expression of Kv7.1, Kv7.3, and Kv7.4, the last showing the highest degree of regulation. In C2C12 cells, Kv7.4 silencing by RNA interference reduced the expression levels of differentiation markers (myogenin, myosin heavy chain, troponinT-1, and Pax3) and impaired myotube formation and multinucleation. In Kv7.4-silenced cells, the differentiation-promoting effect of the Kv7 activator N-(2-amino-4-(4-fluorobenzylamino)-phenyl)-carbamic acid ethyl ester (retigabine) was abrogated. Expression levels for the repressor element-1 silencing transcription factor (REST) declined during myotube formation. Transcript levels for Kv7.4, as well as for myogenin, troponinT-1, and Pax3, were reduced by REST overexpression and enhanced upon REST suppression by RNA interference. Four regions containing potential REST-binding sites in the 5′ untranslated region and in the first intron of the Kv7.4 gene were identified by bioinformatic analysis. Chromatin immunoprecipitation assays showed that REST binds to these regions, exhibiting a higher efficiency in myoblasts than in myotubes. These data suggest that Kv7.4 plays a permissive role in skeletal muscle differentiation and highlight REST as a crucial transcriptional regulator for this K+ channel subunit. PMID:23242999

Retigabine holds KV7 channels open and stabilizes the resting potential

PubMed Central

Corbin-Leftwich, Aaron; Mossadeq, Sayeed M.; Ha, Junghoon; Ruchala, Iwona; Le, Audrey Han Ngoc

2016-01-01

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine’s action remains unknown, previous studies have identified the pore region of KV7 channels as the drug’s target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered. PMID:26880756

Retigabine holds KV7 channels open and stabilizes the resting potential.

PubMed

Corbin-Leftwich, Aaron; Mossadeq, Sayeed M; Ha, Junghoon; Ruchala, Iwona; Le, Audrey Han Ngoc; Villalba-Galea, Carlos A

2016-03-01

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine's action remains unknown, previous studies have identified the pore region of KV7 channels as the drug's target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 and O2, with O2 being more stable. The O1 state was reached after short membrane depolarizations, whereas O2 was reached after prolonged depolarization or during steady state at the typical neuronal resting potentials. We also found that activation and deactivation seem to follow distinct pathways, suggesting that the KV7.2/KV7.3 channel activity displays hysteresis. As for the action of Retigabine, we discovered that this agonist discriminates between open states, preferentially acting on the O2 state and further stabilizing it. Based on these findings, we proposed a novel mechanism for the therapeutic effect of Retigabine whereby this drug reduces excitability by enhancing the resting potential open state stability of KV7.2/KV7.3 channels. To address this hypothesis, we used a model for action potential (AP) in Xenopus laevis oocytes and found that the resting membrane potential became more negative as a function of Retigabine concentration, whereas the threshold potential for AP firing remained unaltered. © 2016 Corbin-Leftwich et al.

Kv7 channels critically determine coronary artery reactivity: left-right differences and down-regulation by hyperglycaemia.

PubMed

Morales-Cano, Daniel; Moreno, Laura; Barreira, Bianca; Pandolfi, Rachele; Chamorro, Virginia; Jimenez, Rosario; Villamor, Eduardo; Duarte, Juan; Perez-Vizcaino, Francisco; Cogolludo, Angel

2015-04-01

Voltage-gated potassium channels encoded by KCNQ genes (Kv7 channels) are emerging as important regulators of vascular tone. In this study, we analysed the contribution of Kv7 channels to the vasodilation induced by hypoxia and the cyclic AMP pathway in the coronary circulation. We also assessed their regional distribution and possible impairment by diabetes. We examined the effects of Kv7 channel modulators on K+ currents and vascular reactivity in rat left and right coronary arteries (LCAs and RCAs, respectively). Currents from LCA were more sensitive to Kv7 channel inhibitors (XE991, linopirdine) and activators (flupirtine, retigabine) than those from RCA. Accordingly, LCAs were more sensitive than RCAs to the relaxation induced by Kv7 channel enhancers. Likewise, relaxation induced by the adenylyl cyclase activator forskolin and hypoxia, which were mediated through Kv7 channel activation, were greater in LCA than in RCA. KCNQ1 and KCNQ5 expression was markedly higher in LCA than in RCA. After incubation with high glucose (HG, 30 mmol/L), myocytes from LCA, but not from RCA, were more depolarized and showed reduced Kv7 currents. In HG-incubated LCA, the effects of Kv7 channel modulators and forskolin were diminished, and the expression of KCNQ1 and KCNQ5 was reduced. Finally, vascular responses induced by Kv7 channel modulators were impaired in LCA, but not in RCA, from type 1 diabetic rats. Our results reveal that the high expression and function of Kv7 channels in the LCA and their down-regulation by diabetes critically determine the sensitivity to key regulators of coronary tone. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Inhibitory effects of pimozide on cloned and native voltage-gated potassium channels.

PubMed

Zhang, Zhi-Hao; Lee, Yan T; Rhodes, Kenneth; Wang, Kewei; Argentieri, Thomas M; Wang, Qiang

2003-07-04

The primary goal of this study was to use the cloned neuronal Kv channels to test if pimozide (PMZD), an antipsychotic drug, modulates the activity of Kv channels. In CHO cells, PMZD blocked Kv2.1, a major neuronal delayed rectifier, in a manner that depends upon time and concentration. The estimated IC50 was 4.2 microM at +50 mV. Tail current analysis shows that PMZD reduced the amplitude of the currents, with no effect on the steady-state activation curve (V(1/2) from 14.1 to 11.1 mV) or the slope (16.7 vs. 14.0 mV). From -120 to -20 mV, PMZD did not impact the deactivation kinetics of Kv2.1. PMZD also blocked Kv1.1, another neuronal delayed rectifier, with 16.1 microM of IC50. When Kv1.1 was co-expressed with Kvbeta1, approximately 50% of the Kv1.1 were converted into an inactivating A-type current and the Kv1.1/Kvbeta1 A-type currents were insensitive to PMZD. PMZD (10 microM) had minimal effect on Kv1.4, and had no effect on the M-current candidates, KCNQ2 and KCNQ3 when co-expressed in Xenopus oocytes. In hippocampal neurons, PMZD inhibited the delayed rectifiers by approximately 60%, and A-type currents were insensitive to PMZD. The results suggest that PMZD inhibits certain neuronal Kv channels in heterologous expression systems and in hippocampal neurons. PMZD was less effective on A-type currents, presumably because its ability to block requires a prolonged opening of the K channels. It is thus conceivable that the time-dependent and/or subunit-specific inhibition of Kv channels may increase the release of neurotransmitters such as serotonin and glutamate.

A-type voltage-gated K+ currents influence firing properties of isolectin B4-positive but not isolectin B4-negative primary sensory neurons.

PubMed

Vydyanathan, Amaresh; Wu, Zi-Zhen; Chen, Shao-Rui; Pan, Hui-Lin

2005-06-01

Voltage-gated K+ channels (Kv) in primary sensory neurons are important for regulation of neuronal excitability. The dorsal root ganglion (DRG) neurons are heterogeneous, and the types of native Kv currents in different groups of nociceptive DRG neurons are not fully known. In this study, we determined the difference in the A-type Kv current and its influence on the firing properties between isolectin B4 (IB4)-positive and -negative DRG neurons. Whole cell voltage- and current-clamp recordings were performed on acutely dissociated small DRG neurons of rats. The total Kv current density was significantly higher in IB+-positive than that in IB(4)-negative neurons. Also, 4-aminopyridine (4-AP) produced a significantly greater reduction in Kv currents in IB4-positive than in IB4-negative neurons. In contrast, IB4-negative neurons exhibited a larger proportion of tetraethylammonium-sensitive Kv currents. Furthermore, IB4-positive neurons showed a longer latency of firing and required a significantly larger amount of current injection to evoke action potentials. 4-AP significantly decreased the latency of firing and increased the firing frequency in IB4-positive but not in IB4-negative neurons. Additionally, IB4-positive neurons are immunoreactive to Kv1.4 but not to Kv1.1 and Kv1.2 subunits. Collectively, this study provides new information that 4-AP-sensitive A-type Kv currents are mainly present in IB4-positive DRG neurons and preferentially dampen the initiation of action potentials of this subpopulation of nociceptors. The difference in the density of A-type Kv currents contributes to the distinct electrophysiological properties of IB4-positive and -negative DRG neurons.

Low tube voltage dual source computed tomography to reduce contrast media doses in adult abdomen examinations: A phantom study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thor, Daniel; Brismar, Torkel B., E-mail: torkel.brismar@gmail.com; Fischer, Michael A.

Purpose: To evaluate the potential of low tube voltage dual source (DS) single energy (SE) and dual energy (DE) computed tomography (CT) to reduce contrast media (CM) dose in adult abdominal examinations of various sizes while maintaining soft tissue and iodine contrast-to-noise ratio (CNR). Methods: Four abdominal phantoms simulating a body mass index of 16 to 35 kg/m{sup 2} with four inserted syringes of 0, 2, 4, and 8 mgI/ml CM were scanned using a 64-slice DS-CT scanner. Six imaging protocols were used; one single source (SS) reference protocol (120 kV, 180 reference mAs), four low kV SE protocols (70more » and 80 kV using both SS and DS), and one DE protocol at 80/140 kV. Potential CM reduction with unchanged CNRs relative to the 120 kV protocol was calculated along with the corresponding increase in radiation dose. Results: The potential contrast media reductions were determined to be approximately 53% for DS 70 kV, 51% for SS 70 kV, 44% for DS 80 kV, 40% for SS 80 kV, and 20% for DE (all differences were significant, P < 0.05). Constant CNR could be achieved by using DS 70 kV for small to medium phantom sizes (16–26 kg/m{sup 2}) and for all sizes (16–35 kg/m{sup 2}) when using DS 80 kV and DE. Corresponding radiation doses increased by 60%–107%, 23%–83%, and 6%–12%, respectively. Conclusions: DS single energy CT can be used to reduce CM dose by 44%–53% with maintained CNR in adult abdominal examinations at the cost of an increased radiation dose. DS dual-energy CT allows reduction of CM dose by 20% at similar radiation dose as compared to a standard 120 kV single source.« less

Immunohistochemical localization of DPP10 in rat brain supports the existence of a Kv4/KChIP/DPPL ternary complex in neurons.

PubMed

Wang, Wan-Chen; Cheng, Chau-Fu; Tsaur, Meei-Ling

2015-03-01

Subthreshold A-type K(+) currents (ISA s) have been recorded from the cell bodies of hippocampal and neocortical interneurons as well as neocortical pyramidal neurons. Kv4 channels are responsible for the somatodendritic ISA s. It has been proposed that neuronal Kv4 channels are ternary complexes including pore-forming Kv4 subunits, K(+) channel-interacting proteins (KChIPs), and dipeptidyl peptidase-like proteins (DPPLs). However, colocalization evidence was still lacking. The distribution of DPP10 mRNA in rodent brain has been reported but its protein localization remains unknown. In this study, we generated a DPP10 antibody to label DPP10 protein in adult rat brain by immunohistochemistry. Absent from glia, DPP10 proteins appear mainly in the cell bodies of DPP10(+) neurons, not only at the plasma membrane but also in the cytoplasm. At least 6.4% of inhibitory interneurons in the hippocampus coexpressed Kv4.3, KChIP1, and DPP10, with the highest density in the CA1 strata alveus/oriens/pyramidale and the dentate hilus. Colocalization of Kv4.3/KChIP1/DPP10 was also detected in at least 6.9% of inhibitory interneurons scattered throughout the neocortex. Both hippocampal and neocortical Kv4.3/KChIP1/DPP10(+) inhibitory interneurons expressed parvalbumin or somatostatin, but not calbindin or calretinin. Furthermore, we found colocalization of Kv4.2/Kv4.3/KChIP3/DPP10 in neocortical layer 5 pyramidal neurons and olfactory bulb mitral cells. Together, although DPP10 is also expressed in some brain neurons lacking Kv4 (such as parvalbumin- and somatostatin-positive Golgi cells in the cerebellum), colocalization of DPP10 with Kv4 and KChIP at the plasma membrane of ISA -expressing neuron somata supports the existence of Kv4/KChIP/DPPL ternary complex in vivo. © 2014 Wiley Periodicals, Inc.

The tetramerization domain potentiates Kv4 channel function by suppressing closed-state inactivation.

PubMed

Tang, Yi-Quan; Zhou, Jing-Heng; Yang, Fan; Zheng, Jie; Wang, KeWei

2014-09-02

A-type Kv4 potassium channels undergo a conformational change toward a nonconductive state at negative membrane potentials, a dynamic process known as pre-open closed states or closed-state inactivation (CSI). CSI causes inhibition of channel activity without the prerequisite of channel opening, thus providing a dynamic regulation of neuronal excitability, dendritic signal integration, and synaptic plasticity at resting. However, the structural determinants underlying Kv4 CSI remain largely unknown. We recently showed that the auxiliary KChIP4a subunit contains an N-terminal Kv4 inhibitory domain (KID) that directly interacts with Kv4.3 channels to enhance CSI. In this study, we utilized the KChIP4a KID to probe key structural elements underlying Kv4 CSI. Using fluorescence resonance energy transfer two-hybrid mapping and bimolecular fluorescence complementation-based screening combined with electrophysiology, we identified the intracellular tetramerization (T1) domain that functions to suppress CSI and serves as a receptor for the binding of KID. Disrupting the Kv4.3 T1-T1 interaction interface by mutating C110A within the C3H1 motif of T1 domain facilitated CSI and ablated the KID-mediated enhancement of CSI. Furthermore, replacing the Kv4.3 T1 domain with the T1 domain from Kv1.4 (without the C3H1 motif) or Kv2.1 (with the C3H1 motif) resulted in channels functioning with enhanced or suppressed CSI, respectively. Taken together, our findings reveal a novel (to our knowledge) role of the T1 domain in suppressing Kv4 CSI, and that KChIP4a KID directly interacts with the T1 domain to facilitate Kv4.3 CSI, thus leading to inhibition of channel function. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Coexpression of high-voltage-activated ion channels Kv3.4 and Cav1.2 in pioneer axons during pathfinding in the developing rat forebrain.

PubMed

Huang, Chia-Yi; Chu, Dachen; Hwang, Wei-Chao; Tsaur, Meei-Ling

2012-11-01

Precise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage-gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage-gated ion channels (Kv1.1-Kv1.3, Kv3.1-Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A-type K⁺ channel Kv3.4 in both pioneer axons and early follower axons and L-type Ca²⁺ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high-voltage-activated ion channels, may act together to control Ca²⁺ -dependent electrical activity of pioneer axons and play important roles during axon pathfinding. Copyright © 2012 Wiley Periodicals, Inc.

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.

PubMed

Bartos, Daniel C; Giudicessi, John R; Tester, David J; Ackerman, Michael J; Ohno, Seiko; Horie, Minoru; Gollob, Michael H; Burgess, Don E; Delisle, Brian P

2014-03-01

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K(+) current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤460 ms). To determine whether a specific molecular mechanism contributes to concealed LQT1. We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations. Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients' genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths. KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Tungsten anode spectral model using interpolating cubic splines: unfiltered x-ray spectra from 20 kV to 640 kV.

PubMed

Hernandez, Andrew M; Boone, John M

2014-04-01

Monte Carlo methods were used to generate lightly filtered high resolution x-ray spectra spanning from 20 kV to 640 kV. X-ray spectra were simulated for a conventional tungsten anode. The Monte Carlo N-Particle eXtended radiation transport code (MCNPX 2.6.0) was used to produce 35 spectra over the tube potential range from 20 kV to 640 kV, and cubic spline interpolation procedures were used to create piecewise polynomials characterizing the photon fluence per energy bin as a function of x-ray tube potential. Using these basis spectra and the cubic spline interpolation, 621 spectra were generated at 1 kV intervals from 20 to 640 kV. The tungsten anode spectral model using interpolating cubic splines (TASMICS) produces minimally filtered (0.8 mm Be) x-ray spectra with 1 keV energy resolution. The TASMICS spectra were compared mathematically with other, previously reported spectra. Using pairedt-test analyses, no statistically significant difference (i.e., p > 0.05) was observed between compared spectra over energy bins above 1% of peak bremsstrahlung fluence. For all energy bins, the correlation of determination (R(2)) demonstrated good correlation for all spectral comparisons. The mean overall difference (MOD) and mean absolute difference (MAD) were computed over energy bins (above 1% of peak bremsstrahlung fluence) and over all the kV permutations compared. MOD and MAD comparisons with previously reported spectra were 2.7% and 9.7%, respectively (TASMIP), 0.1% and 12.0%, respectively [R. Birch and M. Marshall, "Computation of bremsstrahlung x-ray spectra and comparison with spectra measured with a Ge(Li) detector," Phys. Med. Biol. 24, 505-517 (1979)], 0.4% and 8.1%, respectively (Poludniowski), and 0.4% and 8.1%, respectively (AAPM TG 195). The effective energy of TASMICS spectra with 2.5 mm of added Al filtration ranged from 17 keV (at 20 kV) to 138 keV (at 640 kV); with 0.2 mm of added Cu filtration the effective energy was 9 keV at 20 kV and 169 keV at 640 kV. Ranging from 20 kV to 640 kV, 621 x-ray spectra were produced and are available at 1 kV tube potential intervals. The spectra are tabulated at 1 keV intervals. TASMICS spectra were shown to be largely equivalent to published spectral models and are available in spreadsheet format for interested users by emailing the corresponding author (JMB). © 2014 American Association of Physicists in Medicine.

Tungsten anode spectral model using interpolating cubic splines: Unfiltered x-ray spectra from 20 kV to 640 kV

PubMed Central

Hernandez, Andrew M.; Boone, John M.

2014-01-01

Purpose: Monte Carlo methods were used to generate lightly filtered high resolution x-ray spectra spanning from 20 kV to 640 kV. Methods: X-ray spectra were simulated for a conventional tungsten anode. The Monte Carlo N-Particle eXtended radiation transport code (MCNPX 2.6.0) was used to produce 35 spectra over the tube potential range from 20 kV to 640 kV, and cubic spline interpolation procedures were used to create piecewise polynomials characterizing the photon fluence per energy bin as a function of x-ray tube potential. Using these basis spectra and the cubic spline interpolation, 621 spectra were generated at 1 kV intervals from 20 to 640 kV. The tungsten anode spectral model using interpolating cubic splines (TASMICS) produces minimally filtered (0.8 mm Be) x-ray spectra with 1 keV energy resolution. The TASMICS spectra were compared mathematically with other, previously reported spectra. Results: Using paired t-test analyses, no statistically significant difference (i.e., p > 0.05) was observed between compared spectra over energy bins above 1% of peak bremsstrahlung fluence. For all energy bins, the correlation of determination (R2) demonstrated good correlation for all spectral comparisons. The mean overall difference (MOD) and mean absolute difference (MAD) were computed over energy bins (above 1% of peak bremsstrahlung fluence) and over all the kV permutations compared. MOD and MAD comparisons with previously reported spectra were 2.7% and 9.7%, respectively (TASMIP), 0.1% and 12.0%, respectively [R. Birch and M. Marshall, “Computation of bremsstrahlung x-ray spectra and comparison with spectra measured with a Ge(Li) detector,” Phys. Med. Biol. 24, 505–517 (1979)], 0.4% and 8.1%, respectively (Poludniowski), and 0.4% and 8.1%, respectively (AAPM TG 195). The effective energy of TASMICS spectra with 2.5 mm of added Al filtration ranged from 17 keV (at 20 kV) to 138 keV (at 640 kV); with 0.2 mm of added Cu filtration the effective energy was 9 keV at 20 kV and 169 keV at 640 kV. Conclusions: Ranging from 20 kV to 640 kV, 621 x-ray spectra were produced and are available at 1 kV tube potential intervals. The spectra are tabulated at 1 keV intervals. TASMICS spectra were shown to be largely equivalent to published spectral models and are available in spreadsheet format for interested users by emailing the corresponding author (JMB). PMID:24694149

Tungsten anode spectral model using interpolating cubic splines: Unfiltered x-ray spectra from 20 kV to 640 kV

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hernandez, Andrew M.; Boone, John M., E-mail: john.boone@ucdmc.ucdavis.edu

Purpose: Monte Carlo methods were used to generate lightly filtered high resolution x-ray spectra spanning from 20 kV to 640 kV. Methods: X-ray spectra were simulated for a conventional tungsten anode. The Monte Carlo N-Particle eXtended radiation transport code (MCNPX 2.6.0) was used to produce 35 spectra over the tube potential range from 20 kV to 640 kV, and cubic spline interpolation procedures were used to create piecewise polynomials characterizing the photon fluence per energy bin as a function of x-ray tube potential. Using these basis spectra and the cubic spline interpolation, 621 spectra were generated at 1 kV intervalsmore » from 20 to 640 kV. The tungsten anode spectral model using interpolating cubic splines (TASMICS) produces minimally filtered (0.8 mm Be) x-ray spectra with 1 keV energy resolution. The TASMICS spectra were compared mathematically with other, previously reported spectra. Results: Using pairedt-test analyses, no statistically significant difference (i.e., p > 0.05) was observed between compared spectra over energy bins above 1% of peak bremsstrahlung fluence. For all energy bins, the correlation of determination (R{sup 2}) demonstrated good correlation for all spectral comparisons. The mean overall difference (MOD) and mean absolute difference (MAD) were computed over energy bins (above 1% of peak bremsstrahlung fluence) and over all the kV permutations compared. MOD and MAD comparisons with previously reported spectra were 2.7% and 9.7%, respectively (TASMIP), 0.1% and 12.0%, respectively [R. Birch and M. Marshall, “Computation of bremsstrahlung x-ray spectra and comparison with spectra measured with a Ge(Li) detector,” Phys. Med. Biol. 24, 505–517 (1979)], 0.4% and 8.1%, respectively (Poludniowski), and 0.4% and 8.1%, respectively (AAPM TG 195). The effective energy of TASMICS spectra with 2.5 mm of added Al filtration ranged from 17 keV (at 20 kV) to 138 keV (at 640 kV); with 0.2 mm of added Cu filtration the effective energy was 9 keV at 20 kV and 169 keV at 640 kV. Conclusions: Ranging from 20 kV to 640 kV, 621 x-ray spectra were produced and are available at 1 kV tube potential intervals. The spectra are tabulated at 1 keV intervals. TASMICS spectra were shown to be largely equivalent to published spectral models and are available in spreadsheet format for interested users by emailing the corresponding author (JMB)« less

75 FR 75170 - Minnkota Power Cooperative, Inc.: Bemidji to Grand Rapids 230 kV Transmission Line Project

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-02

... Grand Rapids 230 kV Transmission Line Project AGENCY: Rural Utilities Service, USDA. ACTION: Notice of... proposed Bemidji to Grand Rapids 230 kV Transmission Line Project (Project) in Beltrami, Hubbard, Itasca... financing to construct the 230 kilovolt (kV) transmission line between the Wilton Substation near Bemidji...

Comparison of the NIST and NPL Air Kerma Standards Used for X-Ray Measurements Between 10 kV and 80 kV

PubMed Central

O’Brien, M.; Lamperti, P.; Williams, T.; Sander, T.

2000-01-01

A direct comparison was made between the air kerma primary standards used for the measurements of low-energy x rays at the National Institute of Standards and Technology (NIST) and the National Physical Laboratory (NPL). The comparison was conducted at the NPL using NPL reference radiation qualities between 10 kV and 80 kV. The results show the primary air-kerma standards to agree within 0.6 % of their values for beam qualities up to 80 kV. PMID:27551632

Branch Input Resistance and Steady Attenuation for Input to One Branch of a Dendritic Neuron Model

PubMed Central

Rall, Wilfrid; Rinzel, John

1973-01-01

Mathematical solutions and numerical illustrations are presented for the steady-state distribution of membrane potential in an extensively branched neuron model, when steady electric current is injected into only one dendritic branch. Explicit expressions are obtained for input resistance at the branch input site and for voltage attenuation from the input site to the soma; expressions for AC steady-state input impedance and attenuation are also presented. The theoretical model assumes passive membrane properties and the equivalent cylinder constraint on branch diameters. Numerical examples illustrate how branch input resistance and steady attenuation depend upon the following: the number of dendritic trees, the orders of dendritic branching, the electrotonic length of the dendritic trees, the location of the dendritic input site, and the input resistance at the soma. The application to cat spinal motoneurons, and to other neuron types, is discussed. The effect of a large dendritic input resistance upon the amount of local membrane depolarization at the synaptic site, and upon the amount of depolarization reaching the soma, is illustrated and discussed; simple proportionality with input resistance does not hold, in general. Also, branch input resistance is shown to exceed the input resistance at the soma by an amount that is always less than the sum of core resistances along the path from the input site to the soma. PMID:4715583

A new method for fusion, denoising and enhancement of x-ray images retrieved from Talbot-Lau grating interferometry.

PubMed

Scholkmann, Felix; Revol, Vincent; Kaufmann, Rolf; Baronowski, Heidrun; Kottler, Christian

2014-03-21

This paper introduces a new image denoising, fusion and enhancement framework for combining and optimal visualization of x-ray attenuation contrast (AC), differential phase contrast (DPC) and dark-field contrast (DFC) images retrieved from x-ray Talbot-Lau grating interferometry. The new image fusion framework comprises three steps: (i) denoising each input image (AC, DPC and DFC) through adaptive Wiener filtering, (ii) performing a two-step image fusion process based on the shift-invariant wavelet transform, i.e. first fusing the AC with the DPC image and then fusing the resulting image with the DFC image, and finally (iii) enhancing the fused image to obtain a final image using adaptive histogram equalization, adaptive sharpening and contrast optimization. Application examples are presented for two biological objects (a human tooth and a cherry) and the proposed method is compared to two recently published AC/DPC/DFC image processing techniques. In conclusion, the new framework for the processing of AC, DPC and DFC allows the most relevant features of all three images to be combined in one image while reducing the noise and enhancing adaptively the relevant image features. The newly developed framework may be used in technical and medical applications.

Artificial neural networks for AC losses prediction in superconducting round filaments

NASA Astrophysics Data System (ADS)

Leclerc, J.; Makong Hell, L.; Lorin, C.; Masson, P. J.

2016-06-01

An extensive and fast method to estimate superconducting AC losses within a superconducting round filament carrying an AC current and subjected to an elliptical magnetic field (both rotating and oscillating) is presented. Elliptical fields are present in rotating machine stators and being able to accurately predict AC losses in fully superconducting machines is paramount to generating realistic machine designs. The proposed method relies on an analytical scaling law (ASL) combined with two artificial neural network (ANN) estimators taking 9 input parameters representing the superconductor, external field and transport current characteristics. The ANNs are trained with data generated by finite element (FE) computations with a commercial software (FlexPDE) based on the widely accepted H-formulation. After completion, the model is validated through comparison with additional randomly chosen data points and compared for simple field configurations to other predictive models. The loss estimation discrepancy is about 3% on average compared to the FEA analysis. The main advantages of the model compared to FE simulations is the fast computation time (few milliseconds) which allows it to be used in iterated design processes of fully superconducting machines. In addition, the proposed model provides a higher level of fidelity than the scaling laws existing in literature usually only considering pure AC field.

Integral inverter/battery charger for use in electric vehicles

NASA Technical Reports Server (NTRS)

Thimmesch, D.

1983-01-01

The design and test results of a thyristor based inverter/charger are discussed. A battery charger is included integral to the inverter by using a subset of the inverter power circuit components. The resulting charger provides electrical isolation between the vehicle propulsion battery and ac line and is capable of charging a 25 kWh propulsion battery in 8 hours from a 220 volt ac line. The integral charger employs the inverter commutation components at a resonant ac/dc isolated converter rated at 3.6 kW. Charger efficiency and power factor at an output power of 3.6 kW are 86% and 95% respectively. The inverter, when operated with a matching polyphase ac induction motor and nominal 132 volt propulsion battery, can provide a peak shaft power of 34 kW (45 ph) during motoring operation and 45 kW (60 hp) during regeneration. Thyristors are employed for the inverter power switching devices and are arranged in an input-commutated topology. This configuration requires only two thyristors to commutate the six main inverter thyristors. Inverter efficiency during motoring operation at motor shaft speeds above 450 rad/sec (4300 rpm) is 92-94% for output power levels above 11 KW (15 hp). The combined ac inverter/charger package weighs 47 kg (103 lbs).

Repetitive flash x-ray generator having a high-durability diode driven by a two-cable-type line pulser

NASA Astrophysics Data System (ADS)

Shikoda, A.; Sato, E.; Sagae, M.; Oizumi, T.; Tamakawa, Y.; Yanagisawa, T.

1994-04-01

The fundamental studies of a repetitive soft flash x-ray generator having a high-durability diode for high-speed radiography in biomedical and technological fields are described. This generator consisted of the following essential components: a constant negative high-voltage power supply, a line-type high-voltage pulser with two 10 m coaxial-cable condensers, each with a capacity of 1.0 nF, a thyratron pulser as a trigger device, an oil-diffusion pump, and a flash x-ray tube. The x-ray tube was of a diode type which was evacuated by an oil-diffusion pump with a pressure of approximately 6.7×10-3 Pa and was composed of a planar tungsten anode, a planar ferrite cathode, and a polymethylmethacrylate tube body. The space between the anode and cathode electrodes (AC space) could be regulated from the outside of the tube. The two cable condensers were charged from -40 to -60 kV by a power supply, and the output voltage was about -1.5 times the charged voltage. Both the first peak voltage and current increased according to increases in the charged voltage, and the maximum values of the voltage and current were about 90 kV and 0.72 kA, respectively. The pulse widths had values of less than 100 ns, and the maximum x-ray intensity was approximately 1.1 μC/kg at 0.5 m per pulse. The repetition rate was less than 54 Hz, and the maximum focal spot size was about 2.0×2.5 mm.

128 slice computed tomography dose profile measurement using thermoluminescent dosimeter

NASA Astrophysics Data System (ADS)

Salehhon, N.; Hashim, S.; Karim, M. K. A.; Ang, W. C.; Musa, Y.; Bahruddin, N. A.

2017-05-01

The increasing use of computed tomography (CT) in clinical practice marks the needs to understand the dose descriptor and dose profile. The purposes of the current study were to determine the CT dose index free-in-air (CTDIair) in 128 slice CT scanner and to evaluate the single scan dose profile (SSDP). Thermoluminescent dosimeters (TLD-100) were used to measure the dose profile of the scanner. There were three sets of CT protocols where the tube potential (kV) setting was manipulated for each protocol while the rest of parameters were kept constant. These protocols were based from routine CT abdominal examinations for male adult abdomen. It was found that the increase of kV settings made the values of CTDIair increased as well. When the kV setting was changed from 80 kV to 120 kV and from 120 kV to 140 kV, the CTDIair values were increased as much as 147.9% and 53.9% respectively. The highest kV setting (140 kV) led to the highest CTDIair value (13.585 mGy). The p-value of less than 0.05 indicated that the results were statistically different. The SSDP showed that when the kV settings were varied, the peak sharpness and height of Gaussian function profiles were affected. The full width at half maximum (FWHM) of dose profiles for all protocols were coincided with the nominal beam width set for the measurements. The findings of the study revealed much information on the characterization and performance of 128 slice CT scanner.

A potent potassium channel blocker from Mesobuthus eupeus scorpion venom.

PubMed

Gao, Bin; Peigneur, Steve; Tytgat, Jan; Zhu, Shunyi

2010-12-01

Scorpion venom-derived peptidyl toxins are valuable pharmacological tools for investigating the structure-function relationship of ion channels. Here, we report the purification, sequencing and functional characterization of a new K(+) channel blocker (MeuKTX) from the venom of the scorpion Mesobuthus eupeus. Effects of MeuKTX on ten cloned potassium channels in Xenopus oocytes were evaluated using two-electrode voltage-clamp recordings. MeuKTX is the orthologue of BmKTX (α-KTx3.6), a known Kv1.3 blocker from the scorpion Mesobuthus martensii, and classified as α-KTx3.13. MeuKTX potently blocks rKv1.1, rKv1.2 and hKv1.3 channels with 50% inhibitory concentration (IC(50)) of 203.15 ± 4.06 pM, 8.92 ± 2.3 nM and 171 ± 8.56 pM, respectively, but does not affect rKv1.4, rKv1.5, hKv3.1, rKv4.3, and hERG channels even at 2 μM concentration. At this high concentration, MeuKTX is also active on rKv1.6 and Shaker IR. Our results also demonstrate that MeuKTX and BmKTX have the same channel spectrum and similar pharmacological potency. Analysis of the structure-function relationships of α-KTx3 subfamily toxins allows us to recognize several key sites which may be useful for designing toxins with improved activity on hKv1.3, an attractive target for T-cell mediated autoimmune diseases. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

TRIAC/SCR proportional control circuit

DOEpatents

Hughes, W.J.

1999-04-06

A power controller device is disclosed which uses a voltage-to-frequency converter in conjunction with a zero crossing detector to linearly and proportionally control AC power being supplied to a load. The output of the voltage-to frequency converter controls the ``reset`` input of a R-S flip flop, while an ``0`` crossing detector controls the ``set`` input. The output of the flip flop triggers a monostable multivibrator controlling the SCR or TRIAC firing circuit connected to the load. Logic gates prevent the direct triggering of the multivibrator in the rare instance where the ``reset`` and ``set`` inputs of the flip flop are in coincidence. The control circuit can be supplemented with a control loop, providing compensation for line voltage variations. 9 figs.

Gas tube-switched high voltage DC power converter

DOEpatents

She, Xu; Bray, James William; Sommerer, Timothy John; Chokhawala, Rahul

2018-05-15

A direct current (DC)-DC converter includes a transformer and a gas tube-switched inverter circuit. The transformer includes a primary winding and a secondary winding. The gas tube-switched inverter circuit includes first and second inverter load terminals and first and second inverter input terminals. The first and second inverter load terminals are coupled to the primary winding. The first and second inverter input terminals are couplable to a DC node. The gas tube-switched inverter circuit further includes a plurality of gas tube switches respectively coupled between the first and second inverter load terminals and the first and second inverter input terminals. The plurality of gas tube switches is configured to operate to generate an alternating current (AC) voltage at the primary winding.

A potent and Kv1.3-selective analogue of the scorpion toxin HsTX1 as a potential therapeutic for autoimmune diseases

NASA Astrophysics Data System (ADS)

Rashid, M. Harunur; Huq, Redwan; Tanner, Mark R.; Chhabra, Sandeep; Khoo, Keith K.; Estrada, Rosendo; Dhawan, Vikas; Chauhan, Satendra; Pennington, Michael W.; Beeton, Christine; Kuyucak, Serdar; Norton, Raymond S.

2014-03-01

HsTX1 toxin, from the scorpion Heterometrus spinnifer, is a 34-residue, C-terminally amidated peptide cross-linked by four disulfide bridges. Here we describe new HsTX1 analogues with an Ala, Phe, Val or Abu substitution at position 14. Complexes of HsTX1 with the voltage-gated potassium channels Kv1.3 and Kv1.1 were created using docking and molecular dynamics simulations, then umbrella sampling simulations were performed to construct the potential of mean force (PMF) of the ligand and calculate the corresponding binding free energy for the most stable configuration. The PMF method predicted that the R14A mutation in HsTX1 would yield a > 2 kcal/mol gain for the Kv1.3/Kv1.1 selectivity free energy relative to the wild-type peptide. Functional assays confirmed the predicted selectivity gain for HsTX1[R14A] and HsTX1[R14Abu], with an affinity for Kv1.3 in the low picomolar range and a selectivity of more than 2,000-fold for Kv1.3 over Kv1.1. This remarkable potency and selectivity for Kv1.3, which is significantly up-regulated in activated effector memory cells in humans, suggest that these analogues represent valuable leads in the development of therapeutics for autoimmune diseases.

Transfer of Kv3.1 voltage sensor features to the isolated Ci-VSP voltage-sensing domain.

PubMed

Mishina, Yukiko; Mutoh, Hiroki; Knöpfel, Thomas

2012-08-22

Membrane proteins that respond to changes in transmembrane voltage are critical in regulating the function of living cells. The voltage-sensing domains (VSDs) of voltage-gated ion channels are extensively studied to elucidate voltage-sensing mechanisms, and yet many aspects of their structure-function relationship remain elusive. Here, we transplanted homologous amino acid motifs from the tetrameric voltage-activated potassium channel Kv3.1 to the monomeric VSD of Ciona intestinalis voltage-sensitive phosphatase (Ci-VSP) to explore which portions of Kv3.1 subunits depend on the tetrameric structure of Kv channels and which properties of Kv3.1 can be transferred to the monomeric Ci-VSP scaffold. By attaching fluorescent proteins to these chimeric VSDs, we obtained an optical readout to establish membrane trafficking and kinetics of voltage-dependent structural rearrangements. We found that motifs extending from 10 to roughly 100 amino acids can be readily transplanted from Kv3.1 into Ci-VSP to form engineered VSDs that efficiently incorporate into the plasma membrane and sense voltage. Some of the functional features of these engineered VSDs are reminiscent of Kv3.1 channels, indicating that these properties do not require interactions between Kv subunits or between the voltage sensing and the pore domains of Kv channels. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Modulation of KvAP Unitary Conductance and Gating by 1-Alkanols and Other Surface Active Agents

PubMed Central

Finol-Urdaneta, Rocio K.; McArthur, Jeffrey R.; Juranka, Peter F.; French, Robert J.; Morris, Catherine E.

2010-01-01

Abstract The actions of alcohols and anesthetics on ion channels are poorly understood. Controversy continues about whether bilayer restructuring is relevant to the modulatory effects of these surface active agents (SAAs). Some voltage-gated K channels (Kv), but not KvAP, have putative low affinity alcohol-binding sites, and because KvAP structures have been determined in bilayers, KvAP could offer insights into the contribution of bilayer mechanics to SAA actions. We monitored KvAP unitary conductance and macroscopic activation and inactivation kinetics in PE:PG/decane bilayers with and without exposure to classic SAAs (short-chain 1-alkanols, cholesterol, and selected anesthetics: halothane, isoflurane, chloroform). At levels that did not measurably alter membrane specific capacitance, alkanols caused functional changes in KvAP behavior including lowered unitary conductance, modified kinetics, and shifted voltage dependence for activation. A simple explanation is that the site of SAA action on KvAP is its entire lateral interface with the PE:PG/decane bilayer, with SAA-induced changes in surface tension and bilayer packing order combining to modulate the shape and stability of various conformations. The KvAP structural adjustment to diverse bilayer pressure profiles has implications for understanding desirable and undesirable actions of SAA-like drugs and, broadly, predicts that channel gating, conductance and pharmacology may differ when membrane packing order differs, as in raft versus nonraft domains. PMID:20197029

Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions

PubMed Central

Fineberg, Jeffrey D.; Szanto, Tibor G.; Panyi, Gyorgy; Covarrubias, Manuel

2016-01-01

Voltage-gated K+ (Kv) channel activation depends on interactions between voltage sensors and an intracellular activation gate that controls access to a central pore cavity. Here, we hypothesize that this gate is additionally responsible for closed-state inactivation (CSI) in Kv4.x channels. These Kv channels undergo CSI by a mechanism that is still poorly understood. To test the hypothesis, we deduced the state of the Kv4.1 channel intracellular gate by exploiting the trap-door paradigm of pore blockade by internally applied quaternary ammonium (QA) ions exhibiting slow blocking kinetics and high-affinity for a blocking site. We found that inactivation gating seemingly traps benzyl-tributylammonium (bTBuA) when it enters the central pore cavity in the open state. However, bTBuA fails to block inactivated Kv4.1 channels, suggesting gated access involving an internal gate. In contrast, bTBuA blockade of a Shaker Kv channel that undergoes open-state P/C-type inactivation exhibits fast onset and recovery inconsistent with bTBuA trapping. Furthermore, the inactivated Shaker Kv channel is readily blocked by bTBuA. We conclude that Kv4.1 closed-state inactivation modulates pore blockade by QA ions in a manner that depends on the state of the internal activation gate. PMID:27502553

76 FR 19744 - Final Tropic to Hatch 138 kV Transmission Line Project Environmental Impact Statement and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-08

... DEPARTMENT OF AGRICULTURE Forest Service Final Tropic to Hatch 138 kV Transmission Line Project..., has prepared a Final Environmental Impact Statement (FEIS) for the Tropic to Hatch 138 kV Transmission.... ADDRESSES: Copies of the Tropic to Hatch 138 kV Transmission Line Project FEIS/PMPA for the Grand Staircase...

Transient Hippocampal Down-Regulation of Kv1.1 Subunit mRNA during Associative Learning in Rats

ERIC Educational Resources Information Center

Kourrich, Said; Manrique, Christine; Salin, Pascal; Mourre, Christiane

2005-01-01

Voltage-gated potassium channels (Kv) are critically involved in learning and memory processes. It is not known, however, whether the expression of the Kv1.1 subunit, constituting Kv1 channels, can be specifically regulated in brain areas important for learning and memory processing. Radioactive in situ hybridization was used to evaluate the…

76 FR 4371 - Notice of Intent to Prepare an Environmental Impact Statement for the Proposed San Juan Basin...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-25

... requested a right-of-way (ROW) authorization to construct, operate, and maintain a 230 kilovolt (kV... Substation to accommodate the new 230 kV line termination and installation of additional 345/230 kV transformation equipment. The construction involves approximately 35-40 miles of new double-circuit 230 kV...

Synergistic interplay of Gβγ and phosphatidylinositol 4,5-bisphosphate dictates Kv7.4 channel activity.

PubMed

Povstyan, Oleksandr V; Barrese, Vincenzo; Stott, Jennifer B; Greenwood, Iain A

2017-02-01

Kv7.4 channels are key determinants of arterial contractility and cochlear mechanosensation that, like all Kv7 channels, have an obligatory requirement for phosphatidylinositol 4,5-bisphosphate (PIP 2 ). βγ G proteins (Gβγ) have been identified as novel positive regulators of Kv7.4. The present study ascertained whether Gβγ increased Kv7.4 open probability through an increased sensitivity to PIP 2 . In HEK cells stably expressing Kv7.4, PIP 2 or Gβγ increased open probability in a concentration dependent manner. Depleting PIP 2 prevented any Gβγ-mediated stimulation whilst an array of Gβγ inhibitors prohibited any PIP 2 -induced current enhancement. A combination of PIP 2 and Gβγ at sub-efficacious concentrations increased channel open probability considerably. The stimulatory effects of three Kv7.2-7.5 channel activators were also lost by PIP 2 depletion or Gβγ inhibitors. This study alters substantially our understanding of the fundamental processes that dictate Kv7.4 activity, revealing a more complex and subtle paradigm where the reliance on local phosphoinositide is dictated by interaction with Gβγ.

Role of voltage-gated K(+) channels in regulating Ca(2+) entry in rat cortical astrocytes.

PubMed

Wu, King-Chuen; Kuo, Chang-Shin; Chao, Chia-Chia; Huang, Chieh-Chen; Tu, Yuan-Kun; Chan, Paul; Leung, Yuk-Man

2015-03-01

Astrocytes have multiple functions such as provision of nourishment and mechanical support to the nervous system, helping to clear extracellular metabolites of neurons and modulating synaptic transmission by releasing gliotransmitters. In excitable cells, voltage-gated K(+) (Kv) channels serve to repolarize during action potentials. Astrocytes are considered non-excitable cells since they are not able to generate action potentials. There is an abundant expression of various Kv channels in astrocytes but the functions of these Kv channels remain unclear. We examined whether these astrocyte Kv channels regulate astrocyte "excitability" in the form of cytosolic Ca(2+) signaling. Electrophysiological examination revealed that neonatal rat cortical astrocytes possessed both delayed rectifier type and A-type Kv channels. Pharmacological blockade of both delayed rectifier Kv channels by TEA and A-type Kv channels by quinidine significantly suppressed store-operated Ca(2+) influx; however, TEA alone or quinidine alone did not suffice to cause such suppression. TEA and quinidine together dramatically enhanced current injection-triggered membrane potential overshoot (depolarization); either drug alone caused much smaller enhancements. Taken together, the results suggest both delayed rectifier and A-type Kv channels regulate astrocyte Ca(2+) signaling via controlling membrane potential.

Effect of chronic restraint stress on inhibitory gating in the auditory cortex of rats.

PubMed

Ma, Lanlan; Li, Wai; Li, Sibin; Wang, Xuejiao; Qin, Ling

2017-05-01

A fundamental adaptive mechanism of auditory function is inhibitory gating (IG), which refers to the attenuation of neural responses to repeated sound stimuli. IG is drastically impaired in individuals with emotional and cognitive impairments (i.e. posttraumatic stress disorder). The objective of this study was to test whether chronic stress impairs the IG of the auditory cortex (AC). We used the standard two-tone stimulus paradigm and examined the parametric qualities of IG in the AC of rats by recording the electrophysiological signals of a single-unit and local field potential (LFP) simultaneously. The main results of this study were that most of the AC neurons showed a weaker response to the second tone than to the first tone, reflecting an IG of the repeated input. A fast negative wave of LFP showed consistent IG across the sampled AC sites, whereas a slow positive wave of LFP had less IG effect. IG was diminished following chronic restraint stress at both, the single-unit and LFP level, due to the increase in response to the second tone. This study provided new evidence that chronic stress disrupts the physiological function of the AC. Lay Summary The effects of chronic stress on IG were investigated by recording both, single-unit spike and LFP activities, in the AC of rats. In normal rats, most of the single-unit and N25 LFP activities in the AC showed an IG effect. IG was diminished following chronic restraint stress at both, the single-unit and LFP level.

Enabling the Distributed Generation Market of High Temperature Fuel Cell and Absorption Chiller Systems to Support Critical and Commercial Loads

NASA Astrophysics Data System (ADS)

DiMola, Ashley M.

Buildings account for over 18% of the world's anthropogenic Greenhouse Gas (GHG) emissions. As a result, a technology that can offset GHG emissions associated with buildings has the potential to save over 9 Giga-tons of GHG emissions per year. High temperature fuel cell and absorption chiller (HTFC/AC) technology offers a relatively low-carbon option for meeting cooling and electric loads for buildings while producing almost no criteria pollutants. GHG emissions in the state of California would decrease by 7.48 million metric tons per year if every commercial building in the State used HTFC/AC technology to meet its power and cooling requirements. In order to realize the benefits of HTFC/AC technology on a wide scale, the distributed generation market needs to be exposed to the technology and informed of its economic viability and real-world potential. This work characterizes the economics associated with HTFC/AC technology using select scenarios that are representative of realistic applications. The financial impacts of various input factors are evaluated and the HTFC/AC simulations are compared to the economics of traditional building utilities. It is shown that, in addition to the emissions reductions derived from the systems, HTFC/AC technology is financially preferable in all of the scenarios evaluated. This work also presents the design of a showcase environment, centered on a beta-test application, that presents (1) system operating data gathered using a custom data acquisition module, and (2) HTFC/AC technology in a clear and approachable manner in order to serve the target audience of market stakeholders.

Power Conditioning for MEMS-Based Waste Vibrational Energy Harvester

DTIC Science & Technology

2015-06-01

circuits ...........................................................................................18 Figure 18. Full-wave passive MOSFET rectifier...ABBREVIATIONS AC Alternative Current AlN Aluminum Nitride DC Direct Current LIA Lock-In Amplifier MEMS Microelectromechanical Systems MOSFET ...efficiency is achieved when input voltage is over 2–3 V [14]. Using metal-oxide-semiconductor field-effect transistors ( MOSFETs ) in a rectifier instead of

DC-to-AC inverter ratio failure detector

NASA Technical Reports Server (NTRS)

Ebersole, T. J.; Andrews, R. E.

1975-01-01

Failure detection technique is based upon input-output ratios, which is independent of inverter loading. Since inverter has fixed relationship between V-in/V-out and I-in/I-out, failure detection criteria are based on this ratio, which is simply inverter transformer turns ratio, K, equal to primary turns divided by secondary turns.

Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels

PubMed Central

Jukkola, Peter; Gu, Yuanzheng; Lovett-Racke, Amy E.; Gu, Chen

2017-01-01

The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults. PMID:29123469

Repetitive compact flash x-ray generators for soft radiography

NASA Astrophysics Data System (ADS)

Sato, Eiichi; Shikoda, Arimitsu; Kimura, Shingo; Sagae, Michiaki; Oizumi, Teiji; Takahashi, Kei; Hayasi, Yasuomi; Shoji, Tetsuo; Shishido, Koro; Tamakawa, Yoshiharu; Yanagisawa, Toru

1993-01-01

The construction and the fundamental studies for the repetitive flash x-ray generators designed by Japan Impulse Laboratory in Iwate Medical University are described. These generators are classified to the following two major types: (1) generators having diodes, and (2) generators having triodes. In order to generate high-voltage impulses, we employed the following transmission lines (pulsers): (a) high-voltage-inversion type with a maximum output voltage Vom of about 80 kV, (b) high-voltage- inversion type having a coaxial cable (Vom equals 130 kV), (c) two-stage Marx pulser (Vom equals 150 kV), (d) two-cable-type Blumlein (Vom equals 120 kV), (e) modified Blumlein (Vom equals 120 kV), (f) fundamental transmission line for triode (Vom equals 100 kV), and (g) transmission line for an enclosed triode (Vom equals 100 kV). Using these generators we succeeded in performing high-speed radiography as follows: (a) delayed radiography; (b) multiple-shot radiography; and (c) cineradiography.

Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons.

PubMed

Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

2017-01-01

The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K + channel modulators.

Selective Modulation of K+ Channel Kv7.4 Significantly Affects the Excitability of DRN 5-HT Neurons

PubMed Central

Zhao, Chen; Su, Min; Wang, Yingzi; Li, Xinmeng; Zhang, Yongxue; Du, Xiaona; Zhang, Hailin

2017-01-01

The serotonin (5-HT) system originating in the dorsal raphe nucleus (DRN) is implicated in various mood- and emotion-related disorders, such as anxiety, fear and stress. Abnormal activity of DRN 5-HT neurons is the key factor in the development of these disorders. Here, we describe a crucial role for the Kv7.4 potassium channel in modulating DRN 5-HT neuronal excitability. We demonstrate that Kv7.4 is selectively expressed in 5-HT neurons of the DRN. Using selective Kv7.4 opener fasudil and Kv7.4 knock-out mice, we demonstrate that Kv7.4 is a potent modulator of DRN 5-HT neuronal excitability. Furthermore, we demonstrate that the cellular redox signaling mechanism is involved in this 5-HT activation of Kv7.4. The current study suggests a new strategy for treating psychiatric disorders related to altered activity of DRN 5-HT neurons using K+ channel modulators. PMID:29311835

Experimental quantification of the true efficiency of carbon nanotube thin-film thermophones.

PubMed

Bouman, Troy M; Barnard, Andrew R; Asgarisabet, Mahsa

2016-03-01

Carbon nanotube thermophones can create acoustic waves from 1 Hz to 100 kHz. The thermoacoustic effect that allows for this non-vibrating sound source is naturally inefficient. Prior efforts have not explored their true efficiency (i.e., the ratio of the total acoustic power to the electrical input power). All previous works have used the ratio of sound pressure to input electrical power. A method for true power efficiency measurement is shown using a fully anechoic technique. True efficiency data are presented for three different drive signal processing techniques: standard alternating current (AC), direct current added to alternating current (DCAC), and amplitude modulation of an alternating current (AMAC) signal. These signal processing techniques are needed to limit the frequency doubling non-linear effects inherent to carbon nanotube thermophones. Each type of processing affects the true efficiency differently. Using a 72 W(rms) input signal, the measured efficiency ranges were 4.3 × 10(-6) - 319 × 10(-6), 1.7 × 10(-6) - 308 × 10(-6), and 1.2 × 10(-6) - 228 × 10(-6)% for AC, DCAC, and AMAC, respectively. These data were measured in the frequency range of 100 Hz to 10 kHz. In addition, the effects of these processing techniques relative to sound quality are presented in terms of total harmonic distortion.

A 13.56 MHz CMOS Active Rectifier With Switched-Offset and Compensated Biasing for Biomedical Wireless Power Transfer Systems.

PubMed

Yan Lu; Wing-Hung Ki

2014-06-01

A full-wave active rectifier switching at 13.56 MHz with compensated bias current for a wide input range for wirelessly powered high-current biomedical implants is presented. The four diodes of a conventional passive rectifier are replaced by two cross-coupled PMOS transistors and two comparator- controlled NMOS switches to eliminate diode voltage drops such that high voltage conversion ratio and power conversion efficiency could be achieved even at low AC input amplitude |VAC|. The comparators are implemented with switched-offset biasing to compensate for the delays of active diodes and to eliminate multiple pulsing and reverse current. The proposed rectifier uses a modified CMOS peaking current source with bias current that is quasi-inversely proportional to the supply voltage to better control the reverse current over a wide AC input range (1.5 to 4 V). The rectifier was fabricated in a standard 0.35 μm CMOS N-well process with active area of 0.0651 mm(2). For the proposed rectifier measured at |VAC| = 3.0 V, the voltage conversion ratios are 0.89 and 0.93 for RL=500 Ω and 5 kΩ, respectively, and the measured power conversion efficiencies are 82.2% to 90.1% with |VAC| ranges from 1.5 to 4 V for RL=500 Ω.

High power thyristors with 5 kV blocking voltage. Volume 1: Development of high-voltage-thyristors (4.5 kV) with good dynamic properties

NASA Technical Reports Server (NTRS)

Lock, K.; Patalong, H.; Platzoeder, K.

1979-01-01

Using neutron irradiated silicon with considerably lower spread in resistivity as compared to conventionally doped silicon it was possible to produce power thyristors with breakdown voltages between 3.5 kV and 5.5 kV. The thyristor pellets have a diameter of 50 mm. Maximum average on-state currents of 600 to 800 A can be reached with these elements. The dynamic properties of the thryistors could be improved to allow standard applications up to maximum repetitive voltages of 4.5 kV.

Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit.

PubMed

Rettig, J; Heinemann, S H; Wunder, F; Lorra, C; Parcej, D N; Dolly, J O; Pongs, O

1994-05-26

Structural and functional diversity of voltage-gated Kv1-type potassium channels in rat brain is enhanced by the association of two different types of subunits, the membrane-bound, poreforming alpha-subunits and a peripheral beta-subunit. We have cloned a beta-subunit (Kv beta 1) that is specifically expressed in the rat nervous system. Association of Kv beta 1 with alpha-subunits confers rapid A-type inactivation on non-inactivating Kv1 channels (delayed rectifiers) in expression systems in vitro. This effect is mediated by an inactivating ball domain in the Kv beta 1 amino terminus.

Design and testing of 45 kV, 50 kHz pulse power supply for dielectric barrier discharges

NASA Astrophysics Data System (ADS)

Sharma, Surender Kumar; Shyam, Anurag

2016-10-01

The design, construction, and testing of high frequency, high voltage pulse power supply are reported. The purpose of the power supply is to generate dielectric barrier discharges for industrial applications. The power supply is compact and has the advantage of low cost, over current protection, and convenient control for voltage and frequency selection. The power supply can generate high voltage pulses of up to 45 kV at the repetitive frequency range of 1 kHz-50 kHz with 1.2 kW input power. The output current of the power supply is limited to 500 mA. The pulse rise time and fall time are less than 2 μs and the pulse width is 2 μs. The power supply is short circuit proof and can withstand variable plasma load conditions. The power supply mainly consists of a half bridge series resonant converter to charge an intermediate capacitor, which discharges through a step-up transformer at high frequency to generate high voltage pulses. Semiconductor switches and amorphous cores are used for power modulation at higher frequencies. The power supply is tested with quartz tube dielectric barrier discharge load and worked stably. The design details and the performance of the power supply on no load and dielectric barrier discharge load are presented.

Design and testing of 45 kV, 50 kHz pulse power supply for dielectric barrier discharges.

PubMed

Sharma, Surender Kumar; Shyam, Anurag

2016-10-01

The design, construction, and testing of high frequency, high voltage pulse power supply are reported. The purpose of the power supply is to generate dielectric barrier discharges for industrial applications. The power supply is compact and has the advantage of low cost, over current protection, and convenient control for voltage and frequency selection. The power supply can generate high voltage pulses of up to 45 kV at the repetitive frequency range of 1 kHz-50 kHz with 1.2 kW input power. The output current of the power supply is limited to 500 mA. The pulse rise time and fall time are less than 2 μs and the pulse width is 2 μs. The power supply is short circuit proof and can withstand variable plasma load conditions. The power supply mainly consists of a half bridge series resonant converter to charge an intermediate capacitor, which discharges through a step-up transformer at high frequency to generate high voltage pulses. Semiconductor switches and amorphous cores are used for power modulation at higher frequencies. The power supply is tested with quartz tube dielectric barrier discharge load and worked stably. The design details and the performance of the power supply on no load and dielectric barrier discharge load are presented.

A compact, low jitter, nanosecond rise time, high voltage pulse generator with variable amplitude.

PubMed

Mao, Jiubing; Wang, Xin; Tang, Dan; Lv, Huayi; Li, Chengxin; Shao, Yanhua; Qin, Lan

2012-07-01

In this paper, a compact, low jitter, nanosecond rise time, command triggered, high peak power, gas-switch pulse generator system is developed for high energy physics experiment. The main components of the system are a high voltage capacitor, the spark gap switch and R = 50 Ω load resistance built into a structure to obtain a fast high power pulse. The pulse drive unit, comprised of a vacuum planar triode and a stack of avalanche transistors, is command triggered by a single or multiple TTL (transistor-transistor logic) level pulses generated by a trigger pulse control unit implemented using the 555 timer circuit. The control unit also accepts user input TTL trigger signal. The vacuum planar triode in the pulse driving unit that close the first stage switches is applied to drive the spark gap reducing jitter. By adjusting the charge voltage of a high voltage capacitor charging power supply, the pulse amplitude varies from 5 kV to 10 kV, with a rise time of <3 ns and the maximum peak current up to 200 A (into 50 Ω). The jitter of the pulse generator system is less than 1 ns. The maximum pulse repetition rate is set at 10 Hz that limited only by the gas-switch and available capacitor recovery time.

First test of a high voltage feedthrough for liquid Argon TPCs connected to a 300 kV power supply

NASA Astrophysics Data System (ADS)

Cantini, C.; Gendotti, A.; Molina Bueno, L.; Murphy, S.; Radics, B.; Regenfus, C.; Rigaut, Y.-A.; Rubbia, A.; Sergiampietri, F.; Viant, T.; Wu, S.

2017-03-01

Voltages above a hundred kilo-volt will be required to generate the drift field of future very large liquid Argon Time Projection Chambers. One of the most delicate component is the feedthrough whose role is to safely deliver the very high voltage to the cathode through the thick insulating walls of the cryostat without compromising the purity of the argon inside. This requires a feedthrough that is typically meters long and carefully designed to be vacuum tight and have small heat input. Furthermore, all materials should be carefully chosen to allow operation in cryogenic conditions. In addition, electric fields in liquid argon should be kept below a threshold to reduce risks of discharges. The combination of all above requirements represents significant challenges from the design and manufacturing perspective. In this paper, we report on the successful operation of a feedthrough satisfying all the above requirements. The details of the feedthrough design and its manufacturing steps are provided. Very high voltages up to unprecedented voltages of -300 kV could be applied during long periods repeatedly. A source of instability was observed, which was specific to the setup configuration which was used for the test and not due to the feedthrough itself.

Nonlinear control of voltage source converters in AC-DC power system.

PubMed

Dash, P K; Nayak, N

2014-07-01

This paper presents the design of a robust nonlinear controller for a parallel AC-DC power system using a Lyapunov function-based sliding mode control (LYPSMC) strategy. The inputs for the proposed control scheme are the DC voltage and reactive power errors at the converter station and the active and reactive power errors at the inverter station of the voltage-source converter-based high voltage direct current transmission (VSC-HVDC) link. The stability and robust tracking of the system parameters are ensured by applying the Lyapunov direct method. Also the gains of the sliding mode control (SMC) are made adaptive using the stability conditions of the Lyapunov function. The proposed control strategy offers invariant stability to a class of systems having modeling uncertainties due to parameter changes and exogenous inputs. Comprehensive computer simulations are carried out to verify the proposed control scheme under several system disturbances like changes in short-circuit ratio, converter parametric changes, and faults on the converter and inverter buses for single generating system connected to the power grid in a single machine infinite-bus AC-DC network and also for a 3-machine two-area power system. Furthermore, a second order super twisting sliding mode control scheme has been presented in this paper that provides a higher degree of nonlinearity than the LYPSMC and damps faster the converter and inverter voltage and power oscillations. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

Ubiquitin ligase Nedd4-2 modulates Kv1.3 current amplitude and ion channel protein targeting

PubMed Central

Velez, Patricio; Schwartz, Austin B.; Iyer, Subashini R.; Warrington, Anthony

2016-01-01

Voltage-dependent potassium channels (Kv) go beyond the stabilization of the resting potential and regulate biochemical pathways, regulate intracellular signaling, and detect energy homeostasis. Because targeted deletion and pharmacological block of the Kv1.3 channel protein produce marked changes in metabolism, resistance to diet-induced obesity, and changes in olfactory structure and function, this investigation explored Nedd4-2-mediated ubiquitination and degradation to regulate Kv1.3 channel density. Heterologous coexpression of Nedd4-2 ligase and Kv1.3 in HEK 293 cells reduced Kv1.3 current density without modulation of kinetic properties as measured by patch-clamp electrophysiology. Modulation of current density was dependent on ligase activity and was lost through point mutation of cysteine 938 in the catalytic site of the ligase (Nedd4-2CS). Incorporation of adaptor protein Grb10 relieved Nedd4-2-induced current suppression as did application of the proteasome inhibitor Mg-132. SDS-PAGE and immunoprecipitation strategies demonstrated a channel/adaptor/ligase signalplex. Pixel immunodensity was reduced for Kv1.3 in the presence of Nedd4-2, which was eliminated upon additional incorporation of Grb10. We confirmed Nedd4-2/Grb10 coimmunoprecipitation and observed an increased immunodensity for Nedd4-2 in the presence of Kv1.3 plus Grb10, regardless of whether the catalytic site was active. Kv1.3/Nedd4-2 were reciprocally coimmunoprecipated, whereby mutation of the COOH-terminal, SH3-recognition (493–498), or ubiquitination sites on Kv1.3 (lysines 467, 476, 498) retained coimmunoprecipitation, while the latter prevented the reduction in channel density. A model is presented for which an atypical interaction outside the canonical PY motif may permit channel/ligase interaction to lead to protein degradation and reduced current density, which can involve Nedd4-2/Grb10 interactions to disrupt Kv1.3 loss of current density. PMID:27146988

Altered Expression and Localization of Hippocampal A-Type Potassium Channel Subunits in the Pilocarpine-Induced Model of Temporal Lobe Epilepsy

PubMed Central

Monaghan, Michael M.; Menegola, Milena; Vacher, Helene; Rhodes, Kenneth J.; Trimmer, James S.

2010-01-01

Summary Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of two-three weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE. PMID:18727953

Radiation Dose Reduction via Sinogram Affirmed Iterative Reconstruction and Automatic Tube Voltage Modulation (CARE kV) in Abdominal CT

PubMed Central

Shin, Hyun Joo; Lee, Young Han; Choi, Jin-Young; Park, Mi-Suk; Kim, Myeong-Jin; Kim, Ki Whang

2013-01-01

Objective To evaluate the feasibility of sinogram-affirmed iterative reconstruction (SAFIRE) and automated kV modulation (CARE kV) in reducing radiation dose without increasing image noise for abdominal CT examination. Materials and Methods This retrospective study included 77 patients who received CT imaging with an application of CARE kV with or without SAFIRE and who had comparable previous CT images obtained without CARE kV or SAFIRE, using the standard dose (i.e., reference mAs of 240) on an identical CT scanner and reconstructed with filtered back projection (FBP) within 1 year. Patients were divided into two groups: group A (33 patients, CT scanned with CARE kV); and group B (44 patients, scanned after reducing the reference mAs from 240 to 170 and applying both CARE kV and SAFIRE). CT number, image noise for four organs and radiation dose were compared among the two groups. Results Image noise increased after CARE kV application (p < 0.001) and significantly decreased as SAFIRE strength increased (p < 0.001). Image noise with reduced-mAs scan (170 mAs) in group B became similar to that of standard-dose FBP images after applying CARE kV and SAFIRE strengths of 3 or 4 when measured in the aorta, liver or muscle (p ≥ 0.108). Effective doses decreased by 19.4% and 41.3% for groups A and B, respectively (all, p < 0.001) after application of CARE kV with or without SAFIRE. Conclusion Combining CARE kV, reduction of mAs from 240 to 170 mAs and noise reduction by applying SAFIRE strength 3 or 4 reduced the radiation dose by 41.3% without increasing image noise compared with the standard-dose FBP images. PMID:24265563

Contribution of KV1.5 Channel to H2O2-Induced Human Arteriolar Dilation and its Modulation by Coronary Artery Disease

PubMed Central

Nishijima, Yoshinori; Cao, Sheng; Chabowski, Dawid S.; Korishettar, Ankush; Ge, Alyce; Zheng, Xiaodong; Sparapani, Rodney; Gutterman, David D.; Zhang, David X.

2016-01-01

Rationale Hydrogen peroxide (H2O2) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating BKCa channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) as compared to those with CAD remain unknown. Objective We hypothesize that H2O2-elicited dilation involves different K+ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease. Methods and Results H2O2 induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a BKCa channel blocker, and by 4-AP, a KV channel blocker. Assays of mRNA transcripts, protein expression and subcellular localization revealed that KV1.5 is the major KV1 channel expressed in vascular smooth muscle cells (VSMCs) and is abundantly localized on the plasma membrane. The selective KV1.5 blocker DPO-1 and the KV1.3/1.5 blocker Psora-4 reduced H2O2-elicited dilation to a similar extent as 4-AP, but the selective KV1.3 blocker PAP-1 was without effect. In arterioles from CAD subjects, H2O2-induced dilation was significantly reduced and this dilation was inhibited by paxilline but not by 4-AP, DPO-1 or Psora-4. KV1.5 cell membrane localization and DPO-1-sensitive K+ currents were markedly reduced in isolated VSMCs from CAD arterioles, although mRNA or total cellular protein expression were largely unchanged. Conclusions In human arterioles, H2O2-induced dilation is impaired in CAD, which is associated with a transition from a combined BKCa- and KV (KV1.5)-mediated vasodilation toward a BKCa-predominant mechanism of dilation. Loss of KV1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases. PMID:27872049

KV1 channels identified in rodent myelinated axons, linked to Cx29 in innermost myelin: support for electrically active myelin in mammalian saltatory conduction

PubMed Central

Vanderpool, Kimberly G.; Yasumura, Thomas; Hickman, Jordan; Beatty, Jonathan T.; Nagy, James I.

2016-01-01

Saltatory conduction in mammalian myelinated axons was thought to be well understood before recent discoveries revealed unexpected subcellular distributions and molecular identities of the K+-conductance pathways that provide for rapid axonal repolarization. In this study, we visualize, identify, localize, quantify, and ultrastructurally characterize axonal KV1.1/KV1.2 channels in sciatic nerves of rodents. With the use of light microscopic immunocytochemistry and freeze-fracture replica immunogold labeling electron microscopy, KV1.1/KV1.2 channels are localized to three anatomically and compositionally distinct domains in the internodal axolemmas of large myelinated axons, where they form densely packed “rosettes” of 9-nm intramembrane particles. These axolemmal KV1.1/KV1.2 rosettes are precisely aligned with and ultrastructurally coupled to connexin29 (Cx29) channels, also in matching rosettes, in the surrounding juxtaparanodal myelin collars and along the inner mesaxon. As >98% of transmembrane proteins large enough to represent ion channels in these specialized domains, ∼500,000 KV1.1/KV1.2 channels define the paired juxtaparanodal regions as exclusive membrane domains for the voltage-gated K+ conductance that underlies rapid axonal repolarization in mammals. The 1:1 molecular linkage of KV1 channels to Cx29 channels in the apposed juxtaparanodal collars, plus their linkage to an additional 250,000–400,000 Cx29 channels along each inner mesaxon in every large-diameter myelinated axon examined, supports previously proposed K+ conductance directly from juxtaparanodal axoplasm into juxtaparanodal myeloplasm in mammalian axons. With neither Cx29 protein nor myelin rosettes detectable in frog myelinated axons, these data showing axon-to-myelin linkage by abundant KV1/Cx29 channels in rodent axons support renewed consideration of an electrically active role for myelin in increasing both saltatory conduction velocity and maximum propagation frequency in mammalian myelinated axons. PMID:26763782

Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons

PubMed Central

Johnston, Jamie; Griffin, Sarah J; Baker, Claire; Skrzypiec, Anna; Chernova, Tatanya; Forsythe, Ian D

2008-01-01

The medial nucleus of the trapezoid body (MNTB) is specialized for high frequency firing by expression of Kv3 channels, which minimize action potential (AP) duration, and Kv1 channels, which suppress multiple AP firing, during each calyceal giant EPSC. However, the outward K+ current in MNTB neurons is dominated by another unidentified delayed rectifier. It has slow kinetics and a peak conductance of ∼37 nS; it is half-activated at −9.2 ± 2.1 mV and half-inactivated at −35.9 ± 1.5 mV. It is blocked by several non-specific potassium channel antagonists including quinine (100 μm) and high concentrations of extracellular tetraethylammonium (TEA; IC50 = 11.8 mm), but no specific antagonists were found. These characteristics are similar to recombinant Kv2-mediated currents. Quantitative RT-PCR showed that Kv2.2 mRNA was much more prevalent than Kv2.1 in the MNTB. A Kv2.2 antibody showed specific staining and Western blots confirmed that it recognized a protein ∼110 kDa which was absent in brainstem tissue from a Kv2.2 knockout mouse. Confocal imaging showed that Kv2.2 was highly expressed in axon initial segments of MNTB neurons. In the absence of a specific antagonist, Hodgkin–Huxley modelling of voltage-gated conductances showed that Kv2.2 has a minor role during single APs (due to its slow activation) but assists recovery of voltage-gated sodium channels (Nav) from inactivation by hyperpolarizing interspike potentials during repetitive AP firing. Current-clamp recordings during high frequency firing and characterization of Nav inactivation confirmed this hypothesis. We conclude that Kv2.2-containing channels have a distinctive initial segment location and crucial function in maintaining AP amplitude by regulating the interspike potential during high frequency firing. PMID:18511484

Thermal adaptation of the crucian carp (Carassius carassius) cardiac delayed rectifier current, IKs, by homomeric assembly of Kv7.1 subunits without MinK.

PubMed

Hassinen, Minna; Laulaja, Salla; Paajanen, Vesa; Haverinen, Jaakko; Vornanen, Matti

2011-07-01

Ectothermic vertebrates experience acute and chronic temperature changes which affect cardiac excitability and may threaten electrical stability of the heart. Nevertheless, ectothermic hearts function over wide range of temperatures without cardiac arrhythmias, probably due to special molecular adaptations. We examine function and molecular basis of the slow delayed rectifier K(+) current (I(Ks)) in cardiac myocytes of a eurythermic fish (Carassius carassius L.). I(Ks) is an important repolarizing current that prevents excessive prolongation of cardiac action potential, but it is extremely slowly activating when expressed in typical molecular composition of the endothermic animals. Comparison of the I(Ks) of the crucian carp atrial myocytes with the currents produced by homomeric K(v)7.1 and heteromeric K(v)7.1/MinK channels in Chinese hamster ovary cells indicates that activation kinetics and pharmacological properties of the I(Ks) are similar to those of the homomeric K(v)7.1 channels. Consistently with electrophysiological properties and homomeric K(v)7.1 channel composition, atrial transcript expression of the MinK subunit is only 1.6-1.9% of the expression level of the K(v)7.1 subunit. Since activation kinetics of the homomeric K(v)7.1 channels is much faster than activation of the heteromeric K(v)7.1/MinK channels, the homomeric K(v)7.1 composition of the crucian carp cardiac I(Ks) is thermally adaptive: the slow delayed rectifier channels can open despite low body temperatures and curtail the duration of cardiac action potential in ectothermic crucian carp. We suggest that the homomeric K(v)7.1 channel assembly is an evolutionary thermal adaptation of ectothermic hearts and the heteromeric K(v)7.1/MinK channels evolved later to adapt I(Ks) to high body temperature of endotherms.

Early-onset epileptic encephalopathy caused by gain-of-function mutations in the voltage sensor of Kv7.2 and Kv7.3 potassium channel subunits.

PubMed

Miceli, Francesco; Soldovieri, Maria Virginia; Ambrosino, Paolo; De Maria, Michela; Migliore, Michele; Migliore, Rosanna; Taglialatela, Maurizio

2015-03-04

Mutations in Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3) genes, encoding for voltage-gated K(+) channel subunits underlying the neuronal M-current, have been associated with a wide spectrum of early-onset epileptic disorders ranging from benign familial neonatal seizures to severe epileptic encephalopathies. The aim of the present work has been to investigate the molecular mechanisms of channel dysfunction caused by voltage-sensing domain mutations in Kv7.2 (R144Q, R201C, and R201H) or Kv7.3 (R230C) recently found in patients with epileptic encephalopathies and/or intellectual disability. Electrophysiological studies in mammalian cells transfected with human Kv7.2 and/or Kv7.3 cDNAs revealed that each of these four mutations stabilized the activated state of the channel, thereby producing gain-of-function effects, which are opposite to the loss-of-function effects produced by previously found mutations. Multistate structural modeling revealed that the R201 residue in Kv7.2, corresponding to R230 in Kv7.3, stabilized the resting and nearby voltage-sensing domain states by forming an intricate network of electrostatic interactions with neighboring negatively charged residues, a result also confirmed by disulfide trapping experiments. Using a realistic model of a feedforward inhibitory microcircuit in the hippocampal CA1 region, an increased excitability of pyramidal neurons was found upon incorporation of the experimentally defined parameters for mutant M-current, suggesting that changes in network interactions rather than in intrinsic cell properties may be responsible for the neuronal hyperexcitability by these gain-of-function mutations. Together, the present results suggest that gain-of-function mutations in Kv7.2/3 currents may cause human epilepsy with a severe clinical course, thus revealing a previously unexplored level of complexity in disease pathogenetic mechanisms. Copyright © 2015 the authors 0270-6474/15/353782-12$15.00/0.

Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy.

PubMed

Monaghan, M M; Menegola, M; Vacher, H; Rhodes, K J; Trimmer, J S

2008-10-15

Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.

Role of N-terminal domain and accessory subunits in controlling deactivation-inactivation coupling of Kv4.2 channels.

PubMed

Barghaan, Jan; Tozakidou, Magdalini; Ehmke, Heimo; Bähring, Robert

2008-02-15

We examined the relationship between deactivation and inactivation in Kv4.2 channels. In particular, we were interested in the role of a Kv4.2 N-terminal domain and accessory subunits in controlling macroscopic gating kinetics and asked if the effects of N-terminal deletion and accessory subunit coexpression conform to a kinetic coupling of deactivation and inactivation. We expressed Kv4.2 wild-type channels and N-terminal deletion mutants in the absence and presence of Kv channel interacting proteins (KChIPs) and dipeptidyl aminopeptidase-like proteins (DPPs) in human embryonic kidney 293 cells. Kv4.2-mediated A-type currents at positive and deactivation tail currents at negative membrane potentials were recorded under whole-cell voltage-clamp and analyzed by multi-exponential fitting. The observed changes in Kv4.2 macroscopic inactivation kinetics caused by N-terminal deletion, accessory subunit coexpression, or a combination of the two maneuvers were compared with respective changes in deactivation kinetics. Extensive correlation analyses indicated that modulatory effects on deactivation closely parallel respective effects on inactivation, including both onset and recovery kinetics. Searching for the structural determinants, which control deactivation and inactivation, we found that in a Kv4.2 Delta 2-10 N-terminal deletion mutant both the initial rapid phase of macroscopic inactivation and tail current deactivation were slowed. On the other hand, the intermediate and slow phase of A-type current decay, recovery from inactivation, and tail current decay kinetics were accelerated in Kv4.2 Delta 2-10 by KChIP2 and DPPX. Thus, a Kv4.2 N-terminal domain, which may control both inactivation and deactivation, is not necessary for active modulation of current kinetics by accessory subunits. Our results further suggest distinct mechanisms for Kv4.2 gating modulation by KChIPs and DPPs.

Effect of Atmospheric-Pressure Plasma Jet of Neon on 7-Acetoxy-6-(2,3-Dibromopropyl)-4,8-Dimethylcoumarin Molecule

NASA Astrophysics Data System (ADS)

Tanışlı, Murat; Taşal, Erol

2017-06-01

Atmospheric-pressure low-temperature plasma jets and their applications are a topic of great interest in the fields of physics, technology, and medicine. In this study, the used self-made plasma jet is based on a dielectric barrier discharge (DBD) in neon (Ne) with typical processing parameters, such as frequency in the kHz range and voltage in the kV range. The plasma is characterized by optical emission spectroscopy (OES). These types of plasma can be used in various applications such as surface modification, inactivation of microorganisms, and chemical decomposition. This study is concerned with the Fourier transform infrared spectrum (FT-IR) and ultraviolet-visible (UV-vis) absorption spectroscopy of the large 7-acetoxy-6-(2,3-dibromopropyl)-4,8-dimethylcoumarin molecule (abbreviated as 7AC) dissolved in ethanol and methanol solvents and their modification after atmospheric-pressure plasma treatment (APPT) with the DBD. The research is motivated by the significance of this molecule in different fields of application. Also the changes in the structure are recorded. After APPT, the peak corresponding to the carbonyl bond at a wavenumber of 1715 cm-1 disappears in the IR spectrum of the ethanol solution, and when splitting at a wavenumber of 1405 cm-1 is observed, the peak at 1224 cm-1 is found to disappear after plasma is applied. It is seen new peaks at frequencies of 432 and 655 cm-1 are formed. When the same situation is analyzed for the 7AC molecule dissolved in methanol, a new peak is observed at 1634 cm-1. The intensities of the peaks at 3433 and 2075 cm-1 also increase and there is a large change in the wavenumber at 600 cm-1. In the UV spectra, a significant increase in the absorbance of the 7AC molecule dissolved in ethanol is observed after APPT, whereas a small decrease in the absorbance of the 7AC molecule dissolved in methanol is obtained. Owing to the lack of symmetry, many normal bands of vibrations are mixed.

A Role for DPPX Modulating External TEA Sensitivity of Kv4 Channels

PubMed Central

Colinas, Olaia; Pérez-Carretero, Francisco D.; López-López, José R.; Pérez-García, M. Teresa

2008-01-01

Shal-type (Kv4) channels are expressed in a large variety of tissues, where they contribute to transient voltage-dependent K+ currents. Kv4 are the molecular correlate of the A-type current of neurons (ISA), the fast component of ITO current in the heart, and also of the oxygen-sensitive K+ current (KO2) in rabbit carotid body (CB) chemoreceptor cells. The enormous degree of variability in the physiological properties of Kv4-mediated currents can be attributable to the complexity of their regulation together with the large number of ancillary subunits and scaffolding proteins that associate with Kv4 proteins to modify their trafficking and their kinetic properties. Among those, KChIPs and DPPX proteins have been demonstrated to be integral components of ISA and ITO currents, as their coexpression with Kv4 subunits recapitulates the kinetics of native currents. Here, we explore the presence and functional contribution of DPPX to KO2 currents in rabbit CB chemoreceptor cells by using DPPX functional knockdown with siRNA. Additionally, we investigate if the presence of DPPX endows Kv4 channels with new pharmacological properties, as we have observed anomalous tetraethylammonium (TEA) sensitivity in the native KO2 currents. DPPX association with Kv4 channels induced an increased TEA sensitivity both in heterologous expression systems and in CB chemoreceptor cells. Moreover, TEA application to Kv4-DPPX heteromultimers leads to marked kinetic effects that could be explained by an augmented closed-state inactivation. Our data suggest that DPPX proteins are integral components of KO2 currents, and that their association with Kv4 subunits modulate the pharmacological profile of the heteromultimers. PMID:18411327

Overlapping Binding Sites of Structurally Different Antiarrhythmics Flecainide and Propafenone in the Subunit Interface of Potassium Channel Kv2.1*

PubMed Central

Madeja, Michael; Steffen, Wibke; Mesic, Ivana; Garic, Bojan; Zhorov, Boris S.

2010-01-01

Kv2.1 channels, which are expressed in brain, heart, pancreas, and other organs and tissues, are important targets for drug design. Flecainide and propafenone are known to block Kv2.1 channels more potently than other Kv channels. Here, we sought to explore structural determinants of this selectivity. We demonstrated that flecainide reduced the K+ currents through Kv2.1 channels expressed in Xenopus laevis oocytes in a voltage- and time-dependent manner. By systematically exchanging various segments of Kv2.1 with those from Kv1.2, we determined flecainide-sensing residues in the P-helix and inner helix S6. These residues are not exposed to the inner pore, a conventional binding region of open channel blockers. The flecainide-sensing residues also contribute to propafenone binding, suggesting overlapping receptors for the drugs. Indeed, propafenone and flecainide compete for binding in Kv2.1. We further used Monte Carlo-energy minimizations to map the receptors of the drugs. Flecainide docking in the Kv1.2-based homology model of Kv2.1 predicts the ligand ammonium group in the central cavity and the benzamide moiety in a niche between S6 and the P-helix. Propafenone also binds in the niche. Its carbonyl group accepts an H-bond from the P-helix, the amino group donates an H-bond to the P-loop turn, whereas the propyl group protrudes in the pore and blocks the access to the selectivity filter. Thus, besides the binding region in the central cavity, certain K+ channel ligands can expand in the subunit interface whose residues are less conserved between K+ channels and hence may be targets for design of highly desirable subtype-specific K+ channel drugs. PMID:20709754

Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.

PubMed

Battefeld, Arne; Tran, Baouyen T; Gavrilis, Jason; Cooper, Edward C; Kole, Maarten H P

2014-03-05

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of K(v)7 potassium channels and voltage-gated sodium (Na(v)) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these K(v)7 channels and the functional impact of colocalization with Na(v) channels remain poorly understood. Here, we quantitatively examined K(v)7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. K(v)7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ~12 (proximal) to 150 pS μm(-2) (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by K(v)7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (~15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic K(v)7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal K(v)7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains K(v)7.2/7.3 channels were found to increase Na(v) channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, K(v)7 clustering near axonal Na(v) channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential.

Voltage-dependent gating and gating charge measurements in the Kv1.2 potassium channel

PubMed Central

Ishida, Itzel G.; Rangel-Yescas, Gisela E.; Carrasco-Zanini, Julia

2015-01-01

Much has been learned about the voltage sensors of ion channels since the x-ray structure of the mammalian voltage-gated potassium channel Kv1.2 was published in 2005. High resolution structural data of a Kv channel enabled the structural interpretation of numerous electrophysiological findings collected in various ion channels, most notably Shaker, and permitted the development of meticulous computational simulations of the activation mechanism. The fundamental premise for the structural interpretation of functional measurements from Shaker is that this channel and Kv1.2 have the same characteristics, such that correlation of data from both channels would be a trivial task. We tested these assumptions by measuring Kv1.2 voltage-dependent gating and charge per channel. We found that the Kv1.2 gating charge is near 10 elementary charges (eo), ∼25% less than the well-established 13–14 eo in Shaker. Next, we neutralized positive residues in the Kv1.2 S4 transmembrane segment to investigate the cause of the reduction of the gating charge and found that, whereas replacing R1 with glutamine decreased voltage sensitivity to ∼50% of the wild-type channel value, mutation of the subsequent arginines had a much smaller effect. These data are in marked contrast to the effects of charge neutralization in Shaker, where removal of the first four basic residues reduces the gating charge by roughly the same amount. In light of these differences, we propose that the voltage-sensing domains (VSDs) of Kv1.2 and Shaker might undergo the same physical movement, but the septum that separates the aqueous crevices in the VSD of Kv1.2 might be thicker than Shaker’s, accounting for the smaller Kv1.2 gating charge. PMID:25779871

The secret life of ion channels: Kv1.3 potassium channels and proliferation.

PubMed

Pérez-García, M Teresa; Cidad, Pilar; López-López, José R

2018-01-01

Kv1.3 channels are involved in the switch to proliferation of normally quiescent cells, being implicated in the control of cell cycle in many different cell types and in many different ways. They modulate membrane potential controlling K + fluxes, sense changes in potential, and interact with many signaling molecules through their intracellular domains. From a mechanistic point of view, we can describe the role of Kv1.3 channels in proliferation with at least three different models. In the "membrane potential model," membrane hyperpolarization resulting from Kv1.3 activation provides the driving force for Ca 2+ influx required to activate Ca 2+ -dependent transcription. This model explains most of the data obtained from several cells from the immune system. In the "voltage sensor model," Kv1.3 channels serve mainly as sensors that transduce electrical signals into biochemical cascades, independently of their effect on membrane potential. Kv1.3-dependent proliferation of vascular smooth muscle cells (VSMCs) could fit this model. Finally, in the "channelosome balance model," the master switch determining proliferation may be related to the control of the Kv1.3 to Kv1.5 ratio, as described in glial cells and also in VSMCs. Since the three mechanisms cannot function independently, these models are obviously not exclusive. Nevertheless, they could be exploited differentially in different cells and tissues. This large functional flexibility of Kv1.3 channels surely gives a new perspective on their functions beyond their elementary role as ion channels, although a conclusive picture of the mechanisms involved in Kv1.3 signaling to proliferation is yet to be reached.

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation.

PubMed

Glasscock, Edward; Voigt, Niels; McCauley, Mark D; Sun, Qiang; Li, Na; Chiang, David Y; Zhou, Xiao-Bo; Molina, Cristina E; Thomas, Dierk; Schmidt, Constanze; Skapura, Darlene G; Noebels, Jeffrey L; Dobrev, Dobromir; Wehrens, Xander H T

2015-09-01

Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson's trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility.

Expression and function of Kv1.1 potassium channels in human atria from patients with atrial fibrillation

PubMed Central

Glasscock, Edward; Voigt, Niels; McCauley, Mark D.; Sun, Qiang; Li, Na; Chiang, David Y.; Zhou, Xiao-Bo; Molina, Cristina E.; Thomas, Dierk; Schmidt, Constanze; Skapura, Darlene G.; Noebels, Jeffrey L.; Dobrev, Dobromir; Wehrens, Xander H. T.

2016-01-01

Voltage-gated Kv1.1 channels encoded by the Kcna1 gene are traditionally regarded as being neural-specific with no known expression or intrinsic functional role in the heart. However, recent studies in mice reveal low-level Kv1.1 expression in heart and cardiac abnormalities associated with Kv1.1-deficiency suggesting that the channel may have a previously unrecognized cardiac role. Therefore, this study tests the hypothesis that Kv1.1 channels are associated with arrhythmogenesis and contribute to intrinsic cardiac function. In intra-atrial burst pacing experiments, Kcna1-null mice exhibited increased susceptibility to atrial fibrillation (AF). The atria of Kcna1-null mice showed minimal Kv1 family ion channel remodeling and fibrosis as measured by qRT-PCR and Masson’s trichrome histology, respectively. Using RT-PCR, immunocytochemistry, and immunoblotting, KCNA1 mRNA and protein were detected in isolated mouse cardiomyocytes and human atria for the first time. Patients with chronic AF (cAF) showed no changes in KCNA1 mRNA levels relative to controls; however, they exhibited increases in atrial Kv1.1 protein levels, not seen in paroxysmal AF patients. Patch-clamp recordings of isolated human atrial myocytes revealed significant dendrotoxin-K (DTX-K)-sensitive outward current components that were significantly increased in cAF patients, reflecting a contribution by Kv1.1 channels. The concomitant increases in Kv1.1 protein and DTX-K-sensitive currents in atria of cAF patients suggest that the channel contributes to the pathological mechanisms of persistent AF. These findings provide evidence of an intrinsic cardiac role of Kv1.1 channels and indicate that they may contribute to atrial repolarization and AF susceptibility. PMID:26162324

The calmodulin inhibitor CGS 9343B inhibits voltage-dependent K{sup +} channels in rabbit coronary arterial smooth muscle cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Hongliang; Hong, Da Hye; Kim, Han Sol

We investigated the effects of the calmodulin inhibitor CGS 9343B on voltage-dependent K{sup +} (Kv) channels using whole-cell patch clamp technique in freshly isolated rabbit coronary arterial smooth muscle cells. CGS 9343B inhibited Kv currents in a concentration-dependent manner, with a half-maximal inhibitory concentration (IC{sub 50}) value of 0.81 μM. The decay rate of Kv channel inactivation was accelerated by CGS 9343B. The rate constants of association and dissociation for CGS 9343B were 2.77 ± 0.04 μM{sup −1} s{sup −1} and 2.55 ± 1.50 s{sup −1}, respectively. CGS 9343B did not affect the steady-state activation curve, but shifted the inactivationmore » curve toward to a more negative potential. Train pulses (1 or 2 Hz) application progressively increased the CGS 9343B-induced Kv channel inhibition. In addition, the inactivation recovery time constant was increased in the presence of CGS 9343B, suggesting that CGS 9343B-induced inhibition of Kv channel was use-dependent. Another calmodulin inhibitor, W-13, did not affect Kv currents, and did not change the inhibitory effect of CGS 9343B on Kv current. Our results demonstrated that CGS 9343B inhibited Kv currents in a state-, time-, and use-dependent manner, independent of calmodulin inhibition. - Highlights: • We investigated the effects of CGS 9394B on Kv channels. • CGS 9394B inhibited Kv current in a state-, time-, and use-dependent manner. • Caution is required when using CGS 9394B in vascular function studies.« less

A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons.

PubMed

Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

2015-01-01

Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics.

A New Regulatory Mechanism for Kv7.2 Protein During Neuropathy: Enhanced Transport from the Soma to Axonal Terminals of Injured Sensory Neurons

PubMed Central

Cisneros, Elsa; Roza, Carolina; Jackson, Nieka; López-García, José Antonio

2015-01-01

Kv7.2 channel expression has been reported to decrease in dorsal root ganglia (DRG) following the induction of a peripheral neuropathy while other experiments show that Kv7.2 accumulates in peripheral neuromas. The mechanisms underlying these novel expression patterns are poorly understood. Here we use immunofluorescence methods to analyze Kv7.2 protein expression changes in sensory neurons following peripheral axotomy and the potential role of axonal transport. Results indicate that DRG neurons express Kv7.2 in ~16% of neurons and that this number decreases by about 65% after axotomy. Damaged neurons were identified in DRG by application of the tracer Fluoro-ruby at the site of injury during surgery. Reduction of Kv7.2 expression was particularly strong in damaged neurons although some loss was also found in putative uninjured neurons. In parallel to the decrease in the soma of axotomized sensory neurons, Kv7.2 accumulated at neuromatose fiber endings. Blockade of axonal transport with either vinblastine (VLB) or colchicine (COL) abolished Kv7.2 redistribution in neuropathic animals. Channel distribution rearrangements did not occur following induction of inflammation in the hind paw. Behavioral tests indicate that protein rearrangements within sensory afferents are essential to the development of allodynia under neuropathic conditions. These results suggest that axotomy enhances axonal transport in injured sensory neurons, leading to a decrease of somatic expression of Kv7.2 protein and a concomitant accumulation in damaged fiber endings. Localized changes in channel expression patterns under pathological conditions may create novel opportunities for Kv7.2 channel openers to act as analgesics. PMID:26696829

RNA interference-based functional knockdown of the voltage-gated potassium channel Kv7.2 in dorsal root ganglion neurons after in vitro and in vivo gene transfer by adeno-associated virus vectors.

PubMed

Valdor, Markus; Wagner, Anke; Röhrs, Viola; Berg, Johanna; Fechner, Henry; Schröder, Wolfgang; Tzschentke, Thomas M; Bahrenberg, Gregor; Christoph, Thomas; Kurreck, Jens

2018-01-01

Activation of the neuronal potassium channel Kv7.2 encoded by the KCNQ2 gene has recently been shown to be an attractive mechanism to inhibit nociceptive transmission. However, potent, selective, and clinically proven activators of Kv7.2/Kv7.3 currents with analgesic properties are still lacking. An important prerequisite for the development of new drugs is a model to test the selectivity of novel agonists by abrogating Kv7.2/Kv7.3 function. Since constitutive knockout mice are not viable, we developed a model based on RNA interference-mediated silencing of KCNQ2. By delivery of a KCNQ2-specific short hairpin RNA with adeno-associated virus vectors, we completely abolished the activity of the specific Kv7.2/Kv7.3-opener ICA-27243 in rat sensory neurons. Results obtained in the silencing experiments were consistent between freshly prepared and cryopreserved dorsal root ganglion neurons, as well as in dorsal root ganglion neurons dissociated and cultured after in vivo administration of the silencing vector by intrathecal injections into rats. Interestingly, the tested associated virus serotypes substantially differed with respect to their transduction capability in cultured neuronal cell lines and primary dorsal root ganglion neurons and the in vivo transfer of transgenes by intrathecal injection of associated virus vectors. However, our study provides the proof-of-concept that RNA interference-mediated silencing of KCNQ2 is a suitable approach to create an ex vivo model for testing the specificity of novel Kv7.2/Kv7.3 agonists.

Inactivation gating of Kv7.1 channels does not involve concerted cooperative subunit interactions.

PubMed

Meisel, Eshcar; Tobelaim, William; Dvir, Meidan; Haitin, Yoni; Peretz, Asher; Attali, Bernard

2018-01-01

Inactivation is an intrinsic property of numerous voltage-gated K + (Kv) channels and can occur by N-type or/and C-type mechanisms. N-type inactivation is a fast, voltage independent process, coupled to activation, with each inactivation particle of a tetrameric channel acting independently. In N-type inactivation, a single inactivation particle is necessary and sufficient to occlude the pore. C-type inactivation is a slower process, involving the outermost region of the pore and is mediated by a concerted, highly cooperative interaction between all four subunits. Inactivation of Kv7.1 channels does not exhibit the hallmarks of N- and C-type inactivation. Inactivation of WT Kv7.1 channels can be revealed by hooked tail currents that reflects the recovery from a fast and voltage-independent inactivation process. However, several Kv7.1 mutants such as the pore mutant L273F generate an additional voltage-dependent slow inactivation. The subunit interactions during this slow inactivation gating remain unexplored. The goal of the present study was to study the nature of subunit interactions along Kv7.1 inactivation gating, using concatenated tetrameric Kv7.1 channel and introducing sequentially into each of the four subunits the slow inactivating pore mutation L273F. Incorporating an incremental number of inactivating mutant subunits did not affect the inactivation kinetics but slowed down the recovery kinetics from inactivation. Results indicate that Kv7.1 inactivation gating is not compatible with a concerted cooperative process. Instead, adding an inactivating subunit L273F into the Kv7.1 tetramer incrementally stabilizes the inactivated state, which suggests that like for activation gating, Kv7.1 slow inactivation gating is not a concerted process.

Heteromeric Kv7.2/7.3 Channels Differentially Regulate Action Potential Initiation and Conduction in Neocortical Myelinated Axons

PubMed Central

Battefeld, Arne; Tran, Baouyen T.; Gavrilis, Jason; Cooper, Edward C.

2014-01-01

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of Kv7 potassium channels and voltage-gated sodium (Nav) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these Kv7 channels and the functional impact of colocalization with Nav channels remain poorly understood. Here, we quantitatively examined Kv7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. Kv7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ∼12 (proximal) to 150 pS μm−2 (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by Kv7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (∼15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic Kv7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal Kv7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains Kv7.2/7.3 channels were found to increase Nav channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, Kv7 clustering near axonal Nav channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential. PMID:24599470

Postnatal development of A-type and Kv1- and Kv2-mediated potassium channel currents in neocortical pyramidal neurons

PubMed Central

Guan, Dongxu; Horton, Leslie R.; Armstrong, William E.

2011-01-01

Potassium channels regulate numerous aspects of neuronal excitability, and several voltage-gated K+ channel subunits have been identified in pyramidal neurons of rat neocortex. Previous studies have either considered the development of outward current as a whole or divided currents into transient, A-type and persistent, delayed rectifier components but did not differentiate between current components defined by α-subunit type. To facilitate comparisons of studies reporting K+ currents from animals of different ages and to understand the functional roles of specific current components, we characterized the postnatal development of identified Kv channel-mediated currents in pyramidal neurons from layers II/III from rat somatosensory cortex. Both the persistent/slowly inactivating and transient components of the total K+ current increased in density with postnatal age. We used specific pharmacological agents to test the relative contributions of putative Kv1- and Kv2-mediated currents (100 nM α-dendrotoxin and 600 nM stromatoxin, respectively). A combination of voltage protocol, pharmacology, and curve fitting was used to isolate the rapidly inactivating A-type current. We found that the density of all identified current components increased with postnatal age, approaching a plateau at 3–5 wk. We found no significant changes in the relative proportions or kinetics of any component between postnatal weeks 1 and 5, except that the activation time constant for A-type current was longer at 1 wk. The putative Kv2-mediated component was the largest at all ages. Immunocytochemistry indicated that protein expression for Kv4.2, Kv4.3, Kv1.4, and Kv2.1 increased between 1 wk and 4–5 wk of age. PMID:21451062

Postnatal development of A-type and Kv1- and Kv2-mediated potassium channel currents in neocortical pyramidal neurons.

PubMed

Guan, Dongxu; Horton, Leslie R; Armstrong, William E; Foehring, Robert C

2011-06-01

Potassium channels regulate numerous aspects of neuronal excitability, and several voltage-gated K(+) channel subunits have been identified in pyramidal neurons of rat neocortex. Previous studies have either considered the development of outward current as a whole or divided currents into transient, A-type and persistent, delayed rectifier components but did not differentiate between current components defined by α-subunit type. To facilitate comparisons of studies reporting K(+) currents from animals of different ages and to understand the functional roles of specific current components, we characterized the postnatal development of identified Kv channel-mediated currents in pyramidal neurons from layers II/III from rat somatosensory cortex. Both the persistent/slowly inactivating and transient components of the total K(+) current increased in density with postnatal age. We used specific pharmacological agents to test the relative contributions of putative Kv1- and Kv2-mediated currents (100 nM α-dendrotoxin and 600 nM stromatoxin, respectively). A combination of voltage protocol, pharmacology, and curve fitting was used to isolate the rapidly inactivating A-type current. We found that the density of all identified current components increased with postnatal age, approaching a plateau at 3-5 wk. We found no significant changes in the relative proportions or kinetics of any component between postnatal weeks 1 and 5, except that the activation time constant for A-type current was longer at 1 wk. The putative Kv2-mediated component was the largest at all ages. Immunocytochemistry indicated that protein expression for Kv4.2, Kv4.3, Kv1.4, and Kv2.1 increased between 1 wk and 4-5 wk of age.

Analog graphic display method and apparatus

DOEpatents

Kronberg, J.W.

1991-08-13

Disclosed are an apparatus and method for using an output device such as an LED to show the approximate analog level of a variable electrical signal wherein a modulating AC waveform is superimposed either on the signal or a reference voltage, both of which are then fed to a comparator which drives the output device. Said device flashes at a constant perceptible rate with a duty cycle which varies in response to variations in the level of the input signal. The human eye perceives these variations in duty cycle as analogous to variations in the level of the input signal. 21 figures.

Analog graphic display method and apparatus

DOEpatents

Kronberg, James W.

1991-01-01

An apparatus and method for using an output device such as an LED to show the approximate analog level of a variable electrical signal wherein a modulating AC waveform is superimposed either on the signal or a reference voltage, both of which are then fed to a comparator which drives the output device. Said device flashes at a constant perceptible rate with a duty cycle which varies in response to variations in the level of the input signal. The human eye perceives these variations in duty cycle as analogous to variations in the level of the input signal.

Induction voidmeter

DOEpatents

Anderson, Thomas T.; Roop, Conard J.; Schmidt, Kenneth J.; Brewer, John

1986-01-01

An induction voidmeter for detecting voids in a conductive fluid may comprise: a four arm bridge circuit having two adjustable circuit elements connected as opposite arms of said bridge circuit, an input branch, and an output branch; two induction coils, bifilarly wound together, connected as the remaining two opposing arms of said bridge circuit and positioned such that the conductive fluid passes through said coils; applying an AC excitation signal to said input branch; and detecting the output signal generated in response to said excitation signal across said output branch. The induction coils may be located outside or inside a non-magnetic pipe containing the conductive fluid.

Inhibitory effects of cortisone and hydrocortisone on human Kv1.5 channel currents.

PubMed

Yu, Jing; Park, Mi-Hyeong; Jo, Su-Hyun

2015-01-05

Glucocorticoids are the primary hormones that respond to stress and protect organisms from dangerous situations. The glucocorticoids hydrocortisone and its dormant form, cortisone, affect the cardiovascular system with changes such as increased blood pressure and cardioprotection. Kv1.5 channels play a critical role in the maintenance of cellular membrane potential and are widely expressed in pancreatic β-cells, neurons, myocytes, and smooth muscle cells of the pulmonary vasculature. We examined the electrophysiological effects of both cortisone and hydrocortisone on human Kv1.5 channels expressed in Xenopus oocytes using a two-microelectrode voltage clamp technique. Both cortisone and hydrocortisone rapidly and irreversibly suppressed the amplitude of Kv1.5 channel current with IC50 values of 50.2±4.2μM and 33.4±3.2μM, respectively, while sustained the current trace shape of Kv1.5 current. The inhibitory effect of cortisone on Kv1.5 decreased progressively from -10mV to +30mV, while hydrocortisone׳s inhibition of the channel did not change across the same voltage range. Both cortisone and hydrocortisone blocked Kv1.5 channel currents in a non-use-dependent manner and neither altered the channel׳s steady-state activation or inactivation curves. These results show that cortisone and hydrocortisone inhibited Kv1.5 channel currents differently, and that Kv1.5 channels were more sensitive to hydrocortisone than to cortisone. Copyright © 2014 Elsevier B.V. All rights reserved.

Ultra high voltage MOS controlled 4H-SiC power switching devices

NASA Astrophysics Data System (ADS)

Ryu, S.; Capell, C.; Van Brunt, E.; Jonas, C.; O'Loughlin, M.; Clayton, J.; Lam, K.; Pala, V.; Hull, B.; Lemma, Y.; Lichtenwalner, D.; Zhang, Q. J.; Richmond, J.; Butler, P.; Grider, D.; Casady, J.; Allen, S.; Palmour, J.; Hinojosa, M.; Tipton, C. W.; Scozzie, C.

2015-08-01

Ultra high voltage (UHV, >15 kV) 4H-silicon carbide (SiC) power devices have the potential to significantly improve the system performance, reliability, and cost of energy conversion systems by providing reduced part count, simplified circuit topology, and reduced switching losses. In this paper, we compare the two MOS based UHV 4H-SiC power switching devices; 15 kV 4H-SiC MOSFETs and 15 kV 4H-SiC n-IGBTs. The 15 kV 4H-SiC MOSFET shows a specific on-resistance of 204 mΩ cm2 at 25 °C, which increased to 570 mΩ cm2 at 150 °C. The 15 kV 4H-SiC MOSFET provides low, temperature-independent, switching losses which makes the device more attractive for applications that require higher switching frequencies. The 15 kV 4H-SiC n-IGBT shows a significantly lower forward voltage drop (VF), along with reasonable switching performance, which make it a very attractive device for high voltage applications with lower switching frequency requirements. An electrothermal analysis showed that the 15 kV 4H-SiC n-IGBT outperforms the 15 kV 4H-SiC MOSFET for applications with switching frequencies of less than 5 kHz. It was also shown that the use of a carrier storage layer (CSL) can significantly improve the conduction performance of the 15 kV 4H-SiC n-IGBTs.

BmP02 Atypically Delays Kv4.2 Inactivation: Implication for a Unique Interaction between Scorpion Toxin and Potassium Channel

PubMed Central

Wu, Bin; Zhu, Yan; Shi, Jian; Tao, Jie; Ji, Yonghua

2016-01-01

BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (Ito) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2 channel, one of the main contributors to Ito. The present study investigated the effects of BmP02 on Kv4.2 kinetics and its underlying molecular mechanism. The electrophysiological recordings showed that the inactivation of Kv4.2 expressed in HEK293T cells was significantly delayed by BmP02 in a dose-response manner with EC50 of ~850 nM while the peak current, activation and voltage-dependent inactivation of Kv4.2 were not affected. Meanwhile, the recovery from inactivation of Kv4.2 was accelerated and the deactivation was slowed after the application of BmP02. The site-directed mutagenesis combined with computational modelling identified that K347 and K353, located in the turret motif of the Kv4.2, and E4/E5, D20/D21 in BmP02 are key residues to interact with BmP02 through electrostatic force. These findings not only reveal a novel interaction between Kv4.2 channel and its peptidyl modulator, but also provide valuable information for design of highly-selective Kv4.2 modulators. PMID:27690098

Dendritic Kv3.3 potassium channels in cerebellar purkinje cells regulate generation and spatial dynamics of dendritic Ca2+ spikes.

PubMed

Zagha, Edward; Manita, Satoshi; Ross, William N; Rudy, Bernardo

2010-06-01

Purkinje cell dendrites are excitable structures with intrinsic and synaptic conductances contributing to the generation and propagation of electrical activity. Voltage-gated potassium channel subunit Kv3.3 is expressed in the distal dendrites of Purkinje cells. However, the functional relevance of this dendritic distribution is not understood. Moreover, mutations in Kv3.3 cause movement disorders in mice and cerebellar atrophy and ataxia in humans, emphasizing the importance of understanding the role of these channels. In this study, we explore functional implications of this dendritic channel expression and compare Purkinje cell dendritic excitability in wild-type and Kv3.3 knockout mice. We demonstrate enhanced excitability of Purkinje cell dendrites in Kv3.3 knockout mice, despite normal resting membrane properties. Combined data from local application pharmacology, voltage clamp analysis of ionic currents, and assessment of dendritic Ca(2+) spike threshold in Purkinje cells suggest a role for Kv3.3 channels in opposing Ca(2+) spike initiation. To study the physiological relevance of altered dendritic excitability, we measured [Ca(2+)](i) changes throughout the dendritic tree in response to climbing fiber activation. Ca(2+) signals were specifically enhanced in distal dendrites of Kv3.3 knockout Purkinje cells, suggesting a role for dendritic Kv3.3 channels in regulating propagation of electrical activity and Ca(2+) influx in distal dendrites. These findings characterize unique roles of Kv3.3 channels in dendrites, with implications for synaptic integration, plasticity, and human disease.

Cftr controls lumen expansion and function of Kupffer’s vesicle in zebrafish

PubMed Central

Navis, Adam; Marjoram, Lindsay; Bagnat, Michel

2013-01-01

Regulated fluid secretion is crucial for the function of most organs. In vertebrates, the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) is a master regulator of fluid secretion. Although the biophysical properties of CFTR have been well characterized in vitro, little is known about its in vivo role during development. Here, we investigated the function of Cftr during zebrafish development by generating several cftr mutant alleles using TAL effector nucleases. We found that loss of cftr function leads to organ laterality defects. In zebrafish, left-right (LR) asymmetry requires cilia-driven fluid flow within the lumen of Kupffer’s vesicle (KV). Using live imaging we found that KV morphogenesis is disrupted in cftr mutants. Loss of Cftr-mediated fluid secretion impairs KV lumen expansion leading to defects in organ laterality. Using bacterial artificial chromosome recombineering, we generated transgenic fish expressing functional Cftr fusion proteins with fluorescent tags under the control of the cftr promoter. The transgenes completely rescued the cftr mutant phenotype. Live imaging of these transgenic lines showed that Cftr is localized to the apical membrane of the epithelial cells in KV during lumen formation. Pharmacological stimulation of Cftr-dependent fluid secretion led to an expansion of the KV lumen. Conversely, inhibition of ion gradient formation impaired KV lumen inflation. Interestingly, cilia formation and motility in KV were not affected, suggesting that fluid secretion and flow are independently controlled in KV. These findings uncover a new role for cftr in KV morphogenesis and function during zebrafish development. PMID:23487313

The phosphoinositide sensitivity of the KV channel family

PubMed Central

Kruse, Martin; Hille, Bertil

2013-01-01

Recently, we screened several KV channels for possible dependence on plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The channels were expressed in tsA-201 cells and the PI(4,5)P2 was depleted by several manipulations in whole-cell experiments with parallel measurements of channel activity. In contrast to reports on excised-patches using Xenopus laevis oocytes, we found only KV7, but none of the other tested KV channels, to be strongly dependent on PI(4,5)P2. We now have extended our study to KV1.2 channels, a KV channel we had not previously tested, because a new published study on excised patches showed regulation of the voltage-dependence of activation by PI(4,5)P2. In full agreement with those published results, we found a reduction of current amplitude by ~20% after depletion of PI(4,5)P2 and a small left shift in the activation curve of KV1.2 channels. We also found a small reduction of KV11.1 (hERG) currents that was not accompanied by a gating shift. In conclusion, our whole-cell methods yield a PI(4,5)P2-dependence of KV1.2 currents in tsA-201 cells that is comparable to findings from excised patches of Xenopus laevis oocytes. We discuss possible physiological rationales for PI(4,5)P2 sensitivity of some ion channels and insensitivity of others. PMID:23907203

PhKv a toxin isolated from the spider venom induces antinociception by inhibition of cholinesterase activating cholinergic system.

PubMed

Rigo, Flavia Karine; Rossato, Mateus Fortes; Trevisan, Gabriela; De Prá, Samira Dal-Toé; Ineu, Rafael Porto; Duarte, Mariane Bernardo; de Castro Junior, Célio José; Ferreira, Juliano; Gomez, Marcus Vinicius

2017-10-01

Cholinergic agents cause antinociception by mimicking the release of acetylcholine (ACh) from spinal cholinergic nerves. PhKv is a peptide isolated from the venom of the armed spider Phoneutria nigriventer. It has an antiarrythmogenic activity that involves the enhanced release of acetylcholine. The aim of this study was to investigate whether PhKv had an antinociceptive action in mice. Male albino Swiss mice (25-35g) were used in this study. The PhKv toxin was purified from a PhTx3 fraction of the Phoneutria nigriventer spider's venom. Because of its peptide nature, PhKv is not orally available and it was delivered directly into the central nervous system by an intrathecal (i.t.) route. PhKV on the thermal and mechanical sensitivity was evaluated using plantar test apparatus and the up-and-down method. The analgesic effects of PhKv were studied in neuropathic pain (CCI) and in the peripheral capsicin test. In order to test whether PhKv interfered with the cholinergic system, the mice were pre-treated with atropine (5mg/kg, i.p.) or mecamylamine (0.001mg/kg, i.p.) and the PhKv toxin (30pmol/site i.t.) or neostigmine (100pmol/site) were applied 15min before the intraplantar capsaicin (1nmol/paw) administrations. To investigate PhKv action on the AChE activities, was performed in vitro and ex vivo assay for AChE. For the in vitro experiments, mice spinal cord supernatants of tissue homogenates (1mg/ml) were used as source of AChE activity. The AChE assay was monitored at 37°C for 10min in a FlexStation 3 Multi-Mode Microplate Reader (Molecular Devices) at 405nm. PhKv (30 and 100pmol/site, i.t.) had no effect on the thermal or mechanical sensitivity thresholds. However, in a chronic constriction injury model of pain, PhKv (10pmol/site, i.t.) caused a robust reduction in mechanical withdrawal with an antinociceptive effect that lasted 4h. A pretreatment in mice with PhKv (30pmol/site, i.t.) or neostigmine (100pmol/site, i.t.) 15min before an intraplantar injection of capsaicin (1nmol/paw) caused a maximal antinociceptive effect of 69.5±4.9% and 85±2.5%, respectively. A pretreatment in mice with atropine; 5mg/kg, i.p. or mecamylamine 0.001mg/kg, i.p. inhibited a neostigimine and PhKv-induced antinociception, suggesting a cholinergic mechanism. Spinal acetylcholinesterase was inhibited by PhKv with ED 50 of 7.6 (4.6-12.6pmol/site, i.t.). PhKv also inhibited the in vitro AChE activity of spinal cord homogenates with an EC 50 of 20.8 (11.6-37.3nM), shifting the Km value from 0.06mM to 18.5mM, characterizing a competitive inhibition of AChE activity by PhKv. Our findings provide, to our knowledge, the first evidence that PhKv caused inhibition of AChE, it increased the ACh content at the neuronal synapses, leading to an activation of the cholinergic system and an antinociceptive response. Studies regarding the nociceptive mechanisms and the identification of potential targets for the treatment of pain have become top priorities. PhKv, by its action of stimulating the cholinergic receptors muscarinic and nicotinic system, reduces pain it may be an alternative for controlling the pain processes. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

The C-terminus SH3-binding domain of Kv1.3 is required for the actin-mediated immobilization of the channel via cortactin

PubMed Central

Hajdu, Peter; Martin, Geoffrey V.; Chimote, Ameet A.; Szilagyi, Orsolya; Takimoto, Koichi; Conforti, Laura

2015-01-01

Kv1.3 channels play a pivotal role in the activation and migration of T-lymphocytes. These functions are accompanied by the channels' polarization, which is essential for associated downstream events. However, the mechanisms that govern the membrane movement of Kv1.3 channels remain unclear. F-actin polymerization occurs concomitantly to channel polarization, implicating the actin cytoskeleton in this process. Here we show that cortactin, a factor initiating the actin network, controls the membrane mobilization of Kv1.3 channels. FRAP with EGFP-tagged Kv1.3 channels demonstrates that knocking down cortactin decreases the actin-based immobilization of the channels. Using various deletion and mutation constructs, we show that the SH3 motif of Kv1.3 mediates the channel immobilization. Proximity ligation assays indicate that deletion or mutation of the SH3 motif also disrupts interaction of the channel with cortactin. In T-lymphocytes, the interaction between HS1 (the cortactin homologue) and Kv1.3 occurs at the immune synapse and requires the channel's C-terminal domain. These results show that actin dynamics regulates the membrane motility of Kv1.3 channels. They also provide evidence that the SH3 motif of the channel and cortactin plays key roles in this process. PMID:25739456

Effects of dose reduction on the detectability of standardized radiolucent lesions in digital panoramic radiography.

PubMed

Dula, K; Sanderink, G; van der Stelt, P F; Mini, R; Buser, D

1998-08-01

Dose reduction in digital panoramic radiography was studied. Intentional underexposure was performed with the Orthophos DS while six different human mandibles were radiographed. Exposure settings were 69 kV/15 mA (standard), 64 kV/16 mA, and 60 kV/16 mA. Standardized spherical defects, each either 1 or 1.25 mm in diameter, were simulated in 288 of 432 images, and seven observers decided whether defects were present or not. Areas under the receiver operating characteristics curves were calculated. They showed no significant differences in the detectability of the 1-mm defect at 69, 64, or 60 kV. For the 1.25-mm defect, no difference was found between the 69 and 60 kV images, but a statistically significant different detectability was found for 64 kV images in comparison with both 69 and 60 kV images. A dose reduction of up to 43% was ascertained with a Pedo-RT-Humanoid phantom when panoramic radiography was performed at 60 kV/16 mA. The conclusion is that with the Orthophos DS, it seems possible to reduce the dose rate of x-rays without loss of diagnostic quality in the case of radiolucent changes.

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

PubMed Central

Barrese, Vincenzo; Taglialatela, Maurizio; Greenwood, Iain A; Davidson, Colin

2015-01-01

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage. PMID:25966943

Diverse Roles for Auxiliary Subunits in Phosphorylation-Dependent Regulation of Mammalian Brain Voltage-Gated Potassium Channels

PubMed Central

Vacher, Helene; Trimmer, James S.

2012-01-01

Voltage-gated ion channels are a diverse family of signaling proteins that mediate rapid electrical signaling events. Among these, voltage-gated potassium or Kv channels are the most diverse, in part due to the large number of principal (or α) subunits and auxiliary subunits that can assemble in different combinations to generate Kv channel complexes with distinct structures and functions. The diversity of Kv channels underlies much of the variability in the active properties between different mammalian central neurons, and the dynamic changes that lead to experience-dependent plasticity in intrinsic excitability. Recent studies have revealed that Kv channel α subunits and auxiliary subunits are extensively phosphorylated, contributing to additional structural and functional diversity. Here we highlight recent studies that show that auxiliary subunits exert some of their profound effects on dendritic Kv4 and axonal Kv1 channels through phosphorylation-dependent mechanisms, either due to phosphorylation on the auxiliary subunit itself, or by influencing the extent and/or impact of α subunit phosphorylation. The complex effects of auxiliary subunits and phosphorylation provide a potent mechanism to generate additional diversity in the structure and function of Kv4 and Kv1 channels, as well as allowing for dynamic reversible regulation of these important ion channels. PMID:21822597

Tablet—next generation sequence assembly visualization

PubMed Central

Milne, Iain; Bayer, Micha; Cardle, Linda; Shaw, Paul; Stephen, Gordon; Wright, Frank; Marshall, David

2010-01-01

Summary: Tablet is a lightweight, high-performance graphical viewer for next-generation sequence assemblies and alignments. Supporting a range of input assembly formats, Tablet provides high-quality visualizations showing data in packed or stacked views, allowing instant access and navigation to any region of interest, and whole contig overviews and data summaries. Tablet is both multi-core aware and memory efficient, allowing it to handle assemblies containing millions of reads, even on a 32-bit desktop machine. Availability: Tablet is freely available for Microsoft Windows, Apple Mac OS X, Linux and Solaris. Fully bundled installers can be downloaded from http://bioinf.scri.ac.uk/tablet in 32- and 64-bit versions. Contact: tablet@scri.ac.uk PMID:19965881

Performance Analysis of Three-Phase Induction Motor with AC Direct and VFD

NASA Astrophysics Data System (ADS)

Kumar, Dinesh

2018-03-01

The electrical machine analysis and performance calculation is a very important aspect of efficient drive system design. The development of power electronics devices and power converters provide smooth speed control of Induction Motors by changing the frequency of input supply. These converters, on one hand are providing a more flexible speed control that also leads to problems of harmonics and their associated ailments like pulsating torque, distorted current and voltage waveforms, increasing losses etc. This paper includes the performance analysis of three phase induction motor with three-phase AC direct and variable frequency drives (VFD). The comparison has been concluded with respect to various parameters. MATLAB-SIMULINKTM is used for the analysis.

The Kv7 Channel and Cardiovascular Risk Factors.

PubMed

Fosmo, Andreas L; Skraastad, Øyvind B

2017-01-01

Potassium channels play a pivotal role in the regulation of excitability in cells such as neurons, cardiac myocytes, and vascular smooth muscle cells. The KCNQ (Kv7) family of voltage-activated K + channels hyperpolarizes the cell and stabilizes the membrane potential. Here, we outline how Kv7 channel activity may contribute to the development of the cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions and hypotheses regarding previous and future research have been raised. Alterations in the Kv7 channel may contribute to the development of cardiovascular disease (CVD). Pharmacological modification of Kv7 channels may represent a possible treatment for CVD in the future.

The Kv7 Channel and Cardiovascular Risk Factors

PubMed Central

Fosmo, Andreas L.; Skraastad, Øyvind B.

2017-01-01

Potassium channels play a pivotal role in the regulation of excitability in cells such as neurons, cardiac myocytes, and vascular smooth muscle cells. The KCNQ (Kv7) family of voltage-activated K+ channels hyperpolarizes the cell and stabilizes the membrane potential. Here, we outline how Kv7 channel activity may contribute to the development of the cardiovascular risk factors such as hypertension, diabetes, and obesity. Questions and hypotheses regarding previous and future research have been raised. Alterations in the Kv7 channel may contribute to the development of cardiovascular disease (CVD). Pharmacological modification of Kv7 channels may represent a possible treatment for CVD in the future. PMID:29259974

Quantitative Confocal Microscopy Analysis as a Basis for Search and Study of Potassium Kv1.x Channel Blockers

NASA Astrophysics Data System (ADS)

Feofanov, Alexey V.; Kudryashova, Kseniya S.; Nekrasova, Oksana V.; Vassilevski, Alexander A.; Kuzmenkov, Alexey I.; Korolkova, Yuliya V.; Grishin, Eugene V.; Kirpichnikov, Mikhail P.

Artificial KcsA-Kv1.x (x = 1, 3) receptors were recently designed by transferring the ligand-binding site from human Kv1.x voltage-gated potassium channels into corresponding domain of the bacterial KscA channel. We found that KcsA-Kv1.x receptors expressed in E. coli cells are embedded into cell membrane and bind ligands when the cells are transformed to spheroplasts. We supposed that E. coli spheroplasts with membrane-embedded KcsA-Kv1.x and fluorescently labeled ligand agitoxin-2 (R-AgTx2) can be used as elements of an advanced analytical system for search and study of Kv1-channel blockers. To realize this idea, special procedures were developed for measurement and quantitative treatment of fluorescence signals obtained from spheroplast membrane using confocal laser scanning microscopy (CLSM). The worked out analytical "mix and read" systems supported by quantitative CLSM analysis were demonstrated to be reliable alternative to radioligand and electrophysiology techniques in the search and study of selective Kv1.x channel blockers of high scientific and medical importance.

The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1.

PubMed

Schulte, Uwe; Thumfart, Jörg-Oliver; Klöcker, Nikolaj; Sailer, Claudia A; Bildl, Wolfgang; Biniossek, Martin; Dehn, Doris; Deller, Thomas; Eble, Silke; Abbass, Karen; Wangler, Tanja; Knaus, Hans-Günther; Fakler, Bernd

2006-03-02

The voltage-gated potassium (Kv) channel subunit Kv1.1 is a major constituent of presynaptic A-type channels that modulate synaptic transmission in CNS neurons. Here, we show that Kv1.1-containing channels are complexed with Lgi1, the functionally unassigned product of the leucine-rich glioma inactivated gene 1 (LGI1), which is causative for an autosomal dominant form of lateral temporal lobe epilepsy (ADLTE). In the hippocampal formation, both Kv1.1 and Lgi1 are coassembled with Kv1.4 and Kvbeta1 in axonal terminals. In A-type channels composed of these subunits, Lgi1 selectively prevents N-type inactivation mediated by the Kvbeta1 subunit. In contrast, defective Lgi1 molecules identified in ADLTE patients fail to exert this effect resulting in channels with rapid inactivation kinetics. The results establish Lgi1 as a novel subunit of Kv1.1-associated protein complexes and suggest that changes in inactivation gating of presynaptic A-type channels may promote epileptic activity.

Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin

PubMed Central

Ozawa, Shin-ichiro; Kimura, Tomomi; Nozaki, Tomohiro; Harada, Hitomi; Shimada, Ichio; Osawa, Masanori

2015-01-01

Voltage-dependent K+ (Kv) channels play crucial roles in nerve and muscle action potentials. Voltage-sensing domains (VSDs) of Kv channels sense changes in the transmembrane potential, regulating the K+-permeability across the membrane. Gating modifier toxins, which have been used for the functional analyses of Kv channels, inhibit Kv channels by binding to VSD. However, the structural basis for the inhibition remains elusive. Here, fluorescence and NMR analyses of the interaction between VSD derived from KvAP channel and its gating modifier toxin, VSTx1, indicate that VSTx1 recognizes VSD under depolarized condition. We identified the VSD-binding residues of VSTx1 and their proximal residues of VSD by the cross-saturation (CS) and amino acid selective CS experiments, which enabled to build a docking model of the complex. These results provide structural basis for the specific binding and inhibition of Kv channels by gating modifier toxins. PMID:26382304

Low dimensional CH3NH3PbBr3 cubes for persistent luminescence: Energy variation of electron excitation

NASA Astrophysics Data System (ADS)

Besral, N.; Paul, T.; Thakur, S.; Sarkar, S.; Sardar, K.; Chanda, K.; Das, A.; Chattopadhyay, K. K.

2018-04-01

The impact of varying electron beam voltage upon room temperature CL (cathodoluminescence) properties of crystalline organic-inorganic lead halide perovskite CH3NH3PbBr3 (Methylammonium lead tribromide) microcubes have been studied. CH3NH3PbBr3 microcubes were synthesized at room temperature by a very straight forward wet chemical route. After preliminary characterizations like XRD (X-ray diffraction), FESEM (Field emission scanning electron microscopy), UV-Vis spectroscopy, CL study at three different beam voltages i.e. 5 kV, 10 kV and 15 kV respectively was performed at room temperature. Prominent emission signals were obtained with emission peaks at 2.190 eV (FWHM 0.120 eV), 2.222 eV (FWHM 0.108 eV) and 2.242 eV (FWHM 0.095 eV) for electron beam voltages 5 kV, 10 kV and 15 kV respectively.

Role of Kv4.3 in Vibration-Induced Muscle Pain in the Rat.

PubMed

Conner, Lindsay B; Alvarez, Pedro; Bogen, Oliver; Levine, Jon D

2016-04-01

We hypothesized that changes in the expression of voltage-gated potassium channel (Kv) 4.3 contribute to the mechanical hyperalgesia induced by vibration injury, in a rodent model for hand-arm vibration syndrome in humans. Here we show that the exposure of the gastrocnemius muscle to vibration injury induces muscle hyperalgesia that is accompanied by a significant downregulation of Kv4.3 in affected sensory nerve fibers in dorsal root ganglia. We additionally show that the intrathecal administration of antisense oligonucleotides for Kv4.3 messenger RNA itself induces muscle hyperalgesia in the rat. Our results suggest that attenuation in the expression of Kv4.3 may contribute to neuropathic pain in people affected by hand-arm vibration syndrome. Our findings establish Kv4.3 as a potential molecular target for the treatment of hand-arm vibration syndrome. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Modulation of Kv7 channels and excitability in the brain.

PubMed

Greene, Derek L; Hoshi, Naoto

2017-02-01

Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.

Modulation of Kv7 channels and excitability in the brain

PubMed Central

Greene, Derek L; Hoshi, Naoto

2016-01-01

Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits. PMID:27645822

The KCNE Tango – How KCNE1 Interacts with Kv7.1

PubMed Central

Wrobel, Eva; Tapken, Daniel; Seebohm, Guiscard

2012-01-01

The classical tango is a dance characterized by a 2/4 or 4/4 rhythm in which the partners dance in a coordinated way, allowing dynamic contact. There is a surprising similarity between the tango and how KCNE β-subunits “dance” to the fast rhythm of the cell with their partners from the Kv channel family. The five KCNE β-subunits interact with several members of the Kv channels, thereby modifying channel gating via the interaction of their single transmembrane-spanning segment, the extracellular amino terminus, and/or the intracellular carboxy terminus with the Kv α-subunit. Best studied is the molecular basis of interactions between KCNE1 and Kv7.1, which, together, supposedly form the native cardiac IKs channel. Here we review the current knowledge about functional and molecular interactions of KCNE1 with Kv7.1 and try to summarize and interpret the tango of the KCNEs. PMID:22876232

Kv7.2 regulates the function of peripheral sensory neurons.

PubMed

King, Chih H; Lancaster, Eric; Salomon, Daniela; Peles, Elior; Scherer, Steven S

2014-10-01

The Kv7 (KCNQ) family of voltage-gated K(+) channels regulates cellular excitability. The functional role of Kv7.2 has been hampered by the lack of a viable Kcnq2-null animal model. In this study, we generated homozygous Kcnq2-null sensory neurons using the Cre-Lox system; in these mice, Kv7.2 expression is absent in the peripheral sensory neurons, whereas the expression of other molecular components of nodes (including Kv7.3), paranodes, and juxtaparanodes is not altered. The conditional Kcnq2-null animals exhibit normal motor performance but have increased thermal hyperalgesia and mechanical allodynia. Whole-cell patch recording technique demonstrates that Kcnq2-null sensory neurons have increased excitability and reduced spike frequency adaptation. Taken together, our results suggest that the loss of Kv7.2 activity increases the excitability of primary sensory neurons. © 2014 Wiley Periodicals, Inc.

Very low noise AC/DC power supply systems for large detector arrays.

PubMed

Arnaboldi, C; Baù, A; Carniti, P; Cassina, L; Giachero, A; Gotti, C; Maino, M; Passerini, A; Pessina, G

2015-12-01

In this work, we present the first part of the power supply system for the CUORE and LUCIFER arrays of bolometric detectors. For CUORE, it consists of AC/DC commercial power supplies (0-60 V output) followed by custom DC/DC modules (48 V input, ±5 V to ±13.5 V outputs). Each module has 3 floating and independently configurable output voltages. In LUCIFER, the AC/DC + DC/DC stages are combined into a commercial medium-power AC/DC source. At the outputs of both setups, we introduced filters with the aim of lowering the noise and to protect the following stages from high voltage spikes that can be generated by the energy stored in the cables after the release of accidental short circuits. Output noise is very low, as required: in the 100 MHz bandwidth the RMS level is about 37 μV(RMS) (CUORE setup) and 90 μV(RMS) (LUCIFER setup) at a load of 7 A, with a negligible dependence on the load current. Even more importantly, high frequency switching disturbances are almost completely suppressed. The efficiency of both systems is above 85%. Both systems are completely programmable and monitored via CAN bus (optically coupled).

Mariner Mars 1971 attitude control subsystem

NASA Technical Reports Server (NTRS)

Edmunds, R. S.

1974-01-01

The Mariner Mars 1971 attitude control subsystem (ACS) is discussed. It is comprised of a sun sensor set, a Canopus tracker, an inertial reference unit, two cold gas reaction control assemblies, two rocket engine gimbal actuators, and an attitude control electronics unit. The subsystem has the following eight operating modes: (1) launch, (2) sun acquisition, (3) roll search, (4) celestial cruise, (5) all-axes inertial, (6) roll inertial, (7) commanded turn, and (8) thrust vector control. In the celestial cruise mode, the position control is held to plus or minus 0.25 deg. Commanded turn rates are plus or minus 0.18 deg/s. The attitude control logic in conjunction with command inputs from other spacecraft subsystems establishes the ACS operating mode. The logic utilizes Sun and Canopus acquisition signals generated within the ACS to perform automatic mode switching so that dependence of ground control is minimized when operating in the sun acquisition, roll search, and celestial cruise modes. The total ACS weight is 65.7 lb, and includes 5.4 lb of nitrogen gas. Total power requirements vary from 9 W for the celestial cruise mode to 54 W for the commanded turn mode.

Impact of Ancillary Subunits on Ventricular Repolarization

PubMed Central

Abbott, Geoffrey W.; Xu, Xianghua; Roepke, Torsten K.

2007-01-01

Voltage-gated potassium (Kv) channels generate the outward K+ ion currents that constitute the primary force in ventricular repolarization. Kv channels comprise tetramers of pore-forming α subunits and, in probably the majority of cases in vivo, ancillary or β subunits that help define the properties of the Kv current generated. Ancillary subunits can be broadly categorized as cytoplasmic or transmembrane, and can modify Kv channel trafficking, conductance, gating, ion selectivity, regulation and pharmacology. Because of their often profound effects on Kv channel function, studies of the molecular correlates of ventricular repolarization must take into account ancillary subunits as well as α subunits. Cytoplasmic ancillary subunits include the Kvβ subunits, which regulate a range of Kv channels and may link channel gating to redox potential; and the KChIPs, which appear most often associated with Kv4 subfamily channels that generate the ventricular Ito current. Transmembrane ancillary subunits include the MinK-related proteins (MiRPs) encoded by KCNE genes, which modulate members of most Kv α subunit subfamilies; and the putative 12-transmembrane domain KCR1 protein which modulates hERG. In some cases, such as the ventricular IKs channel complex, it is well-established that the KCNQ1 α subunit must co-assemble with the MinK (KCNE1) single transmembrane domain ancillary subunit for recapitulation of the characteristic, unusually slowly-activating IKs current. In other cases it is not so clear-cut, and in particular the roles of the other MinK-related proteins (MiRPs 1–4) in regulating cardiac Kv channels such as KCNQ1 and hERG in vivo are under debate. MiRP1 alters hERG function and pharmacology, and inherited MiRP1 mutations are associated with inherited and acquired arrhythmias, but controversy exists over the native role of MiRP1 in regulating hERG (and therefore ventricular IKr) in vivo. Some ancillary subunits may exhibit varied expression to shape spatial Kv current variation, e.g. KChIP2 and the epicardial-endocardial Ito current density gradient. Indeed, it is likely that most native ventricular Kv channels exhibit temporal and spatial heterogeneity of subunit composition, complicating both modeling of their functional impact on the ventricular action potential and design of specific current-targeted compounds. Here, we discuss current thinking and lines of experimentation aimed at resolving the complexities of the Kv channel complexes that repolarize the human ventricular myocardium. PMID:17993327

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

PubMed Central

Kimm, Tilia; Khaliq, Zayd M.

2015-01-01

Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency–current (f–I) relationship, whereas BK channel inhibition had little effect on the f–I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f–I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. SIGNIFICANCE STATEMENT This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both channel types participate in action potential repolarization about equally, they have contrasting and partially opposite effects in regulating neuronal firing at frequencies typical of bursting. Our analysis shows that this results from their different kinetic properties, with fast-activating BK channels serving to short-circuit activation of Kv2 channels, which tend to slow firing by producing a deep afterhyperpolarization. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. PMID:26674866

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons.

PubMed

Kimm, Tilia; Khaliq, Zayd M; Bean, Bruce P

2015-12-16

Little is known about the voltage-dependent potassium currents underlying spike repolarization in midbrain dopaminergic neurons. Studying mouse substantia nigra pars compacta dopaminergic neurons both in brain slice and after acute dissociation, we found that BK calcium-activated potassium channels and Kv2 channels both make major contributions to the depolarization-activated potassium current. Inhibiting Kv2 or BK channels had very different effects on spike shape and evoked firing. Inhibiting Kv2 channels increased spike width and decreased the afterhyperpolarization, as expected for loss of an action potential-activated potassium conductance. BK inhibition also increased spike width but paradoxically increased the afterhyperpolarization. Kv2 channel inhibition steeply increased the slope of the frequency-current (f-I) relationship, whereas BK channel inhibition had little effect on the f-I slope or decreased it, sometimes resulting in slowed firing. Action potential clamp experiments showed that both BK and Kv2 current flow during spike repolarization but with very different kinetics, with Kv2 current activating later and deactivating more slowly. Further experiments revealed that inhibiting either BK or Kv2 alone leads to recruitment of additional current through the other channel type during the action potential as a consequence of changes in spike shape. Enhancement of slowly deactivating Kv2 current can account for the increased afterhyperpolarization produced by BK inhibition and likely underlies the very different effects on the f-I relationship. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. This work shows that BK calcium-activated potassium channels and Kv2 voltage-activated potassium channels both regulate action potentials in dopamine neurons of the substantia nigra pars compacta. Although both channel types participate in action potential repolarization about equally, they have contrasting and partially opposite effects in regulating neuronal firing at frequencies typical of bursting. Our analysis shows that this results from their different kinetic properties, with fast-activating BK channels serving to short-circuit activation of Kv2 channels, which tend to slow firing by producing a deep afterhyperpolarization. The cross-regulation of BK and Kv2 activation illustrates that the functional role of a channel cannot be defined in isolation but depends critically on the context of the other conductances in the cell. Copyright © 2015 the authors 0270-6474/15/3516404-14$15.00/0.