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Sample records for doubly selective channels

  1. Block Transmissions over Doubly Selective Channels: Iterative Channel Estimation and Turbo Equalization

    NASA Astrophysics Data System (ADS)

    Fang, Kun; Rugini, Luca; Leus, Geert

    2010-12-01

    Modern wireless communication systems require high transmission rates, giving rise to frequency selectivity due to multipath propagation. In addition, high-mobility terminals and scatterers induce Doppler shifts that introduce time selectivity. Therefore, advanced techniques are needed to accurately model the time- and frequency-selective (i.e., doubly selective) channels and to counteract the related performance degradation. In this paper, we develop new receivers for orthogonal frequency-division multiplexing (OFDM) systems and single-carrier (SC) systems in doubly selective channels by embedding the channel estimation task within low-complexity block turbo equalizers. Linear minimum mean-squared error (MMSE) pilot-assisted channel estimators are presented, and the soft data estimates from the turbo equalizers are used to improve the quality of the channel estimates.

  2. Maximum-LikelihoodSemiblind Equalization of Doubly Selective Channels Using the EM Algorithm

    NASA Astrophysics Data System (ADS)

    Kutz, Gideon; Raphaeli, Dan

    2010-12-01

    Maximum-likelihood semi-blind joint channel estimation and equalization for doubly selective channels and single-carrier systems is proposed. We model the doubly selective channel as an FIR filter where each filter tap is modeled as a linear combination of basis functions. This channel description is then integrated in an iterative scheme based on the expectation-maximization (EM) principle that converges to the channel description vector estimation. We discuss the selection of the basis functions and compare various functions sets. To alleviate the problem of convergence to a local maximum, we propose an initialization scheme to the EM iterations based on a small number of pilot symbols. We further derive a pilot positioning scheme targeted to reduce the probability of convergence to a local maximum. Our pilot positioning analysis reveals that for high Doppler rates it is better to spread the pilots evenly throughout the data block (and not to group them) even for frequency-selective channels. The resulting equalization algorithm is shown to be superior over previously proposed equalization schemes and to perform in many cases close to the maximum-likelihood equalizer with perfect channel knowledge. Our proposed method is also suitable for coded systems and as a building block for Turbo equalization algorithms.

  3. Entropy production of doubly stochastic quantum channels

    SciTech Connect

    Müller-Hermes, Alexander; Stilck França, Daniel Wolf, Michael M.

    2016-02-15

    We study the entropy increase of quantum systems evolving under primitive, doubly stochastic Markovian noise and thus converging to the maximally mixed state. This entropy increase can be quantified by a logarithmic-Sobolev constant of the Liouvillian generating the noise. We prove a universal lower bound on this constant that stays invariant under taking tensor-powers. Our methods involve a new comparison method to relate logarithmic-Sobolev constants of different Liouvillians and a technique to compute logarithmic-Sobolev inequalities of Liouvillians with eigenvectors forming a projective representation of a finite abelian group. Our bounds improve upon similar results established before and as an application we prove an upper bound on continuous-time quantum capacities. In the last part of this work we study entropy production estimates of discrete-time doubly stochastic quantum channels by extending the framework of discrete-time logarithmic-Sobolev inequalities to the quantum case.

  4. Entropy production of doubly stochastic quantum channels

    NASA Astrophysics Data System (ADS)

    Müller-Hermes, Alexander; Stilck França, Daniel; Wolf, Michael M.

    2016-02-01

    We study the entropy increase of quantum systems evolving under primitive, doubly stochastic Markovian noise and thus converging to the maximally mixed state. This entropy increase can be quantified by a logarithmic-Sobolev constant of the Liouvillian generating the noise. We prove a universal lower bound on this constant that stays invariant under taking tensor-powers. Our methods involve a new comparison method to relate logarithmic-Sobolev constants of different Liouvillians and a technique to compute logarithmic-Sobolev inequalities of Liouvillians with eigenvectors forming a projective representation of a finite abelian group. Our bounds improve upon similar results established before and as an application we prove an upper bound on continuous-time quantum capacities. In the last part of this work we study entropy production estimates of discrete-time doubly stochastic quantum channels by extending the framework of discrete-time logarithmic-Sobolev inequalities to the quantum case.

  5. Time reversal communication over doubly spread channels.

    PubMed

    Zeng, Wen-Jun; Jiang, Xue

    2012-11-01

    Conventional time reversal can mitigate multipath delay dispersion by temporal focusing. But it is not applicable to time-varying channels with a Doppler spread. Although recently time reversal communication has been adapted to time-variant channels, the modified technique requires frequent channel updates to track channel variations and cannot handle large Doppler spread, which means that it cannot achieve frequency focusing. In this paper, two time reversal receivers for underwater acoustic communications over doubly spread channels are proposed. The proposed approach, which can be interpreted as time-frequency channel matching, is based on the channel spreading function rather than impulse response adopted by the existing techniques; this leads to much less frequent channel updates. Unlike existing methods that only correct a single Doppler shift, the proposed approach uses a rake-like structure to compensate for multiple Doppler shifts and hence can eliminate severe Doppler spread induced by temporal channel variations. Simulation results verify the effectiveness of the proposed approach, indicating that it can simultaneously counteract delay and Doppler spreads, achieving both temporal and frequency focusing.

  6. Fast estimation of sparse doubly spread acoustic channels.

    PubMed

    Zeng, Wen-Jun; Xu, Wen

    2012-01-01

    The estimation of doubly spread underwater acoustic channels is addressed. By exploiting the sparsity in the delay-Doppler domain, this paper proposes a fast projected gradient method (FPGM) that can handle complex-valued data for estimating the delay-Doppler spread function of a time-varying channel. The proposed FPGM formulates the sparse channel estimation as a complex-valued convex optimization using an [script-l](1)-norm constraint. Conventional approaches to complex-valued optimization split the complex variables into their real and imaginary parts; this doubles the dimension compared with the original problem and may break the special data structure. Unlike the conventional methods, the proposed method directly handles the complex variables as a whole without splitting them into real numbers; hence the dimension will not increase. By exploiting the block Toeplitz-like structure of the coefficient matrix, the computational complexity of the FPGM is reduced to O(LNlogN), where L is the dimension of the Doppler shift and N is the signal length. Simulation results verify the accuracy and efficiency of the FPGM, indicating that is robust to parameter selection and is orders-of-magnitude faster than standard convex optimization algorithms. The Kauai experimental data processing results are also provided to demonstrate the performance of the proposed algorithm.

  7. On Measuring and Reducing Selection Bias with a Quasi-Doubly Randomized Preference Trial

    ERIC Educational Resources Information Center

    Joyce, Ted; Remler, Dahlia K.; Jaeger, David A.; Altindag, Onur; O'Connell, Stephen D.; Crockett, Sean

    2017-01-01

    Randomized experiments provide unbiased estimates of treatment effects, but are costly and time consuming. We demonstrate how a randomized experiment can be leveraged to measure selection bias by conducting a subsequent observational study that is identical in every way except that subjects choose their treatment--a quasi-doubly randomized…

  8. Fully Coupled Channel Approach to Doubly Strange s-Shell Hypernuclei

    SciTech Connect

    Nemura, H.; Shinmura, S.; Akaishi, Y.; Myint, Khin Swe

    2005-05-27

    We describe ab initio calculations of doubly strange, S=-2, s-shell hypernuclei ({sub {lambda}}{sub {lambda}}{sup 4}H, {sub {lambda}}{sub {lambda}}{sup 5}H, {sub {lambda}}{sub {lambda}}{sup 5}He, and {sub {lambda}}{sub {lambda}}{sup 6}He) as a first attempt to explore the few-body problem of the full-coupled channel scheme for these systems. The wave function includes {lambda}{lambda}, {lambda}{sigma}, N{xi}, and {sigma}{sigma} channels. Minnesota NN, D2{sup '} YN, and simulated YY potentials based on the Nijmegen hard-core model are used. Bound-state solutions of these systems are obtained. We find that a set of phenomenological B{sub 8}B{sub 8} interactions among the octet baryons in S=0,-1, and -2 sectors, which is consistent with all of the available experimental binding energies of S=0,-1, and -2 s-shell (hyper)nuclei, can predict a particle stable bound state of {sub {lambda}}{sub {lambda}}{sup 4}H. For {sub {lambda}}{sub {lambda}}{sup 5}H and {sub {lambda}}{sub {lambda}}{sup 5}He, {lambda}N-{sigma}N and {xi}N-{lambda}{sigma} potentials significantly affect the net {lambda}{lambda}-N{xi} coupling, and a large {xi} probability is obtained even for a weaker {lambda}{lambda}-N{xi} potential.

  9. Selecting Channels for Institutional Public Relations.

    ERIC Educational Resources Information Center

    Schwartz, Donald F.; Glynn, Carroll J.

    1989-01-01

    Examines communication decision-making in organizations by looking at the extent to which public relations executives have control over channel selection for the media mix in an overall public relations program. Shows a variety of structures and procedures for channel selection decisions in United States organizations. (SR)

  10. Selecting Channels for Institutional Public Relations.

    ERIC Educational Resources Information Center

    Schwartz, Donald F.; Glynn, Carroll J.

    1989-01-01

    Examines communication decision-making in organizations by looking at the extent to which public relations executives have control over channel selection for the media mix in an overall public relations program. Shows a variety of structures and procedures for channel selection decisions in United States organizations. (SR)

  11. Image Discrimination Models With Stochastic Channel Selection

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Beard, Bettina L.; Null, Cynthia H. (Technical Monitor)

    1995-01-01

    Many models of human image processing feature a large fixed number of channels representing cortical units varying in spatial position (visual field direction and eccentricity) and spatial frequency (radial frequency and orientation). The values of these parameters are usually sampled at fixed values selected to ensure adequate overlap considering the bandwidth and/or spread parameters, which are usually fixed. Even high levels of overlap does not always ensure that the performance of the model will vary smoothly with image translation or scale changes. Physiological measurements of bandwidth and/or spread parameters result in a broad distribution of estimated parameter values and the prediction of some psychophysical results are facilitated by the assumption that these parameters also take on a range of values. Selecting a sample of channels from a continuum of channels rather than using a fixed set can make model performance vary smoothly with changes in image position, scale, and orientation. It also facilitates the addition of spatial inhomogeneity, nonlinear feature channels, and focus of attention to channel models.

  12. Image Discrimination Models With Stochastic Channel Selection

    NASA Technical Reports Server (NTRS)

    Ahumada, Albert J., Jr.; Beard, Bettina L.; Null, Cynthia H. (Technical Monitor)

    1995-01-01

    Many models of human image processing feature a large fixed number of channels representing cortical units varying in spatial position (visual field direction and eccentricity) and spatial frequency (radial frequency and orientation). The values of these parameters are usually sampled at fixed values selected to ensure adequate overlap considering the bandwidth and/or spread parameters, which are usually fixed. Even high levels of overlap does not always ensure that the performance of the model will vary smoothly with image translation or scale changes. Physiological measurements of bandwidth and/or spread parameters result in a broad distribution of estimated parameter values and the prediction of some psychophysical results are facilitated by the assumption that these parameters also take on a range of values. Selecting a sample of channels from a continuum of channels rather than using a fixed set can make model performance vary smoothly with changes in image position, scale, and orientation. It also facilitates the addition of spatial inhomogeneity, nonlinear feature channels, and focus of attention to channel models.

  13. Selective channel combination of MRI signal phase.

    PubMed

    Vegh, Viktor; O'Brien, Kieran; Barth, Markus; Reutens, David C

    2016-11-01

    Signal magnitude can robustly be combined using the sum-of-squares approach. Methods have been developed to combine complex images. However, techniques based only on signal phase have not been developed and evaluated. We performed simulations to demonstrate the effect of noise on coil combination. 32-channel 7 Tesla human gradient echo MRI brain data were collected. We combined phase images based on phase noise leading to spatially selective and coil selective combination of phase images. We compared our selective combination approach to optimal noise distribution and adaptive combination methods. We found that selective combination of signal phases leads to improved phase signal-to-noise ratio. Furthermore, a phase shift can be present in combined phase images introduced by the method used to combine multiple channel phases. Mapping of signal phase from ultra-high field MRI data undoubtedly provides a wealth of information about the ageing brain and the effects of neurodegenerative disorders. Measurement of signal phase is essential in frequency shift mapping and in quantitative susceptibility mapping. The method used to combine signal phase should be informed by an understanding of the noise distribution in signal phase at the individual channel level. Magn Reson Med 76:1469-1477, 2016. © 2015 International Society for Magnetic Resonance in Medicine. © 2015 International Society for Magnetic Resonance in Medicine.

  14. HCN Channels Modulators: The Need for Selectivity

    PubMed Central

    Romanelli, Maria Novella; Sartiani, Laura; Masi, Alessio; Mannaioni, Guido; Manetti, Dina; Mugelli, Alessandro; Cerbai, Elisabetta

    2016-01-01

    Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID:26975509

  15. Structure and selectivity in bestrophin ion channels

    SciTech Connect

    Yang, Tingting; Liu, Qun; Kloss, Brian; Bruni, Renato; Kalathur, Ravi C.; Guo, Youzhong; Kloppmann, Edda; Rost, Burkhard; Colecraft, Henry M.; Hendrickson, Wayne A.

    2014-09-25

    Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.

  16. Structure and selectivity in bestrophin ion channels

    DOE PAGES

    Yang, Tingting; Liu, Qun; Kloss, Brian; ...

    2014-09-25

    Human bestrophin 1 (hBest1) is a calcium-activated chloride channel from the retinal pigment epithelium, where it can suffer mutations associated with vitelliform macular degeneration, or Best disease. We describe the structure of a bacterial homolog (KpBest) of hBest1 and functional characterizations of both channels. KpBest is a pentamer that forms a five-helix transmembrane pore, closed by three rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiological analysis of structure-inspired mutations in KpBest and hBest1, we find a subtle control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activationmore » by mutations at the exit restriction. Lastly, a homology model of hBest1 shows the locations of disease-causing mutations and suggests possible roles in regulation.« less

  17. Gated regulation of CRAC channel ion selectivity by STIM1

    PubMed Central

    McNally, Beth A.; Somasundaram, Agila; Yamashita, Megumi; Prakriya, Murali

    2011-01-01

    Two defining functional features of ion channels are ion selectivity and channel gating. Ion selectivity is generally considered an immutable property of the open channel structure, whereas gating involves transitions between open and closed channel states typically without changes in ion selectivity 1. In store-operated Ca2+ release-activated Ca2+ (CRAC) channels, the molecular mechanism of channel gating by the CRAC channel activator, STIM1 (stromal interaction molecule 1) remains unknown. CRAC channels are distinguished by an extraordinarily high Ca2+ selectivity and are instrumental in generating sustained [Ca2+]i elevations necessary for gene expression and effector function in many eukaryotic cells 2. Here, we probed the central features of the STIM1 gating mechanism in the CRAC channel protein, Orai1, and identified V102, a residue located in the extracellular region of the pore, as a candidate for the channel gate. Mutations at V102 produced constitutively active CRAC channels that were open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels were not Ca2+-selective, their Ca2+ selectivity was dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca2+ selectivity also occurred in wild-type (WT) Orai1 channels by increasing the number of STIM1 activation domains directly tethered to Orai1 channels. Thus, exquisite Ca2+ selectivity is not an intrinsic property of CRAC channels, but rather a tunable feature bestowed on otherwise non-selective Orai1 channels by STIM1. Our results demonstrate that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism wherein permeation and gating are closely coupled. PMID:22278058

  18. Amiloride Selectively Blocks the Low Threshold (T) Calcium Channel

    NASA Astrophysics Data System (ADS)

    Tang, Cha-Min; Presser, Fernando; Morad, Martin

    1988-04-01

    More than one type of voltage-gated calcium channel has been identified in muscle cells and neurons. Many specific organic and inorganic blockers of the conventional, slowly inactivating high threshold (L) calcium channel have been reported. No specific blockers of the low threshold (T) channel have been as yet identified. Amiloride, a potassium sparing diuretic, has now been shown to selectively block the low threshold calcium channel in mouse neuroblastoma and chick dorsal root ganglion neurons. The selective blockade of the T-type calcium channel will allow identification of this channel in different tissues and characterization of its specific physiological role.

  19. Channel selective tunnelling through a nanographene assembly.

    PubMed

    Wong, H S; Feng, X; Müllen, K; Chandrasekhar, N; Durkan, C

    2012-03-09

    We report selective tunnelling through a nanographene intermolecular tunnel junction achieved via scanning tunnelling microscope tip functionalization with hexa-peri-hexabenzocoronene (HBC) molecules. This leads to an offset in the alignment between the energy levels of the tip and the molecular assembly, resulting in the imaging of a variety of distinct charge density patterns in the HBC assembly, not attainable using a bare metallic tip. Different tunnelling channels can be selected by the application of an electric field in the tunnelling junction, which changes the condition of the HBC on the tip. Density functional theory-based calculations relate the imaged HBC patterns to the calculated molecular orbitals at certain energy levels. These patterns bear a close resemblance to the π-orbital states of the HBC molecule calculated at the relevant energy levels, mainly below the Fermi energy of HBC. This correlation demonstrates the ability of an HBC functionalized tip as regards accessing an energy range that is restricted to the usual operating bias range around the Fermi energy with a normal metallic tip at room temperature. Apart from relating to molecular orbitals, some patterns could also be described in association with the Clar aromatic sextet formula. Our observations may help pave the way towards the possibility of controlling charge transport between organic interfaces.

  20. AVHRR channel selection for land cover classification

    USGS Publications Warehouse

    Maxwell, S.K.; Hoffer, R.M.; Chapman, P.L.

    2002-01-01

    Mapping land cover of large regions often requires processing of satellite images collected from several time periods at many spectral wavelength channels. However, manipulating and processing large amounts of image data increases the complexity and time, and hence the cost, that it takes to produce a land cover map. Very few studies have evaluated the importance of individual Advanced Very High Resolution Radiometer (AVHRR) channels for discriminating cover types, especially the thermal channels (channels 3, 4 and 5). Studies rarely perform a multi-year analysis to determine the impact of inter-annual variability on the classification results. We evaluated 5 years of AVHRR data using combinations of the original AVHRR spectral channels (1-5) to determine which channels are most important for cover type discrimination, yet stabilize inter-annual variability. Particular attention was placed on the channels in the thermal portion of the spectrum. Fourteen cover types over the entire state of Colorado were evaluated using a supervised classification approach on all two-, three-, four- and five-channel combinations for seven AVHRR biweekly composite datasets covering the entire growing season for each of 5 years. Results show that all three of the major portions of the electromagnetic spectrum represented by the AVHRR sensor are required to discriminate cover types effectively and stabilize inter-annual variability. Of the two-channel combinations, channels 1 (red visible) and 2 (near-infrared) had, by far, the highest average overall accuracy (72.2%), yet the inter-annual classification accuracies were highly variable. Including a thermal channel (channel 4) significantly increased the average overall classification accuracy by 5.5% and stabilized interannual variability. Each of the thermal channels gave similar classification accuracies; however, because of the problems in consistently interpreting channel 3 data, either channel 4 or 5 was found to be a more

  1. Mojave Toxin: A Selective Ca(++) Channel Antagonist

    DTIC Science & Technology

    1988-07-01

    other than maitotoxin, blocking 3H-nitrendipine binding to the high affinity dihydropyridine receptor associated with the Ca++ channel, as well as... dihydropyridine receptors in rat synaptic membranes suggests that this toxin may be a useful proble of the Ca++ channel complex. It is not certain whether MoTX has...increase in intracellular Ca++ resulting from the binding of the toxin to dihydropyridine receptors coupled to Ca++ channels. The resolution of this

  2. A review of channel selection algorithms for EEG signal processing

    NASA Astrophysics Data System (ADS)

    Alotaiby, Turky; El-Samie, Fathi E. Abd; Alshebeili, Saleh A.; Ahmad, Ishtiaq

    2015-12-01

    Digital processing of electroencephalography (EEG) signals has now been popularly used in a wide variety of applications such as seizure detection/prediction, motor imagery classification, mental task classification, emotion classification, sleep state classification, and drug effects diagnosis. With the large number of EEG channels acquired, it has become apparent that efficient channel selection algorithms are needed with varying importance from one application to another. The main purpose of the channel selection process is threefold: (i) to reduce the computational complexity of any processing task performed on EEG signals by selecting the relevant channels and hence extracting the features of major importance, (ii) to reduce the amount of overfitting that may arise due to the utilization of unnecessary channels, for the purpose of improving the performance, and (iii) to reduce the setup time in some applications. Signal processing tools such as time-domain analysis, power spectral estimation, and wavelet transform have been used for feature extraction and hence for channel selection in most of channel selection algorithms. In addition, different evaluation approaches such as filtering, wrapper, embedded, hybrid, and human-based techniques have been widely used for the evaluation of the selected subset of channels. In this paper, we survey the recent developments in the field of EEG channel selection methods along with their applications and classify these methods according to the evaluation approach.

  3. Potassium-selective block of barium permeation through single KcsA channels.

    PubMed

    Piasta, Kene N; Theobald, Douglas L; Miller, Christopher

    2011-10-01

    Ba(2+), a doubly charged analogue of K(+), specifically blocks K(+) channels by virtue of electrostatic stabilization in the permeation pathway. Ba(2+) block is used here as a tool to determine the equilibrium binding affinity for various monovalent cations at specific sites in the selectivity filter of a noninactivating mutant of KcsA. At high concentrations of external K(+), the block-time distribution is double exponential, marking at least two Ba(2+) sites in the selectivity filter, in accord with a Ba(2+)-containing crystal structure of KcsA. By analyzing block as a function of extracellular K(+), we determined the equilibrium dissociation constant of K(+) and of other monovalent cations at an extracellular site, presumably S1, to arrive at a selectivity sequence for binding at this site: Rb(+) (3 µM) > Cs(+) (23 µM) > K(+) (29 µM) > NH(4)(+) (440 µM) > Na(+) and Li(+) (>1 M). This represents an unusually high selectivity for K(+) over Na(+), with |ΔΔG(0)| of at least 7 kcal mol(-1). These results fit well with other kinetic measurements of selectivity as well as with the many crystal structures of KcsA in various ionic conditions.

  4. Channel selection methods for the P300 Speller.

    PubMed

    Colwell, K A; Ryan, D B; Throckmorton, C S; Sellers, E W; Collins, L M

    2014-07-30

    The P300 Speller brain-computer interface (BCI) allows a user to communicate without muscle activity by reading electrical signals on the scalp via electroencephalogram. Modern BCI systems use multiple electrodes ("channels") to collect data, which has been shown to improve speller accuracy; however, system cost and setup time can increase substantially with the number of channels in use, so it is in the user's interest to use a channel set of modest size. This constraint increases the importance of using an effective channel set, but current systems typically utilize the same channel montage for each user. We examine the effect of active channel selection for individuals on speller performance, using generalized standard feature-selection methods, and present a new channel selection method, termed jumpwise regression, that extends the Stepwise Linear Discriminant Analysis classifier. Simulating the selections of each method on real P300 Speller data, we obtain results demonstrating that active channel selection can improve speller accuracy for most users relative to a standard channel set, with particular benefit for users who experience low performance using the standard set. Of the methods tested, jumpwise regression offers accuracy gains similar to the best-performing feature-selection methods, and is robust enough for online use. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Quantum Interference and Selectivity through Biological Ion Channels

    NASA Astrophysics Data System (ADS)

    Salari, Vahid; Naeij, Hamidreza; Shafiee, Afshin

    2017-01-01

    The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17–53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference.

  6. Quantum Interference and Selectivity through Biological Ion Channels

    PubMed Central

    Salari, Vahid; Naeij, Hamidreza; Shafiee, Afshin

    2017-01-01

    The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17–53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference. PMID:28134331

  7. Equilibrium selectivity alone does not create K+-selective ion conduction in K+ channels

    NASA Astrophysics Data System (ADS)

    Liu, Shian; Lockless, Steve W.

    2013-11-01

    Potassium (K+) channels are selective for K+ over Na+ ions during their transport across membranes. We and others have previously shown that tetrameric K+ channels are primarily occupied by K+ ions in their selectivity filters under physiological conditions, demonstrating the channel’s intrinsic equilibrium preference for K+ ions. Based on this observation, we hypothesize that the preference for K+ ions over Na+ ions in the filter determines its selectivity during ion conduction. Here, we ask whether non-selective cation channels, which share an overall structure and similar individual ion-binding sites with K+ channels, have an ion preference at equilibrium. The variants of the non-selective Bacillus cereus NaK cation channel we examine are all selective for K+ over Na+ ions at equilibrium. Thus, the detailed architecture of the K+ channel selectivity filter, and not only its equilibrium ion preference, is fundamental to the generation of selectivity during ion conduction.

  8. Physical origin of selectivity in ionic channels of biological membranes.

    PubMed Central

    Laio, A; Torre, V

    1999-01-01

    This paper shows that the selectivity properties of monovalent cation channels found in biological membranes can originate simply from geometrical properties of the inner core of the channel without any critical contribution from electrostatic interactions between the permeating ions and charged or polar groups. By using well-known techniques of statistical mechanics, such as the Langevin equations and Kramer theory of reaction rates, a theoretical equation is provided relating the permeability ratio PB/PA between ions A and B to simple physical properties, such as channel geometry, thermodynamics of ion hydration, and electrostatic interactions between the ion and charged (or polar) groups. Diffusive corrections and recrossing rates are also considered and evaluated. It is shown that the selectivity found in usual K+, gramicidin, Na+, cyclic nucleotide gated, and end plate channels can be explained also in the absence of any charged or polar group. If these groups are present, they significantly change the permeability ratio only if the ion at the selectivity filter is in van der Waals contact with them, otherwise these groups simply affect the channel conductance, lowering the free energy barrier of the same amount for the two ions, thus explaining why single channel conductance, as it is experimentally observed, can be very different in channels sharing the same selectivity sequence. The proposed theory also provides an estimate of channel minimum radius for K+, gramicidin, Na+, and cyclic nucleotide gated channels. PMID:9876129

  9. Monte Carlo study of gating and selection in potassium channels

    NASA Astrophysics Data System (ADS)

    Andreucci, Daniele; Bellaveglia, Dario; Cirillo, Emilio N. M.; Marconi, Silvia

    2011-08-01

    The study of selection and gating in potassium channels is a very important issue in modern biology. Indeed, such structures are known in essentially all types of cells in all organisms where they play many important functional roles. The mechanism of gating and selection of ionic species is not clearly understood. In this paper we study a model in which gating is obtained via an affinity-switching selectivity filter. We discuss the dependence of selectivity and efficiency on the cytosolic ionic concentration and on the typical pore open state duration. We demonstrate that a simple modification in the way in which the selectivity filter is modeled yields larger channel efficiency.

  10. Drosotoxin, a selective inhibitor of tetrodotoxin-resistant sodium channels.

    PubMed

    Zhu, Shunyi; Gao, Bin; Deng, Meichun; Yuan, Yuzhe; Luo, Lan; Peigneur, Steve; Xiao, Yucheng; Liang, Songping; Tytgat, Jan

    2010-10-15

    The design of animal toxins with high target selectivity has long been a goal in protein engineering. Based on evolutionary relationship between the Drosophila antifungal defensin (drosomycin) and scorpion depressant Na(+) channel toxins, we exploited a strategy to create a novel chimeric molecule (named drosotoxin) with high selectivity for channel subtypes, which was achieved by using drosomycin to substitute the structural core of BmKITc, a depressant toxin acting on both insect and mammalian Na(+) channels. Recombinant drosotoxin selectively inhibited tetrodotoxin-resistant (TTX-R) Na(+) channels in rat dorsal root ganglion (DRG) neurons with a 50% inhibitory concentration (IC(50)) of 2.6+/-0.5muM. This chimeric peptide showed no activity on K(+), Ca(2+) and TTX-sensitive (TTX-S) Na(+) channels in rat DRG neurons and Drosophila para/tipE channels at micromolar concentrations. Drosotoxin represents the first chimeric toxin and example of a non-toxic core scaffold with high selectivity on mammalian TTX-R Na(+) channels.

  11. Anion conductance selectivity mechanism of the CFTR chloride channel.

    PubMed

    Linsdell, Paul

    2016-04-01

    All ion channels are able to discriminate between substrate ions to some extent, a process that involves specific interactions between permeant anions and the so-called selectivity filter within the channel pore. In the cystic fibrosis transmembrane conductance regulator (CFTR) anion-selective channel, both anion relative permeability and anion relative conductance are dependent on anion free energy of hydration--anions that are relatively easily dehydrated tend to show both high permeability and low conductance. In the present work, patch clamp recording was used to investigate the relative conductance of different anions in CFTR, and the effect of mutations within the channel pore. In constitutively-active E1371Q-CFTR channels, the anion conductance sequence was Cl(-) > NO3(-) > Br(-) > formate > SCN(-) > I(-). A mutation that disrupts anion binding in the inner vestibule of the pore (K95Q) disrupted anion conductance selectivity, such that anions with different permeabilities showed almost indistinguishable conductances. Conversely, a mutation at the putative narrowest pore region that is known to disrupt anion permeability selectivity (F337A) had minimal effects on anion relative conductance. Ion competition experiments confirmed that relatively tight binding of permeant anions resulted in relatively low conductance. These results suggest that the relative affinity of ion binding in the inner vestibule of the pore controls the relative conductance of different permeant anions in CFTR, and that the pore has two physically distinct anion selectivity filters that act in series to control anion conductance selectivity and anion permeability selectivity respectively.

  12. Doubly Distributed Transactions

    SciTech Connect

    Jai Dayal, Gerald Lofstead

    2014-08-25

    Doubly Distributed Transactions (D2T) offers a technique for managing operations from a set of parallel clients with a collection of distributed services. It detects and manages faults. Example code with a test harness is also provided

  13. Doubly fed induction machine

    DOEpatents

    Skeist, S. Merrill; Baker, Richard H.

    2005-10-11

    An electro-mechanical energy conversion system coupled between an energy source and an energy load including an energy converter device having a doubly fed induction machine coupled between the energy source and the energy load to convert the energy from the energy source and to transfer the converted energy to the energy load and an energy transfer multiplexer coupled to the energy converter device to control the flow of power or energy through the doubly fed induction machine.

  14. Principles Governing Metal Ion Selectivity in Ion Channel Proteins

    NASA Astrophysics Data System (ADS)

    Lim, Carmay

    2014-03-01

    Our research interests are to (i) unravel the principles governing biological processes and use them to identify novel drug targets and guide drug design, and (ii) develop new methods for studying macromolecular interactions. This talk will provide an overview of our work in these two areas and an example of how our studies have helped to unravel the principles underlying the conversion of Ca2+-selective to Na+-selective channels. Ion selectivity of four-domain voltage-gated Ca2+(Cav) and sodium (Nav) channels, which is controlled by the selectivity filter (SF, the narrowest region of an open pore), is crucial for electrical signaling. Over billions of years of evolution, mutation of the Glu from domain II/III in the EEEE/DEEA SF of Ca2+-selective Cav channels to Lys made these channels Na+-selective. This talk will delineate the physical principles why Lys is sufficient for Na+/Ca2+selectivity and why the DEKA SF is more Na+-selective than the DKEA one.

  15. Structural correlates of selectivity and inactivation in potassium channels

    PubMed Central

    McCoy, Jason G.; Nimigean, Crina M.

    2011-01-01

    Potassium channels are involved in a tremendously diverse range of physiological applications requiring distinctly different functional properties. Not surprisingly, the amino acid sequences for these proteins are diverse as well, except for the region that has been ordained the “selectivity filter”. The goal of this review is to examine our current understanding of the role of the selectivity filter and regions adjacent to it in specifying selectivity as well as its role in gating/inactivation and possible mechanisms by which these processes are coupled. Our working hypothesis is that an amino acid network behind the filter modulates selectivity in channels with the same signature sequence while at the same time affecting channel inactivation properties. PMID:21958666

  16. Ion selectivity and gating mechanisms of FNT channels

    PubMed Central

    Waight, Andrew B.; Czyzewski, Bryan K.; Wang, Da-Neng

    2013-01-01

    The phospholipid bilayer has evolved to be a protective and selective barrier by which the cell maintains high concentrations of life sustaining organic and inorganic material. As gatekeepers responsible for an immense amount of bidirectional chemical traffic between the cytoplasm and extracellular milieu, ion channels have been studied in detail since their postulated existence nearly three-quarters of a century ago. Over the past fifteen years, we have begun to understand how selective permeability can be achieved for both cationic and anionic ions. Our mechanistic knowledge has expanded recently with studies of a large family of anion channels, the Formate Nitrite Transport (FNT) family. This family has proven amenable to structural studies at a resolution high enough to reveal intimate details of ion selectivity and gating. With five representative members having yielded a total of 15 crystal structures, this family represents one of the richest sources of structural information for anion channels. PMID:23773802

  17. Bayesian sparse channel estimation

    NASA Astrophysics Data System (ADS)

    Chen, Chulong; Zoltowski, Michael D.

    2012-05-01

    In Orthogonal Frequency Division Multiplexing (OFDM) systems, the technique used to estimate and track the time-varying multipath channel is critical to ensure reliable, high data rate communications. It is recognized that wireless channels often exhibit a sparse structure, especially for wideband and ultra-wideband systems. In order to exploit this sparse structure to reduce the number of pilot tones and increase the channel estimation quality, the application of compressed sensing to channel estimation is proposed. In this article, to make the compressed channel estimation more feasible for practical applications, it is investigated from a perspective of Bayesian learning. Under the Bayesian learning framework, the large-scale compressed sensing problem, as well as large time delay for the estimation of the doubly selective channel over multiple consecutive OFDM symbols, can be avoided. Simulation studies show a significant improvement in channel estimation MSE and less computing time compared to the conventional compressed channel estimation techniques.

  18. Sodium channel selectivity filter regulates antiarrhythmic drug binding.

    PubMed

    Sunami, A; Dudley, S C; Fozzard, H A

    1997-12-09

    Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel's selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (micro1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment.

  19. Subtype-selective targeting of voltage-gated sodium channels

    PubMed Central

    England, Steve; de Groot, Marcel J

    2009-01-01

    Voltage-gated sodium channels are key to the initiation and propagation of action potentials in electrically excitable cells. Molecular characterization has shown there to be nine functional members of the family, with a high degree of sequence homology between the channels. This homology translates into similar biophysical and pharmacological properties. Confidence in some of the channels as drug targets has been boosted by the discovery of human mutations in the genes encoding a number of them, which give rise to clinical conditions commensurate with the changes predicted from the altered channel biophysics. As a result, they have received much attention for their therapeutic potential. Sodium channels represent well-precedented drug targets as antidysrhythmics, anticonvulsants and local anaesthetics provide good clinical efficacy, driven through pharmacology at these channels. However, electrophysiological characterization of clinically useful compounds in recombinant expression systems shows them to be weak, with poor selectivity between channel types. This has led to the search for subtype-selective modulators, which offer the promise of treatments with improved clinical efficacy and better toleration. Despite developments in high-throughput electrophysiology platforms, this has proven very challenging. Structural biology is beginning to offer us a greater understanding of the three-dimensional structure of voltage-gated ion channels, bringing with it the opportunity to do real structure-based drug design in the future. This discipline is still in its infancy, but developments with the expression and purification of prokaryotic sodium channels offer the promise of structure-based drug design in the not too distant future. PMID:19845672

  20. Sodium and potassium competition in potassium-selective and non-selective channels

    NASA Astrophysics Data System (ADS)

    Sauer, David B.; Zeng, Weizhong; Canty, John; Lam, Yeeling; Jiang, Youxing

    2013-11-01

    Potassium channels selectively conduct K+, primarily to the exclusion of Na+, despite the fact that both ions can bind within the selectivity filter. Here we perform crystallographic titration and single-channel electrophysiology to examine the competition of Na+ and K+ binding within the filter of two NaK channel mutants; one is the potassium-selective NaK2K mutant and the other is the non-selective NaK2CNG, a CNG channel pore mimic. With high-resolution structures of these engineered NaK channel constructs, we explicitly describe the changes in K+ occupancy within the filter upon Na+ competition by anomalous diffraction. Our results demonstrate that the non-selective NaK2CNG still retains a K+-selective site at equilibrium, whereas the NaK2K channel filter maintains two high-affinity K+ sites. A double-barrier mechanism is proposed to explain K+ channel selectivity at low K+ concentrations.

  1. Self-organized models of selectivity in calcium channels

    NASA Astrophysics Data System (ADS)

    Giri, Janhavi; Fonseca, James E.; Boda, Dezső; Henderson, Douglas; Eisenberg, Bob

    2011-04-01

    The role of flexibility in the selectivity of calcium channels is studied using a simple model with two parameters that accounts for the selectivity of calcium (and sodium) channels in many ionic solutions of different compositions and concentrations using two parameters with unchanging values. We compare the distribution of side chains (oxygens) and cations (Na+ and Ca2+) and integrated quantities. We compare the occupancies of cations Ca2+/Na+ and linearized conductance of Na+. The distributions show a strong dependence on the locations of fixed side chains and the flexibility of the side chains. Holding the side chains fixed at certain predetermined locations in the selectivity filter distorts the distribution of Ca2+ and Na+ in the selectivity filter. However, integrated quantities—occupancy and normalized conductance—are much less sensitive. Our results show that some flexibility of side chains is necessary to avoid obstruction of the ionic pathway by oxygen ions in 'unfortunate' fixed positions. When oxygen ions are mobile, they adjust 'automatically' and move 'out of the way', so they can accommodate the permeable cations in the selectivity filter. Structure is the computed consequence of the forces in this model. The structures are self-organized, at their free energy minimum. The relationship of ions and side chains varies with an ionic solution. Monte Carlo simulations are particularly well suited to compute induced-fit, self-organized structures because the simulations yield an ensemble of structures near their free energy minimum. The exact location and mobility of oxygen ions has little effect on the selectivity behavior of calcium channels. Seemingly, nature has chosen a robust mechanism to control selectivity in calcium channels: the first-order determinant of selectivity is the density of charge in the selectivity filter. The density is determined by filter volume along with the charge and excluded volume of structural ions confined within it

  2. Modulation of mechanosensitive calcium-selective cation channels by temperature

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    Gating of associations of mechanosensitive Ca(2+)-selective cation co-channels in the plasmalemma of onion epidermis has a strong and unusual temperature dependence. Tension-dependent activity rises steeply as temperature is lowered from 25 degrees C to about 6 degrees C, but drops to a low level at about 5 degrees C. Under the conditions tested (with Mg2+ and K+ at the cytosolic face of outside-out membrane patches), promotion results both from more bursting at all observed linkage levels and from longer duration of bursts of co-channels linked as quadruplets and quintuplets. Co-channel conductance decreases linearly, but only modestly, with declining temperature. It is proposed that these and related mechanosensitive channels may participate in a variety of responses to temperature, including thermonasty, thermotropism, hydrotropism, and both cold damage and cold acclimation.

  3. Modulation of mechanosensitive calcium-selective cation channels by temperature

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    Gating of associations of mechanosensitive Ca(2+)-selective cation co-channels in the plasmalemma of onion epidermis has a strong and unusual temperature dependence. Tension-dependent activity rises steeply as temperature is lowered from 25 degrees C to about 6 degrees C, but drops to a low level at about 5 degrees C. Under the conditions tested (with Mg2+ and K+ at the cytosolic face of outside-out membrane patches), promotion results both from more bursting at all observed linkage levels and from longer duration of bursts of co-channels linked as quadruplets and quintuplets. Co-channel conductance decreases linearly, but only modestly, with declining temperature. It is proposed that these and related mechanosensitive channels may participate in a variety of responses to temperature, including thermonasty, thermotropism, hydrotropism, and both cold damage and cold acclimation.

  4. Adaptive codebook selection schemes for image classification in correlated channels

    NASA Astrophysics Data System (ADS)

    Hu, Chia Chang; Liu, Xiang Lian; Liu, Kuan-Fu

    2015-09-01

    The multiple-input multiple-output (MIMO) system with the use of transmit and receive antenna arrays achieves diversity and array gains via transmit beamforming. Due to the absence of full channel state information (CSI) at the transmitter, the transmit beamforming vector can be quantized at the receiver and sent back to the transmitter by a low-rate feedback channel, called limited feedback beamforming. One of the key roles of Vector Quantization (VQ) is how to generate a good codebook such that the distortion between the original image and the reconstructed image is the minimized. In this paper, a novel adaptive codebook selection scheme for image classification is proposed with taking both spatial and temporal correlation inherent in the channel into consideration. The new codebook selection algorithm is developed to select two codebooks from the discrete Fourier transform (DFT) codebook, the generalized Lloyd algorithm (GLA) codebook and the Grassmannian codebook to be combined and used as candidates of the original image and the reconstructed image for image transmission. The channel is estimated and divided into four regions based on the spatial and temporal correlation of the channel and an appropriate codebook is assigned to each region. The proposed method can efficiently reduce the required information of feedback under the spatially and temporally correlated channels, where each region is adaptively. Simulation results show that in the case of temporally and spatially correlated channels, the bit-error-rate (BER) performance can be improved substantially by the proposed algorithm compared to the one with only single codebook.

  5. Sodium channel selectivity filter regulates antiarrhythmic drug binding

    PubMed Central

    Sunami, Akihiko; Dudley, Samuel C.; Fozzard, Harry A.

    1997-01-01

    Local anesthetic antiarrhythmic drugs block Na+ channels and have important clinical uses. However, the molecular mechanism by which these drugs block the channel has not been established. The family of drugs is characterized by having an ionizable amino group and a hydrophobic tail. We hypothesized that the charged amino group of the drug may interact with charged residues in the channel’s selectivity filter. Mutation of the putative domain III selectivity filter residue of the adult rat skeletal muscle Na+ channel (μ1) K1237E increased resting lidocaine block, but no change was observed in block by neutral analogs of lidocaine. An intermediate effect on the lidocaine block resulted from K1237S and there was no effect from K1237R, implying an electrostatic effect of Lys. Mutation of the other selectivity residues, D400A (domain I), E755A (domain II), and A1529D (domain IV) allowed block by externally applied quaternary membrane-impermeant derivatives of lidocaine (QX314 and QX222) and accelerated recovery from block by internal QX314. Neo-saxitoxin and tetrodotoxin, which occlude the channel pore, reduced the amount of QX314 bound in D400A and A1529D, respectively. Block by outside QX314 in E755A was inhibited by mutation of residues in transmembrane segment S6 of domain IV that are thought to be part of an internal binding site. The results demonstrate that the Na+ channel selectivity filter is involved in interactions with the hydrophilic part of the drugs, and it normally limits extracellular access to and escape from their binding site just within the selectivity filter. Participation of the selectivity ring in antiarrhythmic drug binding and access locates this structure adjacent to the S6 segment. PMID:9391164

  6. Performance of Digital Communications over Selective Fading Channels.

    DTIC Science & Technology

    1983-09-01

    J. G. Proakis , Digital Communications, McGraw-Hill, New York, 1983. ’ [45] R. D. Gitlin, E. Y. Ho and 3. E. Mazo, "Passband equalization of...7 D-A142 427 PERFORNANCE OF DIGITAL COMMUNICATIONS OVER SELECTIVE 1/2 FADING CHRNNELS(U) ILLINOIS UNIV AT URBANA COORDINATED SCIENCE LAB F D GARBER...PERIOD COVERED Technical Report PERFORMANCE OF DIGITAL COMMUNICATIONS OVER 6. PERFORMING ORG. REPORT NUMBER SELECTIVE FADING CHANNELS R-998; UILU-ENG

  7. Ionic Selectivity and Permeation Properties of Human PIEZO1 Channels.

    PubMed

    Gnanasambandam, Radhakrishnan; Bae, Chilman; Gottlieb, Philip A; Sachs, Frederick

    2015-01-01

    Members of the eukaryotic PIEZO family (the human orthologs are noted hPIEZO1 and hPIEZO2) form cation-selective mechanically-gated channels. We characterized the selectivity of human PIEZO1 (hPIEZO1) for alkali ions: K+, Na+, Cs+ and Li+; organic cations: TMA and TEA, and divalents: Ba2+, Ca2+, Mg2+ and Mn2+. All monovalent ions permeated the channel. At a membrane potential of -100 mV, Cs+, Na+ and K+ had chord conductances in the range of 35-55 pS with the exception of Li+, which had a significantly lower conductance of ~ 23 pS. The divalents decreased the single-channel permeability of K+, presumably because the divalents permeated slowly and occupied the open channel for a significant fraction of the time. In cell-attached mode, 90 mM extracellular divalents had a conductance for inward currents carried by the divalents of: 25 pS for Ba2+ and 15 pS for Ca2+ at -80 mV and 10 pS for Mg2+ at -50 mV. The organic cations, TMA and TEA, permeated slowly and attenuated K+ currents much like the divalents. As expected, the channel K+ conductance increased with K+ concentration saturating at ~ 45 pS and the KD of K+ for the channel was 32 mM. Pure divalent ion currents were of lower amplitude than those with alkali ions and the channel opening rate was lower in the presence of divalents than in the presence of monovalents. Exposing cells to the actin disrupting reagent cytochalasin D increased the frequency of openings in cell-attached patches probably by reducing mechanoprotection.

  8. Gating of a pH-sensitive K(2P) potassium channel by an electrostatic effect of basic sensor residues on the selectivity filter.

    PubMed

    Zúñiga, Leandro; Márquez, Valeria; González-Nilo, Fernando D; Chipot, Christophe; Cid, L Pablo; Sepúlveda, Francisco V; Niemeyer, María Isabel

    2011-01-25

    K(+) channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K(2P) K(+) channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pK(a) of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pH(o)) sensor in the background of a pH(o)-insensitive TASK-3 channel, which leads to the restitution of pH(o)-gating. Using a concatenated channel approach, we also demonstrate that for TASK-2 to open, pH(o) sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K(+) permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pH(o) sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K(2P) channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pH(o). Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pH(o)-sensing arginine 224 side chain gates the TASK-2 channel by electrostatically tuning the conformational stability of its selectivity filter.

  9. Gating of a pH-Sensitive K2P Potassium Channel by an Electrostatic Effect of Basic Sensor Residues on the Selectivity Filter

    PubMed Central

    Zúñiga, Leandro; Márquez, Valeria; González-Nilo, Fernando D.; Chipot, Christophe; Cid, L. Pablo; Sepúlveda, Francisco V.; Niemeyer, María Isabel

    2011-01-01

    K+ channels share common selectivity characteristics but exhibit a wide diversity in how they are gated open. Leak K2P K+ channels TASK-2, TALK-1 and TALK-2 are gated open by extracellular alkalinization. The mechanism for this alkalinization-dependent gating has been proposed to be the neutralization of the side chain of a single arginine (lysine in TALK-2) residue near the pore of TASK-2, which occurs with the unusual pKa of 8.0. We now corroborate this hypothesis by transplanting the TASK-2 extracellular pH (pHo) sensor in the background of a pHo-insensitive TASK-3 channel, which leads to the restitution of pHo-gating. Using a concatenated channel approach, we also demonstrate that for TASK-2 to open, pHo sensors must be neutralized in each of the two subunits forming these dimeric channels with no apparent cross-talk between the sensors. These results are consistent with adaptive biasing force analysis of K+ permeation using a model selectivity filter in wild-type and mutated channels. The underlying free-energy profiles confirm that either a doubly or a singly charged pHo sensor is sufficient to abolish ion flow. Atomic detail of the associated mechanism reveals that, rather than a collapse of the pore, as proposed for other K2P channels gated at the selectivity filter, an increased height of the energetic barriers for ion translocation accounts for channel blockade at acid pHo. Our data, therefore, strongly suggest that a cycle of protonation/deprotonation of pHo-sensing arginine 224 side chain gates the TASK-2 channel by electrostatically tuning the conformational stability of its selectivity filter. PMID:21283586

  10. Frequency selective tunable spin wave channeling in the magnonic network

    SciTech Connect

    Sadovnikov, A. V. Nikitov, S. A.; Beginin, E. N.; Odincov, S. A.; Sheshukova, S. E.; Sharaevskii, Yu. P.; Stognij, A. I.

    2016-04-25

    Using the space-resolved Brillouin light scattering spectroscopy, we study the frequency and wavenumber selective spin-wave channeling. We demonstrate the frequency selective collimation of spin-wave in an array of magnonic waveguides, formed between the adjacent magnonic crystals on the surface of yttrium iron garnet film. We show the control over spin-wave propagation length by the orientation of an in-plane bias magnetic field. Fabricated array of magnonic crystal can be used as a magnonic platform for multidirectional frequency selective signal processing applications in magnonic networks.

  11. Claudin-17 forms tight junction channels with distinct anion selectivity.

    PubMed

    Krug, Susanne M; Günzel, Dorothee; Conrad, Marcel P; Rosenthal, Rita; Fromm, Anja; Amasheh, Salah; Schulzke, Jörg D; Fromm, Michael

    2012-08-01

    Barrier properties of tight junctions are determined by the claudin protein family. Many claudins seal this barrier, but others form paracellular channels. Among these, no claudins with general and clear-cut anion selectivity have yet been described, while for claudin-10a and claudin-4, only circumstantial or small anion selectivities have been shown. A claudin with unknown function and tissue distribution is claudin-17. We characterized claudin-17 by overexpression and knock-down in two renal cell lines. Overexpression in MDCK C7 cell layers caused a threefold increase in paracellular anion permeability and switched these cells from cation- to anion-selective. Knockdown in LLC-PK(1) cells indorsed the finding of claudin-17-based anion channels. Mutagenesis revealed that claudin-17 anion selectivity critically depends on a positive charge at position 65. Claudin-17 expression was found in two organs: marginal in brain but abundant in kidney, where expression was intense in proximal tubules and gradually decreased towards distal segments. As claudin-17 is predominantly expressed in proximal nephrons, which exhibit substantial, though molecularly not defined, paracellular chloride reabsorption, we suggest that claudin-17 has a unique physiological function in this process. In conclusion, claudin-17 forms channels within tight junctions with distinct anion preference.

  12. Mechanosensory calcium-selective cation channels in epidermal cells

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    This paper explores the properties and likely functions of an epidermal Ca(2+)-selective cation channel complex activated by tension. As many as eight or nine linked or linkable equivalent conductance units or co-channels can open together. Open time for co-channel quadruplets and quintuplets tends to be relatively long with millimolar Mg2+ (but not millimolar Ca2+) at the cytosolic face of excised plasma membrane. Sensitivity to tension is regulated by transmembrane voltage and temperature. Under some circumstances channel activity is sychronized in rhythmic pulses. Certain lanthanides and a cytoskeleton-disturbing herbicide that inhibit gravitropic reception act on the channel system at low concentrations. Specifically, ethyl-N-phenylcarbamate promotes tension-dependent activity at micromolar levels. With moderate suction, Gd3+ provided at about 0.5 micromole at the extracellular face of the membrane promotes for several seconds but may then become inhibitory. Provision at 1-2 micromoles promotes and subsequently inhibits more vigorously (often abruptly and totally), and at high levels inhibits immediately. La3+, a poor gravitropic inhibitor, acts similarly but much more gradually and only at much higher concentrations. These properties, particularly these susceptibilities to modulation, indicate that in vivo the mechanosensitive channel must be mechanosensory and mechanoregulatory. It could serve to transduce the shear forces generated in the integrated wall-membrane-cytoskeleton system during turgor changes and cell expansion as well as transducing the stresses induced by gravity, touch and flexure. In so far as such transduction is modulated by voltage and temperature, the channels would also be sensors for these modalities as long as the wall-membrane-cytoskeleton system experiences mechanical stress.

  13. Mechanosensory calcium-selective cation channels in epidermal cells

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    This paper explores the properties and likely functions of an epidermal Ca(2+)-selective cation channel complex activated by tension. As many as eight or nine linked or linkable equivalent conductance units or co-channels can open together. Open time for co-channel quadruplets and quintuplets tends to be relatively long with millimolar Mg2+ (but not millimolar Ca2+) at the cytosolic face of excised plasma membrane. Sensitivity to tension is regulated by transmembrane voltage and temperature. Under some circumstances channel activity is sychronized in rhythmic pulses. Certain lanthanides and a cytoskeleton-disturbing herbicide that inhibit gravitropic reception act on the channel system at low concentrations. Specifically, ethyl-N-phenylcarbamate promotes tension-dependent activity at micromolar levels. With moderate suction, Gd3+ provided at about 0.5 micromole at the extracellular face of the membrane promotes for several seconds but may then become inhibitory. Provision at 1-2 micromoles promotes and subsequently inhibits more vigorously (often abruptly and totally), and at high levels inhibits immediately. La3+, a poor gravitropic inhibitor, acts similarly but much more gradually and only at much higher concentrations. These properties, particularly these susceptibilities to modulation, indicate that in vivo the mechanosensitive channel must be mechanosensory and mechanoregulatory. It could serve to transduce the shear forces generated in the integrated wall-membrane-cytoskeleton system during turgor changes and cell expansion as well as transducing the stresses induced by gravity, touch and flexure. In so far as such transduction is modulated by voltage and temperature, the channels would also be sensors for these modalities as long as the wall-membrane-cytoskeleton system experiences mechanical stress.

  14. Model of Polarization Selectivity of the Intermediate Filament Optical Channels.

    PubMed

    Khmelinskii, Igor; Zueva, Lidia; Inyushin, Michael; Makarov, Vladimir

    2015-08-01

    Recently we have analyzed light transmission and spectral selectivity by optical channels in Müller cells and other transparent cells, proposing a model of their structure, formed by specialized intermediate filaments [1,2]. Our model represents each optical channel by an axially symmetric tube with conductive walls. Presently, we analyze the planar polarization selectivity in long nanostructures, using the previously developed approach extended to structures of the elliptic cross-section. We find that the output light polarization angle depends on the a/b ratio, with a and b the semiaxes of the ellipse. Experimental tests used a Cr nano-strip device to evaluate the transmitted light polarization. The model adapted to the experimental geometry provided an accurate fit of the experimental results.

  15. Doubly robust survival trees.

    PubMed

    Steingrimsson, Jon Arni; Diao, Liqun; Molinaro, Annette M; Strawderman, Robert L

    2016-09-10

    Estimating a patient's mortality risk is important in making treatment decisions. Survival trees are a useful tool and employ recursive partitioning to separate patients into different risk groups. Existing 'loss based' recursive partitioning procedures that would be used in the absence of censoring have previously been extended to the setting of right censored outcomes using inverse probability censoring weighted estimators of loss functions. In this paper, we propose new 'doubly robust' extensions of these loss estimators motivated by semiparametric efficiency theory for missing data that better utilize available data. Simulations and a data analysis demonstrate strong performance of the doubly robust survival trees compared with previously used methods. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  16. The structure and regulation of magnesium selective ion channels.

    PubMed

    Payandeh, Jian; Pfoh, Roland; Pai, Emil F

    2013-11-01

    The magnesium ion (Mg(2+)) is the most abundant divalent cation within cells. In man, Mg(2+)-deficiency is associated with diseases affecting the heart, muscle, bone, immune, and nervous systems. Despite its impact on human health, little is known about the molecular mechanisms that regulate magnesium transport and storage. Complete structural information on eukaryotic Mg(2+)-transport proteins is currently lacking due to associated technical challenges. The prokaryotic MgtE and CorA magnesium transport systems have recently succumbed to structure determination by X-ray crystallography, providing first views of these ubiquitous and essential Mg(2+)-channels. MgtE and CorA are unique among known membrane protein structures, each revealing a novel protein fold containing distinct arrangements of ten transmembrane-spanning α-helices. Structural and functional analyses have established that Mg(2+)-selectivity in MgtE and CorA occurs through distinct mechanisms. Conserved acidic side-chains appear to form the selectivity filter in MgtE, whereas conserved asparagines coordinate hydrated Mg(2+)-ions within the selectivity filter of CorA. Common structural themes have also emerged whereby MgtE and CorA sense and respond to physiologically relevant, intracellular Mg(2+)-levels through dedicated regulatory domains. Within these domains, multiple primary and secondary Mg(2+)-binding sites serve to staple these ion channels into their respective closed conformations, implying that Mg(2+)-transport is well guarded and very tightly regulated. The MgtE and CorA proteins represent valuable structural templates to better understand the related eukaryotic SLC41 and Mrs2-Alr1 magnesium channels. Herein, we review the structure, function and regulation of MgtE and CorA and consider these unique proteins within the expanding universe of ion channel and transporter structural biology.

  17. Selective exclusion and selective binding both contribute to ion selectivity in KcsA, a model potassium channel.

    PubMed

    Renart, M Lourdes; Montoya, Estefanía; Giudici, A Marcela; Poveda, José A; Fernández, Asia M; Morales, Andrés; González-Ros, José M

    2017-09-15

    The selectivity filter in potassium channels, a main component of the ion permeation pathway, configures a stack of binding sites (sites S1-S4) to which K(+) and other cations may bind. Specific ion binding to such sites induces changes in the filter conformation, which play a key role in defining both selectivity and permeation. Here, using the potassium channel KcsA as a model, we contribute new evidence to reinforce this assertion. First, ion binding to KcsA blocked by tetrabutylammonium at the most cytoplasmic site in the selectivity filter (S4) suggests that such a site, when in the nonconductive filter conformation, has a higher affinity for cation binding than the most extracellular S1 site. This filter asymmetry, along with differences in intracellular and extracellular concentrations of K(+)versus Na(+) under physiological conditions, should strengthen selection of the permeant K(+) by the channel. Second, we used different K(+) concentrations to shift the equilibrium between nonconductive and conductive states of the selectivity filter in which to test competitive binding of Na(+) These experiments disclosed a marked decrease in the affinity of Na(+) to bind the channel when the conformational equilibrium shifts toward the conductive state. This finding suggested that in addition to the selective binding of K(+) and other permeant species over Na(+), there is a selective exclusion of nonpermeant species from binding the channel filter, once it reaches a fully conductive conformation. We conclude that selective binding and selective exclusion of permeant and nonpermeant cations, respectively, are important determinants of ion channel selectivity. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Mechanism of K+/Na+ selectivity in potassium channels from the perspective of the non-selective bacterial channel NaK.

    PubMed

    Durdagi, Serdar; Noskov, Sergei Y

    2011-01-01

    Studies of the non-selective NaK channel as a model system provided detailed structural and functional insights into different factors that modulate selective ion conductance. The combination of structural and functional studies of WT- and mutant forms of NaK channel show that apparent conservation of the multiple binding sites in the canonical selectivity filter of K-channel is essential component of the observed robust Na (+) discrimination.

  19. Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels

    PubMed Central

    Kozai, Daisuke; Sakaguchi, Reiko; Ohwada, Tomohiko; Mori, Yasuo

    2015-01-01

    The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms. PMID:26411770

  20. Deciphering Subtype-Selective Modulations in TRPA1 Biosensor Channels.

    PubMed

    Kozai, Daisuke; Sakaguchi, Reiko; Ohwada, Tomohiko; Mori, Yasuo

    2015-01-01

    The transient receptor potential (TRP) proteins are a family of ion channels that act as cellular sensors. Several members of the TRP family are sensitive to oxidative stress mediators. Among them, TRPA1 is remarkably susceptible to various oxidants, and is known to mediate neuropathic pain and respiratory, vascular and gastrointestinal functions, making TRPA1 an attractive therapeutic target. Recent studies have revealed a number of modulators (both activators and inhibitors) that act on TRPA1. Endogenous mediators of oxidative stress and exogenous electrophiles activate TRPA1 through oxidative modification of cysteine residues. Non-electrophilic compounds also activate TRPA1. Certain non-electrophilic modulators may act on critical non-cysteine sites in TRPA1. However, a method to achieve selective modulation of TRPA1 by small molecules has not yet been established. More recently, we found that a novel N-nitrosamine compound activates TRPA1 by S-nitrosylation (the addition of a nitric oxide (NO) group to cysteine thiol), and does so with significant selectivity over other NO-sensitive TRP channels. It is proposed that this subtype selectivity is conferred through synergistic effects of electrophilic cysteine transnitrosylation and molecular recognition of the non-electrophilic moiety on the N-nitrosamine. In this review, we describe the molecular pharmacology of these TRPA1 modulators and discuss their modulatory mechanisms.

  1. Ion selectivity in the selectivity filters of acid-sensing ion channels.

    PubMed

    Dudev, Todor; Lim, Carmay

    2015-01-19

    Sodium-selective acid sensing ion channels (ASICs), which belong to the epithelial sodium channel (ENaC) superfamily, are key players in many physiological processes (e.g. nociception, mechanosensation, cognition, and memory) and are potential therapeutic targets. Central to the ASIC's function is its ability to discriminate Na(+) among cations, which is largely determined by its selectivity filter, the narrowest part of an open pore. However, it is unclear how the ASIC discriminates Na(+) from rival cations such as K(+) and Ca(2+) and why its Na(+)/K(+) selectivity is an order of magnitude lower than that of the ENaC. Here, we show that a well-tuned balance between electrostatic and solvation effects controls ion selectivity in the ASIC1a SF. The large, water-filled ASIC1a pore is selective for Na(+) over K(+) because its backbone ligands form more hydrogen-bond contacts and stronger electrostatic interactions with hydrated Na(+) compared to hydrated K(+). It is selective for Na(+) over divalent Ca(2+) due to its relatively high-dielectric environment, which favors solvated rather than filter-bound Ca(2+). However, higher Na(+)-selectivity could be achieved in a narrow, rigid pore lined by three weak metal-ligating groups, as in the case of ENaC, which provides optimal fit and interactions for Na(+) but not for non-native ions.

  2. Apparatus and method for selectively channeling a fluid

    DOEpatents

    Rightley, Michael Joseph

    2008-01-01

    An apparatus for selectively channeling a high temperature fluid without chemically reacting with the fluid. The apparatus includes an inlet and a membrane positioned adjacent to the inlet, each composed of a chemically inert material. The membrane is formed by compressive preloading techniques. The apparatus further includes a seat disposed on the inlet adjacent to the membrane. The seat is composed of a heat resistant and chemically inert material. Operation of the apparatus requires that the temperature of the fluid remains below the chemical characteristic melting point of the seat. The apparatus further includes an actuator coupled to the membrane for rendering the membrane in an open and a closed position with respect to the seat. Specifically, the actuator supplies a load in the normal direction to the membrane to selectively engage the membrane in a plurality of predetermined configurations. Operatively, the apparatus receives the fluid at the inlet. The fluid is received at a high temperature and is directed from the inlet to the membrane. In the closed position, the actuator engages the membrane to prevent the fluid from flowing from the inlet between the membrane and the seat. Alternatively, in the open position, the actuator engages the membrane to permit fluid flow from the inlet between the membrane and the seat to at least one outlet provided by the apparatus. In one exemplary embodiment, the fluid may be discharged from the at least one outlet to a sensor in fluid communication with the at least one outlet. Accordingly, the sensor may measure the fluid channeled through the heat resistant and chemically inert environment provided by the apparatus.

  3. Doubly Rotated Cut SAW Devices.

    DTIC Science & Technology

    1981-04-01

    AD-AO 545 MOTOROLA INC SCOTTSDALE AZ GOVERNMENT ELECTRONICS DIV F/O 20/2 DOUBLY ROTATED CUT SAW DEVICES.( U) APR 81 0 F WILLIAMS, F Y CHO DAAK2O 79...f we Ma. he0 _TL ft . *VM or seu3f? 6 090100 cove mis interim Report.~arch 198 ’ Doubly Rotated Cut SAW Devices .r etme 9 9. SInFY T ON 6MNY mUUUUf L...exploratory development of doubly rotated cuts of quartz possessing superior Surface Acoustic Wave (SAW) properties for applications involving

  4. Doubly Rotated Cut SAW Devices.

    DTIC Science & Technology

    1981-08-01

    A0-AI03 -728 MOTOROLA INC SCOTTSDALE AZ GOVERNMENT ELECTRONICS DIV FIG 20/2 DOUBLY ROTATED CUT SAW DEVICES. U P AUG 81 0 F WILLIAMS, F Y CHO OAAK20...79-C-0275 UNCLASSIFIED DELET-TR-79-0275-3 ML wIIIIIIIIIIIIIIIIIIIIIII illlllllllllr: K8 MMR UNCLASSIFIED / JZ R-79-0273 Doubly Rotated Cut SAW Devices...towme. e *#* tooeeeimp md fallp p, uh9lbme The objective of this program is the exploratory development of doubly rotated cuts of quartz possessing

  5. Charge Delocalization in Proton Channels, II: The Synthetic LS2 Channel and Proton Selectivity

    PubMed Central

    Wu, Yujie; Ilan, Boaz; Voth, Gregory A.

    2007-01-01

    In this study, the minimalist synthetic LS2 channel is used as a prototype to examine the selectivity of protons over other cations. The free-energy profiles along the transport pathway of LS2 are calculated for three cation species: a realistic delocalized proton (including Grotthuss shuttling)—H+, a classical (nonshuttling) hydronium—H3O+, and a potassium cation—K+. The overall barrier for K+ is approximately twice as large as that for H+, explaining the >100 times larger maximal ion conductance for the latter, in qualitative agreement with the experimental result. The profile for the classical hydronium is quantitatively intermediate between those of H+ and K+ and qualitatively more similar to that of H+, for which the locations of the peaks are well correlated with the troughs of the pore radius profile. There is a strong correlation between the free-energy profiles and the very different characteristic hydration structures of the three cation species. This work suggests that the passage of various cations through ion channels cannot always be explained by simple electrostatic desolvation considerations. PMID:17056732

  6. Unexpected doubly-magic nucleus.

    SciTech Connect

    Janssens, R. V. F.; Physics

    2009-01-01

    Nuclei with a 'magic' number of both protons and neutrons, dubbed doubly magic, are particularly stable. The oxygen isotope {sup 24}O has been found to be one such nucleus - yet it lies just at the limit of stability.

  7. Calcium ions open a selectivity filter gate during activation of the MthK potassium channel.

    PubMed

    Posson, David J; Rusinova, Radda; Andersen, Olaf S; Nimigean, Crina M

    2015-09-23

    Ion channel opening and closing are fundamental to cellular signalling and homeostasis. Gates that control K(+) channel activity were found both at an intracellular pore constriction and within the selectivity filter near the extracellular side but the specific location of the gate that opens Ca(2+)-activated K(+) channels has remained elusive. Using the Methanobacterium thermoautotrophicum homologue (MthK) and a stopped-flow fluorometric assay for fast channel activation, we show that intracellular quaternary ammonium blockers bind to closed MthK channels. Since the blockers are known to bind inside a central channel cavity, past the intracellular entryway, the gate must be within the selectivity filter. Furthermore, the blockers access the closed channel slower than the open channel, suggesting that the intracellular entryway narrows upon pore closure, without preventing access of either the blockers or the smaller K(+). Thus, Ca(2+)-dependent gating in MthK occurs at the selectivity filter with coupled movement of the intracellular helices.

  8. Calcium ions open a selectivity filter gate during activation of the MthK potassium channel

    NASA Astrophysics Data System (ADS)

    Posson, David J.; Rusinova, Radda; Andersen, Olaf S.; Nimigean, Crina M.

    2015-09-01

    Ion channel opening and closing are fundamental to cellular signalling and homeostasis. Gates that control K+ channel activity were found both at an intracellular pore constriction and within the selectivity filter near the extracellular side but the specific location of the gate that opens Ca2+-activated K+ channels has remained elusive. Using the Methanobacterium thermoautotrophicum homologue (MthK) and a stopped-flow fluorometric assay for fast channel activation, we show that intracellular quaternary ammonium blockers bind to closed MthK channels. Since the blockers are known to bind inside a central channel cavity, past the intracellular entryway, the gate must be within the selectivity filter. Furthermore, the blockers access the closed channel slower than the open channel, suggesting that the intracellular entryway narrows upon pore closure, without preventing access of either the blockers or the smaller K+. Thus, Ca2+-dependent gating in MthK occurs at the selectivity filter with coupled movement of the intracellular helices.

  9. Evaluation of the AIRS near-real-time channel selection for application to numerical weather prediction

    NASA Astrophysics Data System (ADS)

    Fourrié, Nadia; Thépaut, Jean-Noël

    2003-07-01

    The Atmospheric Infrared Sounder (AIRS) on board the National Aeronautics and Space Administration (NASA) Earth Observing System (EOS) Aqua satellite provides 2378 channels for each field of view of the instrument. As it is neither feasible nor efficient to assimilate all the channels in a numerical weather-prediction system, a policy of channel selection has to be designed in this context. This paper attempts to assess the optimality of the selection of the AIRS radiance channels that are made available to the scientific community in near real time (hereafter called AIRS NRT) by the National Oceanic and Atmospheric Administration (NOAA) National Environmental Satellite Data and Information Service. This assessment is done by comparing this channel selection with a method preserving the information content of the instrument, the so-called 'global' method. It turns out that although the selected channels are different and the information content as measured by the entropy reduction (ER) and the degrees of freedom for signal (DFS) is slightly smaller for the AIRS NRT channel set than for the 'global' set, both channel selections give similar results in terms of analysis error for temperature, humidity and ozone. The robustness of the results is then evaluated by varying the range of input parameters to the channel-selection scheme, in particular the atmospheric training dataset on which the channel selection is based, and the background-error covariance matrix. It is found that the performance of the 'global' channel selection is sensitive to the training dataset, while the AIRS NRT channel selection remains robust, even, to some extent, for the retrieval of key analysis-error structures. Altogether, the 'manually selected' AIRS NRT channels provide a good compromise between robustness and quality.

  10. Arizona Canal Diversion Channel Selection of Roughness Coefficients for Designing the Concrete-Lined Channel.

    DTIC Science & Technology

    1985-09-01

    CHANNEL STABILIZATION Technical Report Title Date 1 Symposium on Channel Stabilization Problems Volume 1 Sep 1983 Volume 2 May 1964 Volume 3 Jun 1965...Volume 4 Feb 1966 2 Review of Research on Channel Stabilization of the Sep 1963 Mississippi River, 1931-1962 3 Effect of Water Temperature on... Effects on Stage-Discharge Relations Sep 1969 * in Large Alluvial Rivers 7 State of Knowledge of Channel Stabilization in Major Oct 1969 Alluvial

  11. Molecular determinants of anion selectivity in the cystic fibrosis transmembrane conductance regulator chloride channel pore.

    PubMed Central

    Linsdell, P; Evagelidis, A; Hanrahan, J W

    2000-01-01

    Ionic selectivity in many cation channels is achieved over a short region of the pore known as the selectivity filter, the molecular determinants of which have been identified in Ca(2+), Na(+), and K(+) channels. However, a filter controlling selectivity among different anions has not previously been identified in any Cl(-) channel. In fact, because Cl(-) channels are only weakly selective among small anions, and because their selectivity has proved so resistant to site-directed mutagenesis, the very existence of a discrete anion selectivity filter has been called into question. Here we show that mutation of a putative pore-lining phenylalanine residue, F337, in the sixth membrane-spanning region of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel, dramatically alters the relative permeabilities of different anions in the channel. Specifically, mutations that reduce the size of the amino acid side chain present at this position virtually abolish the relationship between anion permeability and hydration energy, a relationship that characterizes the anion selectivity not only of wild-type CFTR, but of most classes of Cl(-) channels. These results suggest that the pore of CFTR may indeed contain a specialized region, analogous to the selectivity filter of cation channels, at which discrimination between different permeant anions takes place. Because F337 is adjacent to another amino acid residue, T338, which also affects anion selectivity in CFTR, we suggest that selectivity is predominantly determined over a physically discrete region of the pore located near these important residues. PMID:10827976

  12. Selectivity filter gating in large-conductance Ca(2+)-activated K+ channels.

    PubMed

    Thompson, Jill; Begenisich, Ted

    2012-03-01

    Membrane voltage controls the passage of ions through voltage-gated K (K(v)) channels, and many studies have demonstrated that this is accomplished by a physical gate located at the cytoplasmic end of the pore. Critical to this determination were the findings that quaternary ammonium ions and certain peptides have access to their internal pore-blocking sites only when the channel gates are open, and that large blocking ions interfere with channel closing. Although an intracellular location for the physical gate of K(v) channels is well established, it is not clear if such a cytoplasmic gate exists in all K(+) channels. Some studies on large-conductance, voltage- and Ca(2+)-activated K(+) (BK) channels suggest a cytoplasmic location for the gate, but other findings question this conclusion and, instead, support the concept that BK channels are gated by the pore selectivity filter. If the BK channel is gated by the selectivity filter, the interactions between the blocking ions and channel gating should be influenced by the permeant ion. Thus, we tested tetrabutyl ammonium (TBA) and the Shaker "ball" peptide (BP) on BK channels with either K(+) or Rb(+) as the permeant ion. When tested in K(+) solutions, both TBA and the BP acted as open-channel blockers of BK channels, and the BP interfered with channel closing. In contrast, when Rb(+) replaced K(+) as the permeant ion, TBA and the BP blocked both closed and open BK channels, and the BP no longer interfered with channel closing. We also tested the cytoplasmically gated Shaker K channels and found the opposite behavior: the interactions of TBA and the BP with these K(v) channels were independent of the permeant ion. Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating.

  13. Selectivity filter gating in large-conductance Ca2+-activated K+ channels

    PubMed Central

    Thompson, Jill

    2012-01-01

    Membrane voltage controls the passage of ions through voltage-gated K (Kv) channels, and many studies have demonstrated that this is accomplished by a physical gate located at the cytoplasmic end of the pore. Critical to this determination were the findings that quaternary ammonium ions and certain peptides have access to their internal pore-blocking sites only when the channel gates are open, and that large blocking ions interfere with channel closing. Although an intracellular location for the physical gate of Kv channels is well established, it is not clear if such a cytoplasmic gate exists in all K+ channels. Some studies on large-conductance, voltage- and Ca2+-activated K+ (BK) channels suggest a cytoplasmic location for the gate, but other findings question this conclusion and, instead, support the concept that BK channels are gated by the pore selectivity filter. If the BK channel is gated by the selectivity filter, the interactions between the blocking ions and channel gating should be influenced by the permeant ion. Thus, we tested tetrabutyl ammonium (TBA) and the Shaker “ball” peptide (BP) on BK channels with either K+ or Rb+ as the permeant ion. When tested in K+ solutions, both TBA and the BP acted as open-channel blockers of BK channels, and the BP interfered with channel closing. In contrast, when Rb+ replaced K+ as the permeant ion, TBA and the BP blocked both closed and open BK channels, and the BP no longer interfered with channel closing. We also tested the cytoplasmically gated Shaker K channels and found the opposite behavior: the interactions of TBA and the BP with these Kv channels were independent of the permeant ion. Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating. PMID:22371364

  14. A General Method of Selecting Quantum Channel for Bidirectional Quantum Teleportation

    NASA Astrophysics Data System (ADS)

    Fu, Hong-Zi; Tian, Xiu-Lao; Hu, Yang

    2014-06-01

    Based on tensor representation and Bell basis measurement in bidirectional quantum teleportation, a criterion that can be used to judge whether a four-qubit quantum state can be regarded as quantum channel or not in bidirectional teleportation is suggested and a theoretical scheme of bidirectional teleportation via four-qubit state as the quantum channel is proposed. In accordance with this criterion we give a general method of selecting quantum channel in bidirectional teleportation, which is determined by the channel parameter matrix R in the Bell basis measurement. This general method provide a theoretical basis for quantum channel selection in bidirectional quantum teleportation experiments.

  15. Size and selectivity of gap junction channels formed from different connexins.

    PubMed

    Veenstra, R D

    1996-08-01

    Gap junction channels have long been viewed as static structures containing a large-diameter, aqueous pore. This pore has a high permeability to hydrophilic molecules of approximately 900 daltons in molecular weight and a weak ionic selectivity. The evidence leading to these conclusions is reviewed in the context of more recent observations primarily coming from unitary channel recordings from transfected connexin channels expressed in communication-deficient cell lines. What is emerging is a more diverse view of connexin-specific gap junction channel structure and function where electrical conductance, ionic selectivity, and dye permeability vary by one full order of magnitude or more. furthermore, the often held contention that channel conductance and ionic or molecular selectivity are inversely proportional is refuted by recent evidence from five distinct connexin channels. The molecular basis for this diversity of channel function remains to be identified for the connexin family of gap junction proteins.

  16. Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites

    SciTech Connect

    Derebe, Mehabaw G.; Sauer, David B.; Zeng, Weizhong; Alam, Amer; Shi, Ning; Jiang, Youxing

    2015-11-30

    Selective ion conduction across ion channel pores is central to cellular physiology. To understand the underlying principles of ion selectivity in tetrameric cation channels, we engineered a set of cation channel pores based on the nonselective NaK channel and determined their structures to high resolution. These structures showcase an ensemble of selectivity filters with a various number of contiguous ion binding sites ranging from 2 to 4, with each individual site maintaining a geometry and ligand environment virtually identical to that of equivalent sites in K{sup +} channel selectivity filters. Combined with single channel electrophysiology, we show that only the channel with four ion binding sites is K{sup +} selective, whereas those with two or three are nonselective and permeate Na{sup +} and K{sup +} equally well. These observations strongly suggest that the number of contiguous ion binding sites in a single file is the key determinant of the channel's selectivity properties and the presence of four sites in K{sup +} channels is essential for highly selective and efficient permeation of K{sup +} ions.

  17. Non-Equilibrium Dynamics Contribute to Ion Selectivity in the KcsA Channel

    PubMed Central

    Haas, Stephan; Farley, Robert A.

    2014-01-01

    The ability of biological ion channels to conduct selected ions across cell membranes is critical for the survival of both animal and bacterial cells. Numerous investigations of ion selectivity have been conducted over more than 50 years, yet the mechanisms whereby the channels select certain ions and reject others are not well understood. Here we report a new application of Jarzynski’s Equality to investigate the mechanism of ion selectivity using non-equilibrium molecular dynamics simulations of Na+ and K+ ions moving through the KcsA channel. The simulations show that the selectivity filter of KcsA adapts and responds to the presence of the ions with structural rearrangements that are different for Na+ and K+. These structural rearrangements facilitate entry of K+ ions into the selectivity filter and permeation through the channel, and rejection of Na+ ions. A mechanistic model of ion selectivity by this channel based on the results of the simulations relates the structural rearrangement of the selectivity filter to the differential dehydration of ions and multiple-ion occupancy and describes a mechanism to efficiently select and conduct K+. Estimates of the K+/Na+ selectivity ratio and steady state ion conductance for KcsA from the simulations are in good quantitative agreement with experimental measurements. This model also accurately describes experimental observations of channel block by cytoplasmic Na+ ions, the “punch through” relief of channel block by cytoplasmic positive voltages, and is consistent with the knock-on mechanism of ion permeation. PMID:24465882

  18. Ion-binding properties of a K+ channel selectivity filter in different conformations.

    PubMed

    Liu, Shian; Focke, Paul J; Matulef, Kimberly; Bian, Xuelin; Moënne-Loccoz, Pierre; Valiyaveetil, Francis I; Lockless, Steve W

    2015-12-08

    K(+) channels are membrane proteins that selectively conduct K(+) ions across lipid bilayers. Many voltage-gated K(+) (KV) channels contain two gates, one at the bundle crossing on the intracellular side of the membrane and another in the selectivity filter. The gate at the bundle crossing is responsible for channel opening in response to a voltage stimulus, whereas the gate at the selectivity filter is responsible for C-type inactivation. Together, these regions determine when the channel conducts ions. The K(+) channel from Streptomyces lividians (KcsA) undergoes an inactivation process that is functionally similar to KV channels, which has led to its use as a practical system to study inactivation. Crystal structures of KcsA channels with an open intracellular gate revealed a selectivity filter in a constricted conformation similar to the structure observed in closed KcsA containing only Na(+) or low [K(+)]. However, recent work using a semisynthetic channel that is unable to adopt a constricted filter but inactivates like WT channels challenges this idea. In this study, we measured the equilibrium ion-binding properties of channels with conductive, inactivated, and constricted filters using isothermal titration calorimetry (ITC). EPR spectroscopy was used to determine the state of the intracellular gate of the channel, which we found can depend on the presence or absence of a lipid bilayer. Overall, we discovered that K(+) ion binding to channels with an inactivated or conductive selectivity filter is different from K(+) ion binding to channels with a constricted filter, suggesting that the structures of these channels are different.

  19. Determination of channel change for selected streams, Maricopa County, Arizona

    USGS Publications Warehouse

    Capesius, Joseph P.; Lehman, Ted W.

    2002-01-01

    In Maricopa County, Arizona, 10 sites on seven streams were studied to determine the lateral and vertical change of the channel. Channel change was studied over time scales ranging from individual floods to decades using cross-section surveys, discharge measurements, changes in the point of zero flow, and repeat photography. All of the channels showed some change in cross-section area or hydraulic radius over the time scales studied, but the direction and mag-nitude of change varied considerably from one flow, or series of flows, to another. The documentation of cross-section geometry for streams in Maricopa County for long-term monitoring was begun in this study.

  20. Protein interactions central to stabilizing the K+ channel selectivity filter in a four-sited configuration for selective K+ permeation

    PubMed Central

    Sauer, David B.; Zeng, Weizhong; Raghunathan, Srinivasan; Jiang, Youxing

    2011-01-01

    The structural and functional conversion of the nonselective NaK channel to a K+ selective channel (NaK2K) allows us to identify two key residues, Tyr and Asp in the filter sequence of TVGYGD, that participate in interactions central to stabilizing the K+ channel selectivity filter. By using protein crystallography and channel electrophysiology, we demonstrate that the K+ channel filter exists as an energetically strained structure and requires these key protein interactions working in concert to hold the filter in the precisely defined four-sited configuration that is essential for selective K+ permeation. Disruption of either interaction, as tested on both the NaK2K and eukaryotic Kv1.6 channels, can reduce or completely abolish K+ selectivity and in some cases may also lead to channel inactivation due to conformational changes at the filter. Additionally, on the scaffold of NaK we recapitulate the protein interactions found in the filter of the Kir channel family, which uses a distinct interaction network to achieve similar stabilization of the filter. PMID:21933962

  1. Tuning the ion selectivity of tetrameric cation channels by changing the number of ion binding sites

    PubMed Central

    Derebe, Mehabaw G.; Sauer, David B.; Zeng, Weizhong; Alam, Amer; Shi, Ning; Jiang, Youxing

    2011-01-01

    Selective ion conduction across ion channel pores is central to cellular physiology. To understand the underlying principles of ion selectivity in tetrameric cation channels, we engineered a set of cation channel pores based on the nonselective NaK channel and determined their structures to high resolution. These structures showcase an ensemble of selectivity filters with a various number of contiguous ion binding sites ranging from 2 to 4, with each individual site maintaining a geometry and ligand environment virtually identical to that of equivalent sites in K+ channel selectivity filters. Combined with single channel electrophysiology, we show that only the channel with four ion binding sites is K+ selective, whereas those with two or three are nonselective and permeate Na+ and K+ equally well. These observations strongly suggest that the number of contiguous ion binding sites in a single file is the key determinant of the channel’s selectivity properties and the presence of four sites in K+ channels is essential for highly selective and efficient permeation of K+ ions. PMID:21187421

  2. Gating the Selectivity Filter in ClC Chloride Channels

    NASA Astrophysics Data System (ADS)

    Dutzler, Raimund; Campbell, Ernest B.; MacKinnon, Roderick

    2003-04-01

    ClC channels conduct chloride (Cl-) ions across cell membranes and thereby govern the electrical activity of muscle cells and certain neurons, the transport of fluid and electrolytes across epithelia, and the acidification of intracellular vesicles. The structural basis of ClC channel gating was studied. Crystal structures of wild-type and mutant Escherichia coli ClC channels bound to a monoclonal Fab fragment reveal three Cl- binding sites within the 15-angstrom neck of an hourglass-shaped pore. The Cl- binding site nearest the extracellular solution can be occupied either by a Cl- ion or by a glutamate carboxyl group. Mutations of this glutamate residue in Torpedo ray ClC channels alter gating in electrophysiological assays. These findings reveal a form of gating in which the glutamate carboxyl group closes the pore by mimicking a Cl- ion.

  3. Piezo1: properties of a cation selective mechanical channel.

    PubMed

    Gottlieb, Philip A; Sachs, Frederick

    2012-01-01

    Piezo ion channels have been found to be essential for mechanical responses in cells. These channels were first shown to exist in Neuro2A cells, and the gene was identified by siRNAs that diminished the mechanical response. Piezo channels are approximately 2500 amino acids long, have between 24-32 transmembrane regions, and appear to assemble into tetramers and require no other proteins for activity. They have a reversal potential around 0 mV and show voltage dependent inactivation. The channel is constitutively active in liposomes, indicating that no cytoskeletal elements are required. Heterologous expression of the Piezo protein can create mechanical sensitivity in otherwise insensitive cells.   Piezo1 currents in outside-out patches were blocked by the extracellular MSC inhibitor peptide GsMTx4. Both enantiomeric forms of GsMTx4 inhibited channel activity in a manner similar to endogenous mechanical channels. Piezo1 can adopt a tonic (non-inactivating) form with repeated stimulation. The transition to the non-inactivating form generally occurs in large groups of channels, indicating that the channels exist in domains, and once the domain is compromised, the members simultaneously adopt new properties. Piezo proteins are associated with physiological responses in cells, such as the reaction to noxious stimulus of Drosophila larvae. Recent work measuring cell crowding, shows that Piezo1 is essential for the removal of extra cells without apoptosis. Piezo1 mutations have also been linked to the pathological response of red blood cells in a genetic disease called Xerocytosis. These finding suggest that Piezo1 is a key player in cells' responses to mechanical stimuli.

  4. Modified kinetics and selectivity of sodium channels in frog skeletal muscle fibers treated with aconitine

    PubMed Central

    1982-01-01

    The effect of the plant alkaloid aconitine on sodium channel kinetics, ionic selectivity, and blockage by protons and tetrodotoxin (TTX) has been studied in frog skeletal muscle. Treatment with 0.25 or 0.3 mM aconitine alters sodium channels so that the threshold of activation is shifted 40-50 mV in the hyperpolarized direction. In contrast to previous results in frog nerve, inactivation is complete for depolarizations beyond about -60 mV. After aconitine treatment, the steady state level of inactivation is shifted approximately 20 mV in the hyperpolarizing direction. Concomitant with changes in channel kinetics, the relative permeability of the sodium channel to NH4,K, and Cs is increased. This altered selectivity is not accompanied by altered block by protons or TTX. The results suggest that sites other than those involved in channel block by protons and TTX are important in determining sodium channel selectivity. PMID:6294221

  5. Cav3 T-type channels: regulators for gating, membrane expression, and cation selectivity.

    PubMed

    Senatore, A; Guan, W; Spafford, J D

    2014-04-01

    Cav3 T-type channels are low-voltage-gated channels with rapid kinetics that are classified among the calcium-selective Cav1 and Cav2 type channels. Here, we outline the fundamental and unique regulators of T-type channels. An ubiquitous and proximally located "gating brake" works in concert with the voltage-sensor domain and S6 alpha-helical segment from domain II to set the canonical low-threshold and transient gating features of T-type channels. Gene splicing of optional exon 25c (and/or exon 26) in the short III-IV linker provides a developmental switch between modes of activity, such as activating in response to membrane depolarization, to channels requiring hyperpolarization input before being available to activate. Downstream of the gating brake in the I-II linker is a key region for regulating channel expression where alternative splicing patterns correlate with functional diversity of spike patterns, pacemaking rate (especially in the heart), stage of development, and animal size. A small but persistent window conductance depolarizes cells and boosts excitability at rest. T-type channels possess an ion selectivity that can resemble not only the calcium ion exclusive Cav1 and Cav2 channels but also the sodium ion selectivity of Nav1 sodium channels too. Alternative splicing in the extracellular turret of domain II generates highly sodium-permeable channels, which contribute to low-threshold sodium spikes. Cav3 channels are more ubiquitous among multicellular animals and more widespread in tissues than the more brain centric Nav1 sodium channels in invertebrates. Highly sodium-permeant Cav3 channels can functionally replace Nav1 channels in species where they are lacking, such as in Caenorhabditis elegans.

  6. Channel selection for simultaneous and proportional myoelectric prosthesis control of multiple degrees-of-freedom

    NASA Astrophysics Data System (ADS)

    Hwang, Han-Jeong; Hahne, Janne Mathias; Müller, Klaus-Robert

    2014-10-01

    Objective. Recent studies have shown the possibility of simultaneous and proportional control of electrically powered upper-limb prostheses, but there has been little investigation on optimal channel selection. The objective of this study is to find a robust channel selection method and the channel subsets most suitable for simultaneous and proportional myoelectric prosthesis control of multiple degrees-of-freedom (DoFs). Approach. Ten able-bodied subjects and one person with congenital upper-limb deficiency took part in this study, and performed wrist movements with various combinations of two DoFs (flexion/extension and radial/ulnar deviation). During the experiment, high density electromyographic (EMG) signals and the actual wrist angles were recorded with an 8 × 24 electrode array and a motion tracking system, respectively. The wrist angles were estimated from EMG features with ridge regression using the subsets of channels chosen by three different channel selection methods: (1) least absolute shrinkage and selection operator (LASSO), (2) sequential feature selection (SFS), and (3) uniform selection (UNI). Main results. SFS generally showed higher estimation accuracy than LASSO and UNI, but LASSO always outperformed SFS in terms of robustness, such as noise addition, channel shift and training data reduction. It was also confirmed that about 95% of the original performance obtained using all channels can be retained with only 12 bipolar channels individually selected by LASSO and SFS. Significance. From the analysis results, it can be concluded that LASSO is a promising channel selection method for accurate simultaneous and proportional prosthesis control. We expect that our results will provide a useful guideline to select optimal channel subsets when developing clinical myoelectric prosthesis control systems based on continuous movements with multiple DoFs.

  7. Sub-surface channels in sapphire made by ultraviolet picosecond laser irradiation and selective etching.

    PubMed

    Moser, Rüdiger; Ojha, Nirdesh; Kunzer, Michael; Schwarz, Ulrich T

    2011-11-21

    We demonstrate the realization of sub-surface channels in sapphire prepared by ultraviolet picosecond laser irradiation and subsequent selective wet etching. By optimizing the pulse energy and the separation between individual laser pulses, an optimization of channel length can be achieved with an aspect ratio as high as 3200. Due to strong variation in channel length, further investigation was done to improve the reproducibility. By multiple irradiations the standard deviation of the channel length could be reduced to 2.2%. The achieved channel length together with the high reproducibility and the use of a commercial picosecond laser system makes the process attractive for industrial application.

  8. Mechanism for selectivity-inactivation coupling in KcsA potassium channels.

    PubMed

    Cheng, Wayland W L; McCoy, Jason G; Thompson, Ameer N; Nichols, Colin G; Nimigean, Crina M

    2011-03-29

    Structures of the prokaryotic K(+) channel, KcsA, highlight the role of the selectivity filter carbonyls from the GYG signature sequence in determining a highly selective pore, but channels displaying this sequence vary widely in their cation selectivity. Furthermore, variable selectivity can be found within the same channel during a process called C-type inactivation. We investigated the mechanism for changes in selectivity associated with inactivation in a model K(+) channel, KcsA. We found that E71A, a noninactivating KcsA mutant in which a hydrogen-bond behind the selectivity filter is disrupted, also displays decreased K(+) selectivity. In E71A channels, Na(+) permeates at higher rates as seen with and flux measurements and analysis of intracellular Na(+) block. Crystal structures of E71A reveal that the selectivity filter no longer assumes the "collapsed," presumed inactivated, conformation in low K(+), but a "flipped" conformation, that is also observed in high K(+), high Na(+), and even Na(+) only conditions. The data reveal the importance of the E71-D80 interaction in both favoring inactivation and maintaining high K(+) selectivity. We propose a molecular mechanism by which inactivation and K(+) selectivity are linked, a mechanism that may also be at work in other channels containing the canonical GYG signature sequence.

  9. Mechanism for Selectivity-inactivation Coupling in KcsA Potassium Channels

    SciTech Connect

    W Cheng; J McCoy; A Thompson; C Nichols; C Nimigean

    2011-12-31

    Structures of the prokaryotic K{sup +} channel, KcsA, highlight the role of the selectivity filter carbonyls from the GYG signature sequence in determining a highly selective pore, but channels displaying this sequence vary widely in their cation selectivity. Furthermore, variable selectivity can be found within the same channel during a process called C-type inactivation. We investigated the mechanism for changes in selectivity associated with inactivation in a model K{sup +} channel, KcsA. We found that E71A, a noninactivating KcsA mutant in which a hydrogen-bond behind the selectivity filter is disrupted, also displays decreased K{sup +} selectivity. In E71A channels, Na{sup +} permeates at higher rates as seen with {sup 86}Rb{sup +} and {sup 22}Na{sup +} flux measurements and analysis of intracellular Na{sup +} block. Crystal structures of E71A reveal that the selectivity filter no longer assumes the 'collapsed,' presumed inactivated, conformation in low K{sup +}, but a 'flipped' conformation, that is also observed in high K{sup +}, high Na{sup +}, and even Na{sup +} only conditions. The data reveal the importance of the E71-D80 interaction in both favoring inactivation and maintaining high K{sup +} selectivity. We propose a molecular mechanism by which inactivation and K{sup +} selectivity are linked, a mechanism that may also be at work in other channels containing the canonical GYG signature sequence.

  10. Ion Permeation Through a Cl--Selective Channel Designed from a CLC Cl-/H+ Exchanger

    SciTech Connect

    Jayaram,H.; Accardi, A.; Wu, F.; Williams, C.; Miller, C.

    2008-01-01

    The CLC family of Cl--transporting proteins includes both Cl- channels and Cl-/H+ exchange transporters. CLC-ec1, a structurally known bacterial homolog of the transporter subclass, exchanges two Cl- ions per proton with strict, obligatory stoichiometry. Point mutations at two residues, Glu148 and Tyr445, are known to impair H+ movement while preserving Cl- transport. In the x-ray crystal structure of CLC-ec1, these residues form putative 'gates' flanking an ion-binding region. In mutants with both of the gate-forming side chains reduced in size, H+ transport is abolished, and unitary Cl- transport rates are greatly increased, well above values expected for transporter mechanisms. Cl- transport rates increase as side-chain volume at these positions is decreased. The crystal structure of a doubly ungated mutant shows a narrow conduit traversing the entire protein transmembrane width. These characteristics suggest that Cl- flux through uncoupled, ungated CLC-ec1 occurs via a channel-like electrodiffusion mechanism rather than an alternating-exposure conformational cycle that has been rendered proton-independent by the gate mutations.

  11. A Portable MIMO Testbed and Selected Channel Measurements

    NASA Astrophysics Data System (ADS)

    Goud, Paul, Jr.; Hang, Robert; Truhachev, Dmitri; Schlegel, Christian

    2006-12-01

    A portable[InlineEquation not available: see fulltext.] multiple-input multiple-output (MIMO) testbed that is based on field programmable gate arrays (FPGAs) and which operates in the 902-928 MHz industrial, scientific, and medical (ISM) band has been developed by the High Capacity Digital Communications (HCDC) Laboratory at the University of Alberta. We present a description of the HCDC testbed along with MIMO channel capacities that were derived from measurements taken with the HCDC testbed for three special locations: a narrow corridor, an athletics field that is surrounded by a metal fence, and a parkade. These locations are special because the channel capacities are different from what is expected for a typical indoor or outdoor channel. For two of the cases, a ray-tracing analysis has been performed and the simulated channel capacity values closely match the values calculated from the measured data. A ray-tracing analysis, however, requires accurate geometrical measurements and sophisticated modeling for each specific location. A MIMO testbed is ideal for quickly obtaining accurate channel capacity information.

  12. Squalyl Crown Ether Self-Assembled Conjugates: An Example of Highly Selective Artificial K(+) Channels.

    PubMed

    Sun, Zhanhu; Gilles, Arnaud; Kocsis, Istvan; Legrand, Yves-Marie; Petit, Eddy; Barboiu, Mihail

    2016-02-01

    The natural KcsA K(+) channel, one of the best-characterized biological pore structures, conducts K(+) cations at high rates while excluding Na(+) cations. The KcsA K(+) channel is of primordial inspiration for the design of artificial channels. Important progress in improving conduction activity and K(+) /Na(+) selectivity has been achieved with artificial ion-channel systems. However, simple artificial systems exhibiting K(+) /Na(+) selectivity and mimicking the biofunctions of the KcsA K(+) channel are unknown. Herein, an artificial ion channel formed by H-bonded stacks of squalyl crown ethers, in which K(+) conduction is highly preferred to Na(+) conduction, is reported. The K(+) -channel behavior is interpreted as arising from discreet stacks of dimers resulting in the formation of oligomeric channels, in which transport of cations occurs through macrocycles mixed with dimeric carriers undergoing dynamic exchange within the bilayer membrane. The present highly K(+) -selective macrocyclic channel can be regarded as a biomimetic alternative to the KcsA channel.

  13. Cation Selectivity in Biological Cation Channels Using Experimental Structural Information and Statistical Mechanical Simulation

    PubMed Central

    Finnerty, Justin John

    2015-01-01

    Cation selective channels constitute the gate for ion currents through the cell membrane. Here we present an improved statistical mechanical model based on atomistic structural information, cation hydration state and without tuned parameters that reproduces the selectivity of biological Na+ and Ca2+ ion channels. The importance of the inclusion of step-wise cation hydration in these results confirms the essential role partial dehydration plays in the bacterial Na+ channels. The model, proven reliable against experimental data, could be straightforwardly used for designing Na+ and Ca2+ selective nanopores. PMID:26460827

  14. Toxicity of Selected Mosquito Sprays to Channel Catfish Sac Fry

    USDA-ARS?s Scientific Manuscript database

    In the spring when channel catfish, Ictalurus punctatus, hatcheries are in full operation, the associated moisture and warm temperatures provide a haven for mosquitoes. Large swarms of biting mosquitoes in a hatchery can make the tedious work of egg-picking (i.e., removing dead and fungus-infested e...

  15. Kv1 channels selectively prevent dendritic hyperexcitability in rat Purkinje cells

    PubMed Central

    Khavandgar, Simin; Walter, Joy T; Sageser, Kristin; Khodakhah, Kamran

    2005-01-01

    Purkinje cells, the sole output of the cerebellar cortex, encode the timing signals required for motor coordination in their firing rate and activity pattern. Dendrites of Purkinje cells express a high density of P/Q-type voltage-gated calcium channels and fire dendritic calcium spikes. Here we show that dendritic subthreshold Kv1.2 subunit-containing Kv1 potassium channels prevent generation of random spontaneous calcium spikes. With Kv1 channels blocked, dendritic calcium spikes drive bursts of somatic sodium spikes and prevent the cell from faithfully encoding motor timing signals. The selective dendritic function of Kv1 channels in Purkinje cells allows them to effectively suppress dendritic hyperexcitability without hindering the generation of somatic action potentials. Further, we show that Kv1 channels also contribute to dendritic integration of parallel fibre synaptic input. Kv1 channels are often targeted to soma and axon and the data presented support a major dendritic function for these channels. PMID:16210348

  16. Joint Antenna Selection for Achieving Diversity in a Two-Way Relaying Channel

    NASA Astrophysics Data System (ADS)

    Xu, Kun; Gao, Yuanyuan; Yi, Xiaoxin; Yang, Weiwei

    Joint transmit and receive antenna selection (JTRAS) is proposed for the multiple-input multiple-output (MIMO) two-way relaying channel. A simple and closed-form lower bound on the outage probability of JTRAS is derived. Furthermore, asymptotic analysis reveals that JTRAS can attain the maximum achievable diversity order of the MIMO dual-hop relaying channel.

  17. Use of color-coded sleeve shutters accelerates oscillograph channel selection

    NASA Technical Reports Server (NTRS)

    Bouchlas, T.; Bowden, F. W.

    1967-01-01

    Sleeve-type shutters mechanically adjust individual galvanometer light beams onto or away from selected channels on oscillograph papers. In complex test setups, the sleeve-type shutters are color coded to separately identify each oscillograph channel. This technique could be used on any equipment using tubular galvanometer light sources.

  18. MIMO Channel Matrix Condition Number Estimation and Threshold Selection for Combined K-Best Sphere Decoders

    NASA Astrophysics Data System (ADS)

    Roger, Sandra; Gonzalez, Alberto; Almenar, Vicenc; Vidal, Antonio M.

    It is known that MIMO channel matrix condition number influences detectors performance. Several authors have proposed combined decoders, mainly suboptimal, to cope with this fact. These combined algorithms require an estimation of the MIMO channel matrix condition number and a selection of a suitable threshold condition number. This letter presents practical algorithms to carry out the referred tasks and shows their performance in practice.

  19. Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel

    PubMed Central

    Brettmann, Joshua B.; Urusova, Darya; Tonelli, Marco; Silva, Jonathan R.; Henzler-Wildman, Katherine A.

    2015-01-01

    Flux-dependent inactivation that arises from functional coupling between the inner gate and the selectivity filter is widespread in ion channels. The structural basis of this coupling has only been well characterized in KcsA. Here we present NMR data demonstrating structural and dynamic coupling between the selectivity filter and intracellular constriction point in the bacterial nonselective cation channel, NaK. This transmembrane allosteric communication must be structurally different from KcsA because the NaK selectivity filter does not collapse under low-cation conditions. Comparison of NMR spectra of the nonselective NaK and potassium-selective NaK2K indicates that the number of ion binding sites in the selectivity filter shifts the equilibrium distribution of structural states throughout the channel. This finding was unexpected given the nearly identical crystal structure of NaK and NaK2K outside the immediate vicinity of the selectivity filter. Our results highlight the tight structural and dynamic coupling between the selectivity filter and the channel scaffold, which has significant implications for channel function. NaK offers a distinct model to study the physiologically essential connection between ion conduction and channel gating. PMID:26621745

  20. Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel.

    PubMed

    Brettmann, Joshua B; Urusova, Darya; Tonelli, Marco; Silva, Jonathan R; Henzler-Wildman, Katherine A

    2015-12-15

    Flux-dependent inactivation that arises from functional coupling between the inner gate and the selectivity filter is widespread in ion channels. The structural basis of this coupling has only been well characterized in KcsA. Here we present NMR data demonstrating structural and dynamic coupling between the selectivity filter and intracellular constriction point in the bacterial nonselective cation channel, NaK. This transmembrane allosteric communication must be structurally different from KcsA because the NaK selectivity filter does not collapse under low-cation conditions. Comparison of NMR spectra of the nonselective NaK and potassium-selective NaK2K indicates that the number of ion binding sites in the selectivity filter shifts the equilibrium distribution of structural states throughout the channel. This finding was unexpected given the nearly identical crystal structure of NaK and NaK2K outside the immediate vicinity of the selectivity filter. Our results highlight the tight structural and dynamic coupling between the selectivity filter and the channel scaffold, which has significant implications for channel function. NaK offers a distinct model to study the physiologically essential connection between ion conduction and channel gating.

  1. Apparent phosphorus availabilities of selected traditional and alternative feedstuffs for channel catfish

    USDA-ARS?s Scientific Manuscript database

    A digestibility trial with channel catfish Ictalurus punctatus was conducted to determine apparent availability coefficients (AACs) of phosphorus for selected common feedstuffs: soybean meal, cottonseed meal, wheat middlings, corn gluten feed (CGF), and corn distillers dried grains with solubles (DD...

  2. Calcium-independent K(+)-selective channel from chromaffin granule membranes.

    PubMed

    Arispe, N; Pollard, H B; Rojas, E

    1992-11-01

    Intact adrenal chromaffin granules and purified granule membrane ghosts were allowed to fuse with acidic phospholipid planar bilayer membranes in the presence of Ca2+ (1 mM). From both preparations, we were able to detect a large conductance potassium channel (ca. 160 pS in symmetrical 400 mM K+), which was highly selective for K+ over Na+ (PK/PNa = 11) as estimated from the reversal potential of the channel current. Channel activity was unaffected by charybdotoxin, a blocker of the [Ca2+]-activated K+ channel of large conductance. Furthermore, this channel proved quite different from the previously described channels from other types of secretory vesicle preparations, not only in its selectivity and conductance, but also in its insensitivity to both calcium and potential across the bilayer. We conclude that the chromaffin granule membrane contains a K(+)-selective channel with large conductance. We suggest that the role of this channel may include ion movement during granule assembly or recycling, and do not rule out events leading to exocytosis.

  3. Morpholin-2-one derivatives as novel selective T-type Ca2+ channel blockers.

    PubMed

    Ku, Il Whea; Cho, Sangwon; Doddareddy, Munikumar Reddy; Jang, Min Seok; Keum, Gyochang; Lee, Jung-Ha; Chung, Bong Young; Kim, Youseung; Rhim, Hyewhon; Kang, Soon Bang

    2006-10-01

    Morpholin-2-one-5-carboxamide derivatives were prepared by using the one-pot Ugi multicomponent reaction and evaluated for blocking effects on T- and N-type Ca(2+) channels. Among them, compound 5i produced the highest potency (IC(50)=0.45+/-0.02 microM), while compounds 5d, 5f, 5k, 5n, 5o, and 6m produced relatively high potency as well as selectivity on T-type Ca(2+) channels. These novel scaffolds showed potent and selective T-type Ca(2+) channel blocking activities.

  4. Study of Internal Channel Surface Roughnesses Manufactured by Selective Laser Melting in Aluminum and Titanium Alloys

    NASA Astrophysics Data System (ADS)

    Pakkanen, Jukka; Calignano, Flaviana; Trevisan, Francesco; Lorusso, Massimo; Ambrosio, Elisa Paola; Manfredi, Diego; Fino, Paolo

    2016-08-01

    Interest in additive manufacturing (AM) has gained considerable impetus over the past decade. One of the driving factors for AM success is the ability to create unique designs with intrinsic characteristics as, e.g., internal channels used for hydraulic components, cooling channels, and heat exchangers. However, a couple of the main problems in internal channels manufactured by AM technologies are the high surface roughness obtained and the distortion of the channel shape. There is still much to understand in these design aspects. In this study, a cylindrical geometry for internal channels to be built with different angles with respect to the building plane in AlSi10Mg and Ti6Al4V alloys by selective laser melting was considered. The internal surfaces of the channels produced in both materials were analyzed by means of a surface roughness tester and by optical and electron microscopy to evaluate the effects of the material and design choices.

  5. Altered ion channel conductance and ionic selectivity induced by large imposed membrane potential pulse.

    PubMed Central

    Chen, W; Lee, R C

    1994-01-01

    The effects of large magnitude transmembrane potential pulses on voltage-gated Na and K channel behavior in frog skeletal muscle membrane were studied using a modified double vaseline-gap voltage clamp. The effects of electroconformational damage to ionic channels were separated from damage to lipid bilayer (electroporation). A 4 ms transmembrane potential pulse of -600 mV resulted in a reduction of both Na and K channel conductivities. The supraphysiologic pulses also reduced ionic selectivity of the K channels against Na+ ions, resulting in a depolarization of the membrane resting potential. However, TTX and TEA binding effects were unaltered. The kinetics of spontaneous reversal of the electroconformational damage of channel proteins was found to be dependent on the magnitude of imposed membrane potential pulse. These results suggest that muscle and nerve dysfunction after electrical shock may be in part caused by electroconformational damage to voltage-gated ion channels. PMID:7948676

  6. Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

    PubMed Central

    Fujiwara, Yuichiro; Arrigoni, Cristina; Domigan, Courtney; Ferrara, Giuseppina; Pantoja, Carlos; Thiel, Gerhard; Moroni, Anna; Minor, Daniel L.

    2009-01-01

    Background Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features. PMID:19834614

  7. Enhancement of transport selectivity through nano-channels by non-specific competition.

    PubMed

    Zilman, Anton; Di Talia, Stefano; Jovanovic-Talisman, Tijana; Chait, Brian T; Rout, Michael P; Magnasco, Marcelo O

    2010-06-10

    The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a 'closed' to an 'open' state) and do not require a direct input of metabolic energy during transport. Nevertheless, these 'always open' channels are highly selective and pass only their cognate molecules, while efficiently excluding all others; indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such 'always open' channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena.

  8. Enhancement of Transport Selectivity through Nano-Channels by Non-Specific Competition

    PubMed Central

    Zilman, Anton; Di Talia, Stefano; Jovanovic-Talisman, Tijana; Chait, Brian T.; Rout, Michael P.; Magnasco, Marcelo O.

    2010-01-01

    The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a ‘closed’ to an ‘open’ state) and do not require a direct input of metabolic energy during transport. Nevertheless, these ‘always open’ channels are highly selective and pass only their cognate molecules, while efficiently excluding all others; indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such ‘always open’ channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena. PMID:20548778

  9. Doubly Rotated Cut SAW Devices.

    DTIC Science & Technology

    1980-06-01

    A D A O S G 7 3 A M T O R A I N C S C O T T S A L E A R I Z G V E R N M E N T E L C T R O N I C S I V F / B 2 0 / 2 DOUBLY ROTATED CUT SAW DEVICES...IEEEEI-/ II//E///III I jjj 5.1 -I I II II II F~ ~ 2, I UUGLASSIF1 U100TVw CLAMOGmeIawor OU I lulP&g EWhm oe ae & oubly Rotated Cut SAW Devices& . r...doubly rotated cuts of quartz possessing speri r Surface Acoustic Wave (SAW) properties for applications involving environmentally hardened devices. The

  10. The signatures of doubly charged leptons in future linear colliders

    NASA Astrophysics Data System (ADS)

    Guo, Yu-Chen; Yue, Chong-Xing; Liu, Zhi-Cheng

    2017-08-01

    We discuss the production of the doubly charged leptons in future linear electron positron colliders, such as the International Linear Collider and Compact Linear Collider. Such states are introduced in extended weak-isospin multiplets by composite models. We discuss the production cross section of {e}-γ \\to {L}--{W}+ and carry out analyses for hadronic, semi-leptonic and pure leptonic channels based on the full simulation performance of the silicon detector. The 3- and 5-sigma statistical significance exclusion curves are provided in the model parameter space. It is found that the hadronic channel could offer the most possible detectable signature.

  11. A novel channel selection method for multiple motion classification using high-density electromyography

    PubMed Central

    2014-01-01

    Background Selecting an appropriate number of surface electromyography (EMG) channels with desired classification performance and determining the optimal placement of EMG electrodes would be necessary and important in practical myoelectric control. In previous studies, several methods such as sequential forward selection (SFS) and Fisher-Markov selector (FMS) have been used to select the appropriate number of EMG channels for a control system. These exiting methods are dependent on either EMG features and/or classification algorithms, which means that when using different channel features or classification algorithm, the selected channels would be changed. In this study, a new method named multi-class common spatial pattern (MCCSP) was proposed for EMG selection in EMG pattern-recognition-based movement classification. Since MCCSP is independent on specific EMG features and classification algorithms, it would be more convenient for channel selection in developing an EMG control system than the exiting methods. Methods The performance of the proposed MCCSP method in selecting some optimal EMG channels (designated as a subset) was assessed with high-density EMG recordings from twelve mildly-impaired traumatic brain injury (TBI) patients. With the MCCSP method, a subset of EMG channels was selected and then used for motion classification with pattern recognition technique. In order to justify the performance of the MCCSP method against different electrode configurations, features and classification algorithms, two electrode configurations (unipolar and bipolar) as well as two EMG feature sets and two types of pattern recognition classifiers were considered in the study, respectively. And the performance of the proposed MCCSP method was compared with that of two exiting channel selection methods (SFS and FMS) in EMG control system. Results The results showed that in comparison with the previously used SFS and FMS methods, the newly proposed MCCSP method had better

  12. On Optimal Input Design and Model Selection for Communication Channels

    SciTech Connect

    Li, Yanyan; Djouadi, Seddik M; Olama, Mohammed M

    2013-01-01

    In this paper, the optimal model (structure) selection and input design which minimize the worst case identification error for communication systems are provided. The problem is formulated using metric complexity theory in a Hilbert space setting. It is pointed out that model selection and input design can be handled independently. Kolmogorov n-width is used to characterize the representation error introduced by model selection, while Gel fand and Time n-widths are used to represent the inherent error introduced by input design. After the model is selected, an optimal input which minimizes the worst case identification error is shown to exist. In particular, it is proven that the optimal model for reducing the representation error is a Finite Impulse Response (FIR) model, and the optimal input is an impulse at the start of the observation interval. FIR models are widely popular in communication systems, such as, in Orthogonal Frequency Division Multiplexing (OFDM) systems.

  13. Salting out the ionic selectivity of a wide channel: the asymmetry of OmpF.

    PubMed

    Alcaraz, Antonio; Nestorovich, Ekaterina M; Aguilella-Arzo, Marcel; Aguilella, Vicente M; Bezrukov, Sergey M

    2004-08-01

    Although the crystallographic structure of the bacterial porin OmpF has been known for a decade, the physical mechanisms of its ionic selectivity are still under investigation. We address this issue in a series of experiments with varied pH, salt concentrations, inverted salt gradient, and charged and uncharged lipids. Measuring reversal potential, we show that OmpF selectivity (traditionally regarded as slightly cationic) depends strongly on pH and salt concentration and is conditionally asymmetric, that is, the calculated selectivity is sensitive to the direction of salt concentration gradient. At neutral pH and subdecimolar salt concentrations the channel exhibits nearly ideal cation selectivity (t(G)(+)=0.98+/-0.01). Substituting neutral DPhPC with DPhPS, we demonstrate that the fixed charge of the host lipid has a small but measurable effect on the channel reversal potential. The available structural information allows for a qualitative explanation of our experimental findings. These findings now lead us to re-examine the ionization state of 102 titratable sites of the OmpF channel. Using standard methods of continuum electrostatics tailored to our particular purpose, we find the charge distribution in the channel as a function of solution acidity and relate the pH-dependent asymmetry in channel selectivity to the pH-dependent asymmetry in charge distribution. In an attempt to find a simple phenomenological description of our results, we also discuss different macroscopic models of electrodiffusion through large channels.

  14. OccK channels from Pseudomonas aeruginosa exhibit diverse single-channel electrical signatures but conserved anion selectivity.

    PubMed

    Liu, Jiaming; Eren, Elif; Vijayaraghavan, Jagamya; Cheneke, Belete R; Indic, Mridhu; van den Berg, Bert; Movileanu, Liviu

    2012-03-20

    Pseudomonas aeruginosa is a Gram-negative bacterium that utilizes substrate-specific outer membrane (OM) proteins for the uptake of small, water-soluble nutrients employed in the growth and function of the cell. In this paper, we present for the first time a comprehensive single-channel examination of seven members of the OM carboxylate channel K (OccK) subfamily. Recent biochemical, functional, and structural characterization of the OccK proteins revealed their common features, such as a closely related, monomeric, 18-stranded β-barrel conformation with a kidney-shaped transmembrane pore and the presence of a basic ladder within the channel lumen. Here, we report that the OccK proteins exhibited fairly distinct unitary conductance values, in a much broader range than previously expected, which includes low (~40-100 pS) and medium (~100-380 pS) conductance. These proteins showed diverse single-channel dynamics of current gating transitions, revealing one-open substate (OccK3), two-open substate (OccK4-OccK6), and three-open substate (OccK1, OccK2, and OccK7) kinetics with functionally distinct conformations. Interestingly, we discovered that anion selectivity is a conserved trait among the members of the OccK subfamily, confirming the presence of a net pool of positively charged residues within their central constriction. Moreover, these results are in accord with an increased specificity and selectivity of these protein channels for negatively charged, carboxylate-containing substrates. Our findings might ignite future functional examinations and full atomistic computational studies for unraveling a mechanistic understanding of the passage of small molecules across the lumen of substrate-specific, β-barrel OM proteins.

  15. Hysteresis of KcsA potassium channel's activation- deactivation gating is caused by structural changes at the channel's selectivity filter.

    PubMed

    Tilegenova, Cholpon; Cortes, D Marien; Cuello, Luis G

    2017-03-21

    Mode-shift or hysteresis has been reported in ion channels. Voltage-shift for gating currents is well documented for voltage-gated cation channels (VGCC), and it is considered a voltage-sensing domain's (VSD) intrinsic property. However, uncoupling the Shaker K(+) channel's pore domain (PD) from the VSD prevented the mode-shift of the gating currents. Consequently, it was proposed that an open-state stabilization of the PD imposes a mechanical load on the VSD, which causes its mode-shift. Furthermore, the mode-shift displayed by hyperpolarization-gated cation channels is likely caused by structural changes at the channel's PD similar to those underlying C-type inactivation. To demonstrate that the PD of VGCC undergoes hysteresis, it is imperative to study its gating process in the absence of the VSD. A back-door strategy is to use KcsA (a K(+) channel from the bacteria Streptomyces lividans) as a surrogate because it lacks a VSD and exhibits an activation coupled to C-type inactivation. By directly measuring KcsA's activation gate opening and closing in conditions that promote or halt C-type inactivation, we have found (i) that KcsA undergoes mode-shift of gating when having K(+) as the permeant ion; (ii) that Cs(+) or Rb(+), known to halt C-inactivation, prevented mode-shift of gating; and (iii) that, in the total absence of C-type inactivation, KcsA's mode-shift was prevented. Finally, our results demonstrate that an allosteric communication causes KcsA's activation gate to "remember" the conformation of the selectivity filter, and hence KcsA requires a different amount of energy for opening than for closing.

  16. Single voltage-dependent chloride-selective channels of large conductance in cultured rat muscle.

    PubMed Central

    Blatz, A L; Magleby, K L

    1983-01-01

    Single-channel currents of an anion-selective channel in the plasma membrane of cultured rat muscle cells (myotubes) were recorded with the patch-clamp technique (Hamill, O.P., A. Marty, E. Neher, B. Sakmann, and F.J. Sigworth, 1981. Pfluegers Arch. Eur. J. Physiol., 391:85-100). The channel is selective for Cl- over cations, and has an unusually large single-channel conductance of approximately 430 pS in symmetrical 143 mM KCl. The channel is often active at 0 mV, opening and closing spontaneously. When active, steps from 0 mV to either negative or positive membrane potentials close the channel to an apparent inactivated state. The mean effective time that a channel is open before it inactivates is approximately 1.19 s for steps to -30 mV and 0.48 s for steps to +30 mV. Returning the membrane potential to 0 mV results in recovery from inactivation. Calcium ions are not required for channel activity. PMID:6311302

  17. Selectivities of dihydropyridine derivatives in blocking Ca(2+) channel subtypes expressed in Xenopus oocytes.

    PubMed

    Furukawa, T; Yamakawa, T; Midera, T; Sagawa, T; Mori, Y; Nukada, T

    1999-11-01

    Some dihydropyridines (DHPs), such as amlodipine and cilnidipine, have been shown to block not only L-type but also N-type Ca(2+) channels; therefore, DHPs are no longer considered as L-type-specific Ca(2+) channel blockers. However, selectivity of DHPs for Ca(2+) channel subtypes including N-, P/Q-, and R-types are poorly understood. To address this issue at the molecular level, blocking effects of 10 DHPs (nifedipine, nilvadipine, barnidipine, nimodipine, nitrendipine, amlodipine, nicardipine, benidipine, felodipine, and cilnidipine) on four subtypes of Ca(2+) channels (L-, N-, P/Q-, and R-types) were investigated in the Xenopus oocyte expression system with the use of the two-microelectrode voltage-clamp technique. L-type Ca(2+) channels expressed as alpha(1C)alpha(2)beta(1a) combination were profoundly blocked by all DHPs examined, whereas blocking actions of these DHPs on R-type (alpha(1E)alpha(2)beta(1a)) channels were equally weak. In contrast, 5 of the 10 DHPs (amlodipine, benidipine, cilnidipine, nicardipine, and barnidipine) significantly blocked N-type (alpha(1B)alpha(2)beta(1a)) and P/Q-type (alpha(1A)alpha(2)beta(1a)) Ca(2+) channels. These selectivities of DHPs in blocking Ca(2+) channel subtypes would provide useful pharmacological and clinical information on the mode of action of the drugs including side effects and adverse effects.

  18. Picomolar, selective and subtype specific small-molecule inhibition of TRPC1/4/5 channels.

    PubMed

    Rubaiy, Hussein N; Ludlow, Melanie J; Henrot, Matthias; Gaunt, Hannah J; Miteva, Katarina; Cheung, Sin Yin; Tanahashi, Yasuyuki; Hamzah, Nurasyikin; Musialowski, Katie E; Blythe, Nicola M; Appleby, Hollie L; Bailey, Marc A; McKeown, Lynn; Taylor, Roger; Foster, Richard; Waldmann, Herbert; Nussbaumer, Peter; Christmann, Mathias; Bon, Robin S; Muraki, Katsuhiko; Beech, David J

    2017-03-21

    The concentration of free cytosolic Ca(2+) and the voltage across the plasma membrane are major determinants of cell function. Ca(2+)-permeable non-selective cationic channels are known to regulate these parameters but understanding of these channels remains inadequate. Here we focus on Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) which assemble as homomers or heteromerize with TRPC1 to form Ca(2+)-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested including in epilepsy, innate fear, pain and cardiac remodeling but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools which are high-quality, reliable, easy to use and readily accessible for all investigators. Here, through chemical synthesis and studies of native and over-expressed channels by Ca(2+) and patch-clamp assays, we describe compound 31 (C31), a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pM, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8 and store-operated Ca(2+) entry mediated by Orai1. These findings suggest identification of an important experimental tool compound which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.

  19. Alternative splicing switches the divalent cation selectivity of TRPM3 channels.

    PubMed

    Oberwinkler, Johannes; Lis, Annette; Giehl, Klaus M; Flockerzi, Veit; Philipp, Stephan E

    2005-06-10

    TRPM3 is a poorly understood member of the large family of transient receptor potential (TRP) ion channels. Here we describe five novel splice variants of TRPM3, TRPM3alpha1-5. These variants are characterized by a previously unknown amino terminus of 61 residues. The differences between the five variants arise through splice events at three different sites. One of these splice sites might be located in the pore region of the channel as indicated by sequence alignment with other, better-characterized TRP channels. We selected two splice variants, TRPM3alpha1 and TRPM3alpha2, that differ only in this presumed pore region and analyzed their biophysical characteristics after heterologous expression in human embryonic kidney 293 cells. TRPM3alpha1 as well as TRPM3alpha2 induced a novel, outwardly rectifying cationic conductance that was tightly regulated by intracellular Mg(2+). However, these two variants are highly different in their ionic selectivity. Whereas TRPM3alpha1-encoded channels are poorly permeable for divalent cations, TRPM3alpha2-encoded channels are well permeated by Ca(2+) and Mg(2+). Additionally, we found that currents through TRPM3alpha2 are blocked by extracellular monovalent cations, whereas currents through TRPM3alpha1 are not. These differences unambiguously show that TRPM3 proteins constitute a pore-forming channel subunit and localize the position of the ion-conducting pore within the TRPM3 protein. Although the ionic selectivity of ion channels has traditionally been regarded as rather constant for a given channel-encoding gene, our results show that alternative splicing can be a mechanism to produce channels with very different selectivity profiles.

  20. Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels

    PubMed Central

    Xia, Mengdie

    2016-01-01

    Voltage-gated sodium (Nav) channels are critical in the generation and transmission of neuronal signals in mammals. The crystal structures of several prokaryotic Nav channels determined in recent years inspire the mechanistic studies on their selection upon the permeable cations (especially between Na+ and K+ ions), a property that is proposed to be mainly determined by residues in the selectivity filter. However, the mechanism of cation selection in mammalian Nav channels lacks direct explanation at atomic level due to the difference in amino acid sequences between mammalian and prokaryotic Nav homologues, especially at the constriction site where the DEKA motif has been identified to determine the Na+/K+ selectivity in mammalian Nav channels but is completely absent in the prokaryotic counterparts. Among the DEKA residues, Lys is of the most importance since its mutation to Arg abolishes the Na+/K+ selectivity. In this work, we modeled the pore domain of mammalian Nav channels by mutating the four residues at the constriction site of a prokaryotic Nav channel (NavRh) to DEKA, and then mechanistically investigated the contribution of Lys in cation selection using molecular dynamics simulations. The DERA mutant was generated as a comparison to understand the loss of ion selectivity caused by the K-to-R mutation. Simulations and free energy calculations on the mutants indicate that Lys facilitates Na+/K+ selection by electrostatically repelling the cation to a highly Na+-selective location sandwiched by the carboxylate groups of Asp and Glu at the constriction site. In contrast, the electrostatic repulsion is substantially weakened when Lys is mutated to Arg, because of two intrinsic properties of the Arg side chain: the planar geometric design and the sparse charge distribution of the guanidine group. PMID:27584582

  1. Conversion of aquaporin 6 from an anion channel to a water-selective channel by a single amino acid substitution

    PubMed Central

    Liu, Kun; Kozono, David; Kato, Yasuhiro; Agre, Peter; Hazama, Akihiro; Yasui, Masato

    2005-01-01

    Aquaporin (AQP) 6 belongs to the aquaporin water channel family. Unlike other aquaporins, AQP6 functions not as a water channel but as an anion-selective channel. Single-channel analyses have shown AQP6 to flicker rapidly between closed and open status. The atomic structure of AQP1 and amino acid sequence alignments of the mammalian aquaporins reveal two well conserved glycine residues: Gly-57 in transmembrane helix (TM) 2 and Gly-173 in TM5 reside at the contact point where the two helices cross in human AQP1. Uniquely, all known mammalian orthologs of AQP6 have an asparagine residue (Asn-60) at the position corresponding to Gly-57. Here we show that a single residue substitution (N60G in rat AQP6) totally eliminates the anion permeability of AQP6 when expressed in Xenopus oocytes, but the N60G oocytes exhibit significantly higher osmotic water permeability under basal conditions. Replacement of the glycine at this site in AQP0, AQP1, and AQP2 blocked expression of the mutants at the oocyte plasma membrane. We propose that the asparagine residue at the contact point between TM2 and TM5 in AQP6 may function as a teeter board needed for rapid structural oscillations during anion permeation. PMID:15671159

  2. Conversion of aquaporin 6 from an anion channel to a water-selective channel by a single amino acid substitution.

    PubMed

    Liu, Kun; Kozono, David; Kato, Yasuhiro; Agre, Peter; Hazama, Akihiro; Yasui, Masato

    2005-02-08

    Aquaporin (AQP) 6 belongs to the aquaporin water channel family. Unlike other aquaporins, AQP6 functions not as a water channel but as an anion-selective channel. Single-channel analyses have shown AQP6 to flicker rapidly between closed and open status. The atomic structure of AQP1 and amino acid sequence alignments of the mammalian aquaporins reveal two well conserved glycine residues: Gly-57 in transmembrane helix (TM) 2 and Gly-173 in TM5 reside at the contact point where the two helices cross in human AQP1. Uniquely, all known mammalian orthologs of AQP6 have an asparagine residue (Asn-60) at the position corresponding to Gly-57. Here we show that a single residue substitution (N60G in rat AQP6) totally eliminates the anion permeability of AQP6 when expressed in Xenopus oocytes, but the N60G oocytes exhibit significantly higher osmotic water permeability under basal conditions. Replacement of the glycine at this site in AQP0, AQP1, and AQP2 blocked expression of the mutants at the oocyte plasma membrane. We propose that the asparagine residue at the contact point between TM2 and TM5 in AQP6 may function as a teeter board needed for rapid structural oscillations during anion permeation.

  3. A Wearable Channel Selection-Based Brain-Computer Interface for Motor Imagery Detection

    PubMed Central

    Lo, Chi-Chun; Chien, Tsung-Yi; Chen, Yu-Chun; Tsai, Shang-Ho; Fang, Wai-Chi; Lin, Bor-Shyh

    2016-01-01

    Motor imagery-based brain-computer interface (BCI) is a communication interface between an external machine and the brain. Many kinds of spatial filters are used in BCIs to enhance the electroencephalography (EEG) features related to motor imagery. The approach of channel selection, developed to reserve meaningful EEG channels, is also an important technique for the development of BCIs. However, current BCI systems require a conventional EEG machine and EEG electrodes with conductive gel to acquire multi-channel EEG signals and then transmit these EEG signals to the back-end computer to perform the approach of channel selection. This reduces the convenience of use in daily life and increases the limitations of BCI applications. In order to improve the above issues, a novel wearable channel selection-based brain-computer interface is proposed. Here, retractable comb-shaped active dry electrodes are designed to measure the EEG signals on a hairy site, without conductive gel. By the design of analog CAR spatial filters and the firmware of EEG acquisition module, the function of spatial filters could be performed without any calculation, and channel selection could be performed in the front-end device to improve the practicability of detecting motor imagery in the wearable EEG device directly or in commercial mobile phones or tablets, which may have relatively low system specifications. Finally, the performance of the proposed BCI is investigated, and the experimental results show that the proposed system is a good wearable BCI system prototype. PMID:26861347

  4. A Wearable Channel Selection-Based Brain-Computer Interface for Motor Imagery Detection.

    PubMed

    Lo, Chi-Chun; Chien, Tsung-Yi; Chen, Yu-Chun; Tsai, Shang-Ho; Fang, Wai-Chi; Lin, Bor-Shyh

    2016-02-06

    Motor imagery-based brain-computer interface (BCI) is a communication interface between an external machine and the brain. Many kinds of spatial filters are used in BCIs to enhance the electroencephalography (EEG) features related to motor imagery. The approach of channel selection, developed to reserve meaningful EEG channels, is also an important technique for the development of BCIs. However, current BCI systems require a conventional EEG machine and EEG electrodes with conductive gel to acquire multi-channel EEG signals and then transmit these EEG signals to the back-end computer to perform the approach of channel selection. This reduces the convenience of use in daily life and increases the limitations of BCI applications. In order to improve the above issues, a novel wearable channel selection-based brain-computer interface is proposed. Here, retractable comb-shaped active dry electrodes are designed to measure the EEG signals on a hairy site, without conductive gel. By the design of analog CAR spatial filters and the firmware of EEG acquisition module, the function of spatial filters could be performed without any calculation, and channel selection could be performed in the front-end device to improve the practicability of detecting motor imagery in the wearable EEG device directly or in commercial mobile phones or tablets, which may have relatively low system specifications. Finally, the performance of the proposed BCI is investigated, and the experimental results show that the proposed system is a good wearable BCI system prototype.

  5. Channels

    NASA Image and Video Library

    2014-04-29

    Two channels are visible in this image from NASA 2001 Mars Odyssey spacecraft . The smaller one near the bottom did not carve as deeply as the larger channel at the top. The channel near the top of the image is near the origin of Mamers Valles.

  6. Evoked potential correlates of selective attention with multi-channel auditory inputs

    NASA Technical Reports Server (NTRS)

    Schwent, V. L.; Hillyard, S. A.

    1975-01-01

    Ten subjects were presented with random, rapid sequences of four auditory tones which were separated in pitch and apparent spatial position. The N1 component of the auditory vertex evoked potential (EP) measured relative to a baseline was observed to increase with attention. It was concluded that the N1 enhancement reflects a finely tuned selective attention to one stimulus channel among several concurrent, competing channels. This EP enhancement probably increases with increased information load on the subject.

  7. Evoked potential correlates of selective attention with multi-channel auditory inputs

    NASA Technical Reports Server (NTRS)

    Schwent, V. L.; Hillyard, S. A.

    1975-01-01

    Ten subjects were presented with random, rapid sequences of four auditory tones which were separated in pitch and apparent spatial position. The N1 component of the auditory vertex evoked potential (EP) measured relative to a baseline was observed to increase with attention. It was concluded that the N1 enhancement reflects a finely tuned selective attention to one stimulus channel among several concurrent, competing channels. This EP enhancement probably increases with increased information load on the subject.

  8. Non-selective voltage-activated cation channel in the human red blood cell membrane.

    PubMed

    Kaestner, L; Bollensdorff, C; Bernhardt, I

    1999-02-04

    Using the patch-clamp technique, a non-selective voltage-activated Na+ and K+ channel in the human red blood cell membrane was found. The channel operates only at positive membrane potentials from about +30 mV (inside positive) onwards. For sodium and potassium ions, similar conductances of about 21 pS were determined. Together with the recently described K+(Na+)/H+ exchanger, this channel is responsible for the increase of residual K+ and Na+ fluxes across the human red blood cell membrane when the cells are suspended in low ionic strength medium.

  9. The mechanosensory calcium-selective ion channel: key component of a plasmalemmal control centre?

    NASA Technical Reports Server (NTRS)

    Pickard, B. G.; Ding, J. P.

    1993-01-01

    Mechanosensory calcium-selective ion channels probably serve to detect not only mechanical stress but also electrical, thermal, and diverse chemical stimuli. Because all stimuli result in a common output, most notably a shift in second messenger calcium concentration, the channels are presumed to serve as signal integrators. Further, insofar as second messenger calcium in turn gives rise to mechanical, electrical, and diverse chemical changes, the channels are postulated to initiate regulatory feedbacks. It is proposed that the channels and the feedback loops play a wide range of roles in regulating normal plant function, as well as in mediating disturbance of normal function by environmental stressors and various pathogens. In developing evidence for the physiological performance of the channel, a model for a cluster of regulatory plasmalemmal proteins and cytoskeletal elements grouped around a set of wall-to-membrane and transmembrane linkers has proved useful. An illustration of how the model might operate is presented. It is founded on the demonstration that several xenobiotics interfere both with normal channel behaviour and with gravitropic reception. Accordingly, the first part of the illustration deals with how the channels and the control system within which they putatively operate might initiate gravitropism. Assuming that gravitropism is an asymmetric expression of growth, the activities of the channels and the plasmalemmal control system are extrapolated to account for regulation of both rate and allometry of cell expansion. Finally, it is discussed how light, hormones, redox agents and herbicides could in principle affect growth via the putative plasmalemmal control cluster or centre.

  10. The mechanosensory calcium-selective ion channel: key component of a plasmalemmal control centre?

    NASA Technical Reports Server (NTRS)

    Pickard, B. G.; Ding, J. P.

    1993-01-01

    Mechanosensory calcium-selective ion channels probably serve to detect not only mechanical stress but also electrical, thermal, and diverse chemical stimuli. Because all stimuli result in a common output, most notably a shift in second messenger calcium concentration, the channels are presumed to serve as signal integrators. Further, insofar as second messenger calcium in turn gives rise to mechanical, electrical, and diverse chemical changes, the channels are postulated to initiate regulatory feedbacks. It is proposed that the channels and the feedback loops play a wide range of roles in regulating normal plant function, as well as in mediating disturbance of normal function by environmental stressors and various pathogens. In developing evidence for the physiological performance of the channel, a model for a cluster of regulatory plasmalemmal proteins and cytoskeletal elements grouped around a set of wall-to-membrane and transmembrane linkers has proved useful. An illustration of how the model might operate is presented. It is founded on the demonstration that several xenobiotics interfere both with normal channel behaviour and with gravitropic reception. Accordingly, the first part of the illustration deals with how the channels and the control system within which they putatively operate might initiate gravitropism. Assuming that gravitropism is an asymmetric expression of growth, the activities of the channels and the plasmalemmal control system are extrapolated to account for regulation of both rate and allometry of cell expansion. Finally, it is discussed how light, hormones, redox agents and herbicides could in principle affect growth via the putative plasmalemmal control cluster or centre.

  11. Doubly Rotated Cut SAW Devices.

    DTIC Science & Technology

    1982-01-01

    A O-AIIO 663 NOTO AOI.A INC SCOTTS A LEJ AZ S0V RNmF.NT ELECTRONICS DV F/S WI1 DOUBLY ROTATED CUT SAV DEVICES.(U) JAN 82 D F WIL.IANMS F T CHO DAK20...quartz substrates for the purpose of locating promising angular ranges with properties superior to the singly rotated cuts now in existence More...detailed calculations follow to refine the angular coordinates in order to specify cuts for experimental erification in Task I1. In Task II, sets of

  12. Demonstration of arbitrary channel selection utilizing a pulse-injected semiconductor laser with a phase-locked loop.

    PubMed

    Juan, Yu-Shan; Lin, Fan-Yi

    2011-01-17

    An arbitrary channel selection system based on a pulse-injected semiconductor laser with a phase-locked loop (PLL) is experimentally demonstrated and characterized. Through optical injection from a tunable laser, channels formed by the frequency components of a microwave frequency comb generated in the pulse-injected semiconductor laser are individually selected and enhanced. Selections of a primary channel at the fundamental frequency of 1.2 GHz and a secondary channel in a range from 10.8 to 18 GHz are shown, where the selection is done by adjusting the injection strength from the tunable laser. Suppression ratios of 44.5 and 25.9 dB between the selected primary and secondary channels to the averaged magnitude of the unwanted channels are obtained, respectively. To show the spectral quality of the pulse-injected laser, a single sideband (SSB) phase noise of -60 dBc/kHz at an offset frequency of 25 kHz is measured. Moreover, the conversion gain between the primary and secondary channels and the crosstalk between the selected channels to the adjacent unwanted channels are also investigated. Without the need of expensive external modulators, arbitrary channel selection is realized in the proposed system where the channel spacing and selection can be continuously adjusted through tuning the controllable laser parameters.

  13. Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

    PubMed Central

    Finol-Urdaneta, Rocio K.; Wang, Yibo; Al-Sabi, Ahmed; Zhao, Chunfeng

    2014-01-01

    Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) and asymmetric, bi-ionic reversal potentials when the Na/K gradient is reversed. We performed coordinated experimental and computational studies, respectively, on the prokaryotic Nav channels NaChBac and NavAb. NaChBac shows an “anomalous,” nonmonotonic mole-fraction dependence in the presence of certain sodium–potassium mixtures; to our knowledge, no comparable observation has been reported for eukaryotic Nav channels. NaChBac’s preferential selectivity for sodium is reduced either by partial titration of its highly charged selectivity filter, when extracellular pH is lowered from 7.4 to 5.8, or by perturbation—likely steric—associated with a nominally electro-neutral substitution in the selectivity filter (E191D). Although no single molecular feature or energetic parameter appears to dominate, our atomistic simulations, based on the published NavAb crystal structure, revealed factors that may contribute to the normally observed selectivity for Na over K. These include: (a) a thermodynamic penalty to exchange one K+ for one Na+ in the wild-type (WT) channel, increasing the relative likelihood of Na+ occupying the binding site; (b) a small tendency toward weaker ion binding to the selectivity filter in Na–K mixtures, consistent with the higher conductance observed with both sodium and potassium present; and (c) integrated 1-D potentials of mean force for sodium or potassium movement that show less separation for the less selective E/D mutant than for WT. Overall, tight binding of a single favored ion to the selectivity filter, together with crucial inter-ion interactions within the pore

  14. Sodium channel selectivity and conduction: prokaryotes have devised their own molecular strategy.

    PubMed

    Finol-Urdaneta, Rocio K; Wang, Yibo; Al-Sabi, Ahmed; Zhao, Chunfeng; Noskov, Sergei Y; French, Robert J

    2014-02-01

    Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) and asymmetric, bi-ionic reversal potentials when the Na/K gradient is reversed. We performed coordinated experimental and computational studies, respectively, on the prokaryotic Nav channels NaChBac and NavAb. NaChBac shows an "anomalous," nonmonotonic mole-fraction dependence in the presence of certain sodium-potassium mixtures; to our knowledge, no comparable observation has been reported for eukaryotic Nav channels. NaChBac's preferential selectivity for sodium is reduced either by partial titration of its highly charged selectivity filter, when extracellular pH is lowered from 7.4 to 5.8, or by perturbation-likely steric-associated with a nominally electro-neutral substitution in the selectivity filter (E191D). Although no single molecular feature or energetic parameter appears to dominate, our atomistic simulations, based on the published NavAb crystal structure, revealed factors that may contribute to the normally observed selectivity for Na over K. These include: (a) a thermodynamic penalty to exchange one K(+) for one Na(+) in the wild-type (WT) channel, increasing the relative likelihood of Na(+) occupying the binding site; (b) a small tendency toward weaker ion binding to the selectivity filter in Na-K mixtures, consistent with the higher conductance observed with both sodium and potassium present; and (c) integrated 1-D potentials of mean force for sodium or potassium movement that show less separation for the less selective E/D mutant than for WT. Overall, tight binding of a single favored ion to the selectivity filter, together with crucial inter-ion interactions within the pore, suggests

  15. High spin spectroscopy near the N=Z line: Channel selection and excitation energy systematics

    SciTech Connect

    Svensson, C.E.; Cameron, J.A.; Flibotte, S.

    1996-12-31

    The total {gamma}-ray and charged-particle energies emitted in fusion-evaporation reactions leading to N=Z compound systems in the A = 50-70 mass region have been measured with the 8{pi} {gamma}-ray spectrometer and the miniball charged-particle detector array. A new method of channel selection has been developed which combines particle identification with these total energy measurements and greatly improves upon the selectivity possible with particle detection alone. In addition, the event by event measurement of total {gamma}-ray energies using the BGO ball of the 8{pi} spectrometer has allowed a determination of excitation energies following particle evaporation for a large number of channels in several different reactions. The new channel selection procedure and excitation energy systematics are illustrated with data from the reaction of {sup 24}Mg on {sup 40}Ca at E{sub lab} = 80MeV.

  16. Autocrine-Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries.

    PubMed

    Zhang, Hongkai; Du, Mingjuan; Xie, Jia; Liu, Xiao; Sun, Jingying; Wang, Wei; Xin, Xiu; Possani, Lourival D; Yea, Kyungmoo; Lerner, Richard A

    2016-08-01

    Animal venoms represent a rich source of pharmacologically active peptides that interact with ion channels. However, a challenge to discovering drugs remains because of the slow pace at which venom peptides are discovered and refined. An efficient autocrine-based high-throughput selection system was developed to discover and refine venom peptides that target ion channels. The utility of this system was demonstrated by the discovery of novel Kv1.3 channel blockers from a natural venom peptide library that was formatted for autocrine-based selection. We also engineered a Kv1.3 blocker peptide (ShK) derived from sea anemone to generate a subtype-selective Kv1.3 blocker with a long half-life in vivo.

  17. Structural and Thermodynamic Properties of Selective Ion Binding in a K+ Channel

    PubMed Central

    Lockless, Steve W; Zhou, Ming; MacKinnon, Roderick

    2007-01-01

    Thermodynamic measurements of ion binding to the Streptomyces lividans K+ channel were carried out using isothermal titration calorimetry, whereas atomic structures of ion-bound and ion-free conformations of the channel were characterized by x-ray crystallography. Here we use these assays to show that the ion radius dependence of selectivity stems from the channel's recognition of ion size (i.e., volume) rather than charge density. Ion size recognition is a function of the channel's ability to adopt a very specific conductive structure with larger ions (K+, Rb+, Cs+, and Ba2+) bound and not with smaller ions (Na+, Mg2+, and Ca2+). The formation of the conductive structure involves selectivity filter atoms that are in direct contact with bound ions as well as protein atoms surrounding the selectivity filter up to a distance of 15 Å from the ions. We conclude that ion selectivity in a K+ channel is a property of size-matched ion binding sites created by the protein structure. PMID:17472437

  18. Selectivity and permeation in calcium release channel of cardiac muscle: alkali metal ions.

    PubMed Central

    Chen, D P; Xu, L; Tripathy, A; Meissner, G; Eisenberg, B

    1999-01-01

    Current was measured from single open channels of the calcium release channel (CRC) of cardiac sarcoplasmic reticulum (over the range +/-180 mV) in pure and mixed solutions (e.g., biionic conditions) of the alkali metal ions Li+, K+, Na+, Rb+, Cs+, ranging in concentration from 25 mM to 2 M. The current-voltage (I-V) relations were analyzed by an extension of the Poisson-Nernst-Planck (PNP) formulation of electrodiffusion, which includes local chemical interaction described by an offset in chemical potential, which likely reflects the difference in dehydration/solvation/rehydration energies in the entry/exit steps of permeation. The theory fits all of the data with few adjustable parameters: the diffusion coefficient of each ion species, the average effective charge distribution on the wall of the pore, and an offset in chemical potential for lithium and sodium ions. In particular, the theory explains the discrepancy between "selectivities" defined by conductance sequence and "selectivities" determined by the permeability ratios (i.e., reversal potentials) in biionic conditions. The extended PNP formulation seems to offer a successful combined treatment of selectivity and permeation. Conductance selectivity in this channel arises mostly from friction: different species of ions have different diffusion coefficients in the channel. Permeability selectivity of an ion is determined by its electrochemical potential gradient and local chemical interaction with the channel. Neither selectivity (in CRC) seems to involve different electrostatic interaction of different ions with the channel protein, even though the ions have widely varying diameters. PMID:10049318

  19. Molecular strategies to achieve selective conductance in NaK channel variants.

    PubMed

    Wang, Yibo; Chamberlin, Adam C; Noskov, Sergei Yu

    2014-02-27

    A recent crystallization of several ion channels has provided strong impetus for efforts aimed at understanding the different strategies employed by nature for selective ion transport. In this work, we used two variants of the selectivity filter of NaK channel to explore molecular mechanisms that give rise to K(+)-selectivity. We computed one-dimensional (1D) and two-dimensional (2D) potentials of mean force (PMFs) for ion permeation across the channel. The results indicate that the energies for Na(+) and K(+) permeation across the selectivity filter display significant differences in positions of the binding sites and barriers. One characteristic signature of a K(+)-selective channel is the apparent preservation of the site analogous to that of S2 in KcsA. The S2-bound ion can be almost ideally dehydrated and coordinated by 6 to 8 carbonyls. In a striking contrast, the PMFs controlling transport of ions in a nonselective variant show almost identical profiles for either K(+) or Na(+) and significant involvement of water molecules in ion coordination across the entire selectivity filter. An analysis of differences in 1D PMFs for Na(+) and K(+) suggests that coordination number alone is an insufficient predictor of site selectivity, while chemical composition (ratio of carbonyls and water molecules) correlates well with preference for K(+). Multi-ion effects such as dependence of the barriers and wells for permeant ion on the type of copermeant ion were found to play a significant role in the selectivity signature of the channel as well.

  20. Reconstitution and regulation of cation-selective channels from cardiac sarcoplasmic reticulum.

    PubMed

    Rousseau, E; Chabot, H; Beaudry, C; Muller, B

    1992-09-08

    In order to study the conductances of the Sarcoplasmic Reticulum (SR) membrane, microsomal fractions from cardiac SR were isolated by differential and sucrose gradient centrifugations and fused into planar lipid bilayers (PLB) made of phospholipids. Using either KCl or K-gluconate solutions, a large conducting K+ selective channel was characterized by its ohmic conductance (152 pS in 150 mM K+), and the presence of short and long lasting subconducting states. Its open probability Po increased with depolarizing voltages, thus supporting the idea that this channel might allow counter-charge movements of monovalent cations during rapid SR Ca2+ release. An heterogeneity in the kinetic behavior of this channel would suggest that the cardiac SR K+ channels might be regulated by cytoplasmic, luminal, or intra SR membrane biochemical mechanisms. Since the behavior was not modified by variations of [Ca2+] nor by the addition of soluble metabolites such as ATP, GTP, cAMP, cGMP, nor by phosphorylation conditions on both sides of the PLB, a specific interaction with a SR membrane component is postulated. Another cation selective channel was studied in asymmetric Ca2+, Ba2+ or Mg(2+)-HEPES buffers. This channel displayed large conductance values for the above divalent cations 90, 100, and 40 pS, respectively. This channel was activated by microM Ca2+ while its Ca2+ sensitivity was potentiated by millimolar ATP. However Mg2+ and calmodulin modulated its gating behavior. Ca2+ releasing drugs such as caffeine and ryanodine increased its Po. All these features are characteristics of the SR Ca2+ release channel. The ryanodine receptor which has been purified and reconstituted into PLB, may form a cation selective pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Low-Complexity User Selection for Rate Maximization in MIMO Broadcast Channels with Downlink Beamforming

    PubMed Central

    Silva, Adão; Gameiro, Atílio

    2014-01-01

    We present in this work a low-complexity algorithm to solve the sum rate maximization problem in multiuser MIMO broadcast channels with downlink beamforming. Our approach decouples the user selection problem from the resource allocation problem and its main goal is to create a set of quasiorthogonal users. The proposed algorithm exploits physical metrics of the wireless channels that can be easily computed in such a way that a null space projection power can be approximated efficiently. Based on the derived metrics we present a mathematical model that describes the dynamics of the user selection process which renders the user selection problem into an integer linear program. Numerical results show that our approach is highly efficient to form groups of quasiorthogonal users when compared to previously proposed algorithms in the literature. Our user selection algorithm achieves a large portion of the optimum user selection sum rate (90%) for a moderate number of active users. PMID:24574928

  2. The Doubly Exceptional Child: A Principal's Dilemma.

    ERIC Educational Resources Information Center

    Kesner, Rebecca J., Ed.

    2002-01-01

    This document contains two articles concerned with doubly exceptional children and gifted education. In "The Doubly Exceptional Child: A Principal's Dilemma," (Carol J. Mills and Linda E. Brody), such children do not fit into the usual categories for sorting children because their gifts and disabilities often mask each other. Suggestions are…

  3. Reduced Complexity in Antenna Selection for Polarized MIMO System with SVD for the Practical MIMO Communication Channel Environment

    NASA Astrophysics Data System (ADS)

    Sann Maw, Maung; Sasase, Iwao

    In the conventional multi-input multi-output (MIMO) communication systems, most of the antenna selection methods considered are suitable only for spatially separated uni-polarized system under Rayleigh fading channel in non-line of sight (NLOS) condition. There have a few antenna selection schemes for the cross-polarized system in LOS condition and Ricean fading channel, and no antenna selection scheme for the MIMO channel with both LOS and NLOS. In the practical MIMO channel case, influence of LOS and NLOS conditions in the channel can vary from time to time according to the channel parameters and user movement in the system. Based on these influences and channel condition, uni-polarized system may outperform a cross-polarized. Thus, we should consider this kind of practical MIMO channel environment when developing the antenna selection scheme. Moreover, no research work has been done on reducing the complexity of antenna selection for this kind of practical MIMO channel environment. In this paper, reduced complexity in antenna selection is proposed to give the higher throughput in the practical MIMO channel environment. In the proposed scheme, suitable polarized antennas are selected based on the calculation of singular value decomposition (SVD) of channel matrix and then adaptive bit loading is applied. Simulation results show that throughput of the system can be improved under the constraint of target BER and total transmit power of the MIMO system.

  4. Comparison of the single channel and multichannel (multivariate) concepts of selectivity in analytical chemistry.

    PubMed

    Dorkó, Zsanett; Verbić, Tatjana; Horvai, George

    2015-07-01

    Different measures of selectivity are in use for single channel and multichannel linear analytical measurements, respectively. It is important to understand that these two measures express related but still distinctly different features of the respective measurements. These relationships are clarified by introducing new arguments. The most widely used selectivity measure of multichannel linear methods (which is based on the net analyte signal, NAS, concept) expresses the sensitivity to random errors of a determination where all bias from interferents is computationally eliminated using pure component spectra. The conventional selectivity measure of single channel linear measurements, on the other hand, helps to estimate the bias caused by an interferent in a biased measurement. In single channel methods expert knowledge about the samples is used to limit the possible range of interferent concentrations. The same kind of expert knowledge allows improved (lower mean squared error, MSE) analyte determinations also in "classical" multichannel measurements if those are intractable due to perfect collinearity or to high noise inflation. To achieve this goal bias variance tradeoff is employed, hence there remains some bias in the results and therefore the concept of single channel selectivity can be extended in a natural way to multichannel measurements. This extended definition and the resulting selectivity measure can also be applied to the so-called inverse multivariate methods like partial least squares regression (PLSR), principal component regression (PCR) and ridge regression (RR).

  5. Selective blockade of T-type Ca2+ channels suppresses human breast cancer cell proliferation.

    PubMed

    Taylor, James T; Huang, Luping; Pottle, Jonathan E; Liu, Kai; Yang, Yali; Zeng, Xiangbin; Keyser, Brian M; Agrawal, Krishna C; Hansen, J Bondo; Li, Ming

    2008-08-18

    We have measured the expression of T-type Ca2+ channel mRNA in breast cancer cell lines (MCF-7 (ERalpha+) using Western blot and quantitative real-time PCR (Q-RT-PCR). These results revealed that the MCF-7 cells express both alpha1G and alpha1H isoforms of T-type Ca2+ channels. In order to further clarify the role of T-type Ca2+ channels in proliferation, we tested the effects of a selective T-type Ca2+ channel inhibitor NNC-55-0396 on cellular proliferation. MCF-7 (ERalpha+) cellular proliferation was inhibited by the compound. In contrast, NNC-55-0396 at same concentration had no effect on the proliferation of MCF-10A cells, a non-cancer breast epithelial cell line. We also found that message expression of the T-type Ca2+ channels were only expressed in rapidly growing non-confluent cells but not in the cytostatic confluent cells. Knocking down the expression of T-type Ca2+ channels with siRNA targeting both alpha1G and alpha1H resulted in growth inhibition as much as 45%+/-5.0 in MCF-7 cells as compared to controls. In conclusion, our results suggest that T-type Ca2+ channel antagonism/silencing may reduce cellular proliferation in mitogenic breast cells.

  6. Selective T-type calcium channel blockade alleviates hyperalgesia in ob/ob mice.

    PubMed

    Latham, Janelle R; Pathirathna, Sriyani; Jagodic, Miljen M; Choe, Won Joo; Levin, Michaela E; Nelson, Michael T; Lee, Woo Yong; Krishnan, Kathiresan; Covey, Douglas F; Todorovic, Slobodan M; Jevtovic-Todorovic, Vesna

    2009-11-01

    Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy. In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice. We found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, alpha1H (Ca(v)3.2), was most strongly affected. Moreover, (3beta,5alpha,17beta)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice. Our results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy.

  7. Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

  8. Aluminium and hydrogen ions inhibit a mechanosensory calcium-selective cation channel

    NASA Technical Reports Server (NTRS)

    Ding, J. P.; Pickard, B. G.

    1993-01-01

    The tension-dependent activity of mechanosensory calcium-selective cation channels in excised plasmalemmal patches from onion bulb scale epidermis is modulated by pH in the physiologically meaningful range between 4.5 and 7.2. It is rapidly lowered by lowering pH and rapidly raised by raising pH. Channel activity is effectively inhibited by low levels of aluminium ions and activity can be partially restored by washing for a few minutes. We suggest that under normal conditions the sensitivity of the mechanosensory channels to pH of the wall free space plays important roles in regulation of plant activities such as growth. We further suggest that, when levels of acid and aluminium ions in the soil solution are high, they might inhibit similar sensory channels in cells of the root tip, thus contributing critically to the acid soil syndrome.

  9. A channel-selection criterion for suppressing reverberation in cochlear implants

    PubMed Central

    Kokkinakis, Kostas; Hazrati, Oldooz; Loizou, Philipos C.

    2011-01-01

    Little is known about the extent to which reverberation affects speech intelligibility by cochlear implant (CI) listeners. Experiment 1 assessed CI users’ performance using Institute of Electrical and Electronics Engineers (IEEE) sentences corrupted with varying degrees of reverberation. Reverberation times of 0.30, 0.60, 0.80, and 1.0 s were used. Results indicated that for all subjects tested, speech intelligibility decreased exponentially with an increase in reverberation time. A decaying-exponential model provided an excellent fit to the data. Experiment 2 evaluated (offline) a speech coding strategy for reverberation suppression using a channel-selection criterion based on the signal-to-reverberant ratio (SRR) of individual frequency channels. The SRR reflects implicitly the ratio of the energies of the signal originating from the early (and direct) reflections and the signal originating from the late reflections. Channels with SRR larger than a preset threshold were selected, while channels with SRR smaller than the threshold were zeroed out. Results in a highly reverberant scenario indicated that the proposed strategy led to substantial gains (over 60 percentage points) in speech intelligibility over the subjects’ daily strategy. Further analysis indicated that the proposed channel-selection criterion reduces the temporal envelope smearing effects introduced by reverberation and also diminishes the self-masking effects responsible for flattened formants. PMID:21568424

  10. Reverberation suppression in cochlear implants using a blind channel-selection strategy

    PubMed Central

    Hazrati, Oldooz; Loizou, Philipos C.

    2013-01-01

    Reverberation severely degrades speech intelligibility for cochlear implant (CI) users. The ideal reverberant mask (IRM), a binary mask for reverberation suppression which is computed using signal-to-reverberant ratio, was found to yield substantial intelligibility gains for CI users even in highly reverberant environments (e.g., T60 = 1.0 s). Motivated by the intelligibility improvements obtained from IRM, a monaural blind channel-selection criterion for reverberation suppression is proposed. The proposed channel-selection strategy is blind, meaning that prior knowledge of neither the room impulse response nor the anechoic signal is required. By the use of a residual signal obtained from linear prediction analysis of the reverberant signal, the residual-to-reverberant ratio (RRR) of individual frequency channels was employed as the channel-selection criterion. In each frame, the channels with RRR less than an adaptive threshold were retained while the rest were zeroed out. Performance of the proposed strategy was evaluated via intelligibility listening tests conducted with CI users in simulated rooms with two reverberation times of 0.6 and 0.8 s. The results indicate significant intelligibility improvements in both reverberant conditions (over 30 and 40 percentage points in T60 = 0.6 and 0.8 s, respectively). The improvement is comparable to that obtained with the IRM strategy. PMID:23742370

  11. Optimal channel selection for analysis of EEG-sleep patterns of neonates.

    PubMed

    Piryatinska, Alexandra; Woyczynski, Wojbor A; Scher, Mark S; Loparo, Kenneth A

    2012-04-01

    This paper extends our previous work on automated detection and classification of neonate EEG sleep stages. In [19] we adapted and integrated a range of computational, mathematical and statistical tools for the analysis of neonatal electroencephalogram (EEG) sleep recordings with the aim of facilitating the assessment of neonatal brain maturation and dismaturity by studying the structure and temporal patterns of their sleep. That work relied on algorithms using a single channel of EEG. The present paper builds on our previous work by incorporating a larger selection of EEG channels that capture both the spatial distribution and temporal patterns of EEG during sleep. Using a multivariate analysis approach, we obtain the "optimal" selection of the EEG channels and characteristics that are most suitable for EEG sleep state separation. Copyright © 2011. Published by Elsevier Ireland Ltd.

  12. The effect of protein dielectric coefficient on the ionic selectivity of a calcium channel.

    PubMed

    Boda, Dezso; Valiskó, Mónika; Eisenberg, Bob; Nonner, Wolfgang; Henderson, Douglas; Gillespie, Dirk

    2006-07-21

    Calcium-selective ion channels are known to have carboxylate-rich selectivity filters, a common motif that is primarily responsible for their high Ca(2+) affinity. Different Ca(2+) affinities ranging from micromolar (the L-type Ca channel) to millimolar (the ryanodine receptor channel) are closely related to the different physiological functions of these channels. To understand the physical mechanism for this range of affinities given similar amino acids in their selectivity filters, we use grand canonical Monte Carlo simulations to assess the binding of monovalent and divalent ions in the selectivity filter of a model Ca channel. We use a reduced model where the electolyte is modeled by hard-sphere ions embedded in a continuum dielectric solvent, while the interior of protein surrounding the channel is allowed to have a dielectric coefficient different from that of the electrolyte. The induced charges that appear on the protein/lumen interface are calculated by the induced charge computation method [Boda et al., Phys. Rev. E 69, 046702 (2004)]. It is shown that decreasing the dielectric coefficient of the protein attracts more cations into the pore because the protein's carboxyl groups induce negative charges on the dielectric boundary. As the density of the hard-sphere ions increases in the filter, Ca(2+) is absorbed into the filter with higher probability than Na(+) because Ca(2+) provides twice the charge to neutralize the negative charge of the pore (both structural carboxylate oxygens and induced charges) than Na(+) while occupying about the same space (the charge/space competition mechanism). As a result, Ca(2+) affinity is improved an order of magnitude by decreasing the protein dielectric coefficient from 80 to 5. Our results indicate that adjusting the dielectric properties of the protein surrounding the permeation pathway is a possible way for evolution to regulate the Ca(2+) affinity of the common four-carboxylate motif.

  13. Electrostatics of aquaporin and aquaglyceroporin channels correlates with their transport selectivity

    PubMed Central

    Oliva, Romina; Calamita, Giuseppe; Thornton, Janet M.; Pellegrini-Calace, Marialuisa

    2010-01-01

    Aquaporins are homotetrameric channel proteins, which allow the diffusion of water and small solutes across biological membranes. According to their transport function, aquaporins can be divided into “orthodox aquaporins”, which allow the flux of water molecules only, and “aquaglyceroporins”, which facilitate the diffusion of glycerol and other small solutes in addition to water. The contribution of individual residues in the pore to the selectivity of orthodox aquaporins and aquaglyceroporins is not yet fully understood. To gain insights into aquaporin selectivity, we focused on the sequence variation and electrostatics of their channels. The continuum Poisson-Boltzmann electrostatic potential along the channel was calculated and compared for ten three-dimensional-structures which are representatives of different aquaporin subfamilies, and a panel of functionally characterized mutants, for which high-accuracy three-dimensional-models could be derived. Interestingly, specific electrostatic profiles associated with the main selectivity to water or glycerol could be identified. In particular: (i) orthodox aquaporins showed a distinctive electrostatic potential maximum at the periplasmic side of the channel around the aromatic/Arg (ar/R) constriction site; (ii) aquaporin-0 (AQP0), a mammalian aquaporin with considerably low water permeability, had an additional deep minimum at the cytoplasmic side; (iii) aquaglyceroporins showed a rather flat potential all along the channel; and (iv) the bifunctional protozoan PfAQP had an unusual all negative profile. Evaluation of electrostatics of the mutants, along with a thorough sequence analysis of the aquaporin pore-lining residues, illuminated the contribution of specific residues to the electrostatics of the channels and possibly to their selectivity. PMID:20147624

  14. Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes

    SciTech Connect

    Baconguis, Isabelle; Gouaux, Eric

    2012-07-29

    Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na+-selective currents in chicken ASIC1a at pH7.25 and 5.5, respectively. Crystal structures of ASIC1a–psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH7.25 the pore is approximately 10Å in diameter, whereas at pH5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

  15. Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes.

    PubMed

    Baconguis, Isabelle; Gouaux, Eric

    2012-09-20

    Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na(+)-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a-psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 Å in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

  16. Energetics of discrete selectivity bands and mutation-induced transitions in the calcium-sodium ion channels family.

    PubMed

    Kaufman, I; Luchinsky, D G; Tindjong, R; McClintock, P V E; Eisenberg, R S

    2013-11-01

    We use Brownian dynamics (BD) simulations to study the ionic conduction and valence selectivity of a generic electrostatic model of a biological ion channel as functions of the fixed charge Q(f) at its selectivity filter. We are thus able to reconcile the discrete calcium conduction bands recently revealed in our BD simulations, M0 (Q(f)=1e), M1 (3e), M2 (5e), with a set of sodium conduction bands L0 (0.5e), L1 (1.5e), thereby obtaining a completed pattern of conduction and selectivity bands vs Q(f) for the sodium-calcium channels family. An increase of Q(f) leads to an increase of calcium selectivity: L0 (sodium-selective, nonblocking channel) → M0 (nonselective channel) → L1 (sodium-selective channel with divalent block) → M1 (calcium-selective channel exhibiting the anomalous mole fraction effect). We create a consistent identification scheme where the L0 band is putatively identified with the eukaryotic sodium channel The scheme created is able to account for the experimentally observed mutation-induced transformations between nonselective channels, sodium-selective channels, and calcium-selective channels, which we interpret as transitions between different rows of the identification table. By considering the potential energy changes during permeation, we show explicitly that the multi-ion conduction bands of calcium and sodium channels arise as the result of resonant barrierless conduction. The pattern of periodic conduction bands is explained on the basis of sequential neutralization taking account of self-energy, as Q(f)(z,i)=ze(1/2+i), where i is the order of the band and z is the valence of the ion. Our results confirm the crucial influence of electrostatic interactions on conduction and on the Ca(2+)/Na(+) valence selectivity of calcium and sodium ion channels. The model and results could be also applicable to biomimetic nanopores with charged walls.

  17. Unraveling the mechanism of selective ion transport in hydrophobic subnanometer channels.

    PubMed

    Li, Hui; Francisco, Joseph S; Zeng, Xiao Cheng

    2015-09-01

    Recently reported synthetic organic nanopore (SONP) can mimic a key feature of natural ion channels, i.e., selective ion transport. However, the physical mechanism underlying the K(+)/Na(+) selectivity for the SONPs is dramatically different from that of natural ion channels. To achieve a better understanding of the selective ion transport in hydrophobic subnanometer channels in general and SONPs in particular, we perform a series of ab initio molecular dynamics simulations to investigate the diffusivity of aqua Na(+) and K(+) ions in two prototype hydrophobic nanochannels: (i) an SONP with radius of 3.2 Å, and (ii) single-walled carbon nanotubes (CNTs) with radii of 3-5 Å (these radii are comparable to those of the biological potassium K(+) channels). We find that the hydration shell of aqua Na(+) ion is smaller than that of aqua K(+) ion but notably more structured and less yielding. The aqua ions do not lower the diffusivity of water molecules in CNTs, but in SONP the diffusivity of aqua ions (Na(+) in particular) is strongly suppressed due to the rugged inner surface. Moreover, the aqua Na(+) ion requires higher formation energy than aqua K(+) ion in the hydrophobic nanochannels. As such, we find that the ion (K(+) vs. Na(+)) selectivity of the (8, 8) CNT is ∼20× higher than that of SONP. Hence, the (8, 8) CNT is likely the most efficient artificial K(+) channel due in part to its special interior environment in which Na(+) can be fully solvated, whereas K(+) cannot. This work provides deeper insights into the physical chemistry behind selective ion transport in nanochannels.

  18. Unraveling the mechanism of selective ion transport in hydrophobic subnanometer channels

    PubMed Central

    Li, Hui; Francisco, Joseph S.; Zeng, Xiao Cheng

    2015-01-01

    Recently reported synthetic organic nanopore (SONP) can mimic a key feature of natural ion channels, i.e., selective ion transport. However, the physical mechanism underlying the K+/Na+ selectivity for the SONPs is dramatically different from that of natural ion channels. To achieve a better understanding of the selective ion transport in hydrophobic subnanometer channels in general and SONPs in particular, we perform a series of ab initio molecular dynamics simulations to investigate the diffusivity of aqua Na+ and K+ ions in two prototype hydrophobic nanochannels: (i) an SONP with radius of 3.2 Å, and (ii) single-walled carbon nanotubes (CNTs) with radii of 3–5 Å (these radii are comparable to those of the biological potassium K+ channels). We find that the hydration shell of aqua Na+ ion is smaller than that of aqua K+ ion but notably more structured and less yielding. The aqua ions do not lower the diffusivity of water molecules in CNTs, but in SONP the diffusivity of aqua ions (Na+ in particular) is strongly suppressed due to the rugged inner surface. Moreover, the aqua Na+ ion requires higher formation energy than aqua K+ ion in the hydrophobic nanochannels. As such, we find that the ion (K+ vs. Na+) selectivity of the (8, 8) CNT is ∼20× higher than that of SONP. Hence, the (8, 8) CNT is likely the most efficient artificial K+ channel due in part to its special interior environment in which Na+ can be fully solvated, whereas K+ cannot. This work provides deeper insights into the physical chemistry behind selective ion transport in nanochannels. PMID:26283377

  19. Theoretical analysis of selectivity mechanisms in molecular transport through channels and nanopores

    SciTech Connect

    Agah, Shaghayegh; Pasquali, Matteo; Kolomeisky, Anatoly B.

    2015-01-28

    Selectivity is one of the most fundamental concepts in natural sciences, and it is also critically important in various technological, industrial, and medical applications. Although there are many experimental methods that allow to separate molecules, frequently they are expensive and not efficient. Recently, a new method of separation of chemical mixtures based on utilization of channels and nanopores has been proposed and successfully tested in several systems. However, mechanisms of selectivity in the molecular transport during the translocation are still not well understood. Here, we develop a simple theoretical approach to explain the origin of selectivity in molecular fluxes through channels. Our method utilizes discrete-state stochastic models that take into account all relevant chemical transitions and can be solved analytically. More specifically, we analyze channels with one and two binding sites employed for separating mixtures of two types of molecules. The effects of the symmetry and the strength of the molecular-pore interactions are examined. It is found that for one-site binding channels, the differences in the strength of interactions for two species drive the separation. At the same time, in more realistic two-site systems, the symmetry of interaction potential becomes also important. The most efficient separation is predicted when the specific binding site is located near the entrance to the nanopore. In addition, the selectivity is higher for large entrance rates into the channel. It is also found that the molecular transport is more selective for repulsive interactions than for attractive interactions. The physical-chemical origin of the observed phenomena is discussed.

  20. Gating at the selectivity filter of ion channels that conduct Na+ and K+ ions.

    PubMed

    Furini, Simone; Domene, Carmen

    2011-10-05

    The NaK channel is a cation selective channel with similar permeability for K(+) and Na(+). The available crystallographic structure of wild-type (WT) NaK is usually associated with a conductive state of the channel. Here, potential of mean force for complete conduction events of Na(+) and K(+) ions through NaK show that: i), large energy barriers prevent the passage of ions through the WT NaK structure, ii), the barriers are correlated to the presence of a hydrogen bond between Asp-66 and Asn-68, and iii), the structure of NaK mutated to mimic cyclic nucleotide-gated channels conducts Na(+) and K(+). These results support the hypothesis that the filter of cation selective channels can adopt at least two different structures: a conductive one, represented by the x-ray structures of the NaK-CNG chimeras, and a closed one, represented by the x-ray structures of the WT NaK. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  1. Gating at the Selectivity Filter of Ion Channels that Conduct Na+ and K+ Ions

    PubMed Central

    Furini, Simone; Domene, Carmen

    2011-01-01

    The NaK channel is a cation selective channel with similar permeability for K+ and Na+. The available crystallographic structure of wild-type (WT) NaK is usually associated with a conductive state of the channel. Here, potential of mean force for complete conduction events of Na+ and K+ ions through NaK show that: i), large energy barriers prevent the passage of ions through the WT NaK structure, ii), the barriers are correlated to the presence of a hydrogen bond between Asp-66 and Asn-68, and iii), the structure of NaK mutated to mimic cyclic nucleotide-gated channels conducts Na+ and K+. These results support the hypothesis that the filter of cation selective channels can adopt at least two different structures: a conductive one, represented by the x-ray structures of the NaK-CNG chimeras, and a closed one, represented by the x-ray structures of the WT NaK. PMID:21961588

  2. Event-related brain potentials to irrelevant auditory stimuli during selective listening: effects of channel probability.

    PubMed

    Akai, Toshiyuki

    2004-03-01

    The purpose of this study was to identify the cognitive process reflected by a positive deflection to irrelevant auditory stimuli (Pdi) during selective listening. Event-related brain potentials were recorded from 9 participants in a two-channel (left/right ears) selective listening task. Relative event probabilities of the relevant/irrelevant channels were 25%/75%, 50%/50%, and 75%/25%. With increasing probability of the relevant channel, behavioral performances (the reaction time and hit rate) for the targets within the relevant channel improved, reflecting development of a more robust attentional trace. At the same time, the amplitude of the early Pdi (200-300 ms after stimulus onset) elicited by the stimuli in the irrelevant channel with a decreased probability was enhanced in the central region. This positive relation between the strength of the attentional trace and the amplitude of the early Pdi suggests that the early Pdi is elicited by a mismatching between an incoming irrelevant stimulus and an attentional trace.

  3. Emotion recognition based on EEG features in movie clips with channel selection.

    PubMed

    Özerdem, Mehmet Siraç; Polat, Hasan

    2017-07-15

    Emotion plays an important role in human interaction. People can explain their emotions in terms of word, voice intonation, facial expression, and body language. However, brain-computer interface (BCI) systems have not reached the desired level to interpret emotions. Automatic emotion recognition based on BCI systems has been a topic of great research in the last few decades. Electroencephalogram (EEG) signals are one of the most crucial resources for these systems. The main advantage of using EEG signals is that it reflects real emotion and can easily be processed by computer systems. In this study, EEG signals related to positive and negative emotions have been classified with preprocessing of channel selection. Self-Assessment Manikins was used to determine emotional states. We have employed discrete wavelet transform and machine learning techniques such as multilayer perceptron neural network (MLPNN) and k-nearest neighborhood (kNN) algorithm to classify EEG signals. The classifier algorithms were initially used for channel selection. EEG channels for each participant were evaluated separately, and five EEG channels that offered the best classification performance were determined. Thus, final feature vectors were obtained by combining the features of EEG segments belonging to these channels. The final feature vectors with related positive and negative emotions were classified separately using MLPNN and kNN algorithms. The classification performance obtained with both the algorithms are computed and compared. The average overall accuracies were obtained as 77.14 and 72.92% by using MLPNN and kNN, respectively.

  4. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel

    PubMed Central

    Nagel, Georg; Szellas, Tanjef; Huhn, Wolfram; Kateriya, Suneel; Adeishvili, Nona; Berthold, Peter; Ollig, Doris; Hegemann, Peter; Bamberg, Ernst

    2003-01-01

    Microbial-type rhodopsins are found in archaea, prokaryotes, and eukaryotes. Some of them represent membrane ion transport proteins such as bacteriorhodopsin, a light-driven proton pump, or channelrhodopsin-1 (ChR1), a recently identified light-gated proton channel from the green alga Chlamydomonas reinhardtii. ChR1 and ChR2, a related microbial-type rhodopsin from C. reinhardtii, were shown to be involved in generation of photocurrents of this green alga. We demonstrate by functional expression, both in oocytes of Xenopus laevis and mammalian cells, that ChR2 is a directly light-switched cation-selective ion channel. This channel opens rapidly after absorption of a photon to generate a large permeability for monovalent and divalent cations. ChR2 desensitizes in continuous light to a smaller steady-state conductance. Recovery from desensitization is accelerated by extracellular H+ and negative membrane potential, whereas closing of the ChR2 ion channel is decelerated by intracellular H+. ChR2 is expressed mainly in C. reinhardtii under low-light conditions, suggesting involvement in photoreception in dark-adapted cells. The predicted seven-transmembrane α helices of ChR2 are characteristic for G protein-coupled receptors but reflect a different motif for a cation-selective ion channel. Finally, we demonstrate that ChR2 may be used to depolarize small or large cells, simply by illumination. PMID:14615590

  5. Selectivity and permeation of alkali metal ions in K+-channels.

    PubMed

    Furini, Simone; Domene, Carmen

    2011-06-24

    Ion conduction in K(+)-channels is usually described in terms of concerted movements of K(+) progressing in a single file through a narrow pore. Permeation is driven by an incoming ion knocking on those ions already inside the protein. A fine-tuned balance between high-affinity binding and electrostatic repulsive forces between permeant ions is needed to achieve efficient conduction. While K(+)-channels are known to be highly selective for K(+) over Na(+), some K(+) channels conduct Na(+) in the absence of K(+). Other ions are known to permeate K(+)-channels with a more moderate preference and unusual conduction features. We describe an extensive computational study on ion conduction in K(+)-channels rendering free energy profiles for the translocation of three different alkali ions and some of their mixtures. The free energy maps for Rb(+) translocation show at atomic level why experimental Rb(+) conductance is slightly lower than that of K(+). In contrast to K(+) or Rb(+), external Na(+) block K(+) currents, and the sites where Na(+) transport is hindered are characterized. Translocation of K(+)/Na(+) mixtures is energetically unfavorable owing to the absence of equally spaced ion-binding sites for Na(+), excluding Na(+) from a channel already loaded with K(+). Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. The omega-atracotoxins: selective blockers of insect M-LVA and HVA calcium channels.

    PubMed

    Chong, Youmie; Hayes, Jessica L; Sollod, Brianna; Wen, Suping; Wilson, David T; Hains, Peter G; Hodgson, Wayne C; Broady, Kevin W; King, Glenn F; Nicholson, Graham M

    2007-08-15

    The omega-atracotoxins (omega-ACTX) are a family of arthropod-selective peptide neurotoxins from Australian funnel-web spider venoms (Hexathelidae: Atracinae) that are candidates for development as biopesticides. We isolated a 37-residue insect-selective neurotoxin, omega-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the omega-ACTX-1 family. The peptide induced potent excitatory symptoms, followed by flaccid paralysis leading to death, in acute toxicity tests in house crickets. Using isolated smooth and skeletal nerve-muscle preparations, the toxin was shown to lack overt vertebrate toxicity at concentrations up to 1 microM. To further characterize the target of the omega-ACTXs, voltage-clamp analysis using the whole-cell patch-clamp technique was undertaken using cockroach dorsal unpaired median neurons. It is shown here for the first time that omega-ACTX-Ar1a, and its homolog omega-ACTX-Hv1a from Hadronyche versuta, reversibly block both mid-low- (M-LVA) and high-voltage-activated (HVA) insect calcium channel (Ca(v)) currents. This block occurred in the absence of alterations in the voltage-dependence of Ca(v) channel activation, and was voltage-independent, suggesting that omega-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 microM omega-ACTX-Ar1a failed to significantly affect global K(v) channel currents. However, 1 microM omega-ACTX-Ar1a caused a modest 18% block of insect Na(v) channel currents, similar to the minor block of Na(v) channels reported for other insect Ca(v) channel blockers such as omega-agatoxin IVA. These findings validate both M-LVA and HVA Ca(v) channels as potential targets for insecticides.

  7. Ion Selectivity Mechanism in a Bacterial Pentameric Ligand-Gated Ion Channel

    SciTech Connect

    Fritsch, Sebastian; Ivanov, Ivaylo; Wang, Hailong; Cheng, Xiaolin

    2010-01-01

    The proton-gated ion channel from Gloeobacter violaceus (GLIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. Recent emergence of a high-resolution crystal structure of GLIC captured in a potentially open state allowed detailed, atomic-level insight into ion conduction and selectivity mechanisms in these channels. Herein, we have examined the barriers to ion conduction and origins of ion selectivity in the GLIC channel by the construction of potential-of-mean-force profiles for sodium and chloride ions inside the transmembrane region. Our calculations reveal that the GLIC channel is open for a sodium ion to transport, but presents a 11 kcal/mol free energy barrier for a chloride ion. Our collective findings identify three distinct contributions to the observed preference for the permeant ions. First, there is a substantial contribution due to a ring of negatively charged glutamate residues (E-2 ) at the narrow intracellular end of the channel. The negative electrostatics of this region and the ability of the glutamate side chains to directly bind cations would strongly favor the passage of sodium ions while hindering translocation of chloride ions. Second, our results imply a significant hydrophobic contribution to selectivity linked to differences in the desolvation penalty for the sodium versus chloride ions in the central hydrophobic region of the pore. This hydrophobic contribution is evidenced by the large free energy barriers experienced by Cl in the middle of the pore for both GLIC and the E-2 A mutant. Finally, there is a distinct contribution arising from the overall negative electrostatics of the channel.

  8. Channel-morphology data for the Tongue River and selected tributaries, southeastern Montana, 2001-02

    USGS Publications Warehouse

    Chase, Katherine J.

    2004-01-01

    Coal-bed methane exploration and production have begun within the Tongue River watershed in southeastern Montana. The development of coal-bed methane requires production of large volumes of ground water, some of which may be discharged to streams, potentially increasing stream discharge and sediment load. Changes in stream discharge or sediment load may result in changes to channel morphology through changes in erosion and vegetation. These changes might be subtle and difficult to detect without baseline data that indicate stream-channel conditions before extensive coal-bed methane development began. In order to provide this baseline channel-morphology data, the U.S. Geological Survey, in cooperation with the Bureau of Land Management, collected channel-morphology data in 2001-02 to document baseline conditions for several reaches along the Tongue River and selected tributaries. This report presents channel-morphology data for five sites on the mainstem Tongue River and four sites on its tributaries. Bankfull, water-surface, and thalweg elevations, channel sections, and streambed-particle sizes were measured along reaches near streamflow-gaging stations. At each site, the channel was classified using methods described by Rosgen. For six sites, bankfull discharge was determined from the stage- discharge relation at the gage for the stage corresponding to the bankfull elevation. For three sites, the step-backwater computer model HEC-RAS was used to estimate bankfull discharge. Recurrence intervals for the bankfull discharge also were estimated for eight of the nine sites. Channel-morphology data for each site are presented in maps, tables, graphs, and photographs.

  9. Controls on the distribution of channel reach morphology in selectively glaciated catchments

    NASA Astrophysics Data System (ADS)

    Addy, S.; Soulsby, C.; Hartley, A. J.

    2014-04-01

    To assess the controls on the distribution of channel reach morphology in a selectively glaciated landscape, we used field mapping and a geographical information system (GIS) in the River Dee catchment, northeast Scotland. Controls on channel morphology were investigated using (1) continuous longitudinal assessment of channel morphology distribution in relation to geology, glacial history, topography, and total stream power (Ω) in two subcatchments, and (2) slope (S), Ω, and a slope-drainage area (S-A) framework to understand the occurrence of 173 widely distributed bedrock, mixed bedrock-alluvial, and alluvial (three different types) reaches. The S-A framework used indicators of transport capacity (Qc) and sediment supply (Qs) to differentiate channel types. The study highlights the disjointed nature of channel reach distribution at the river scale that reflects variable lithology and glacial modification. Because of the subdued topography in contrast to other regions, colluvial forcing of channel morphology in the headwaters was lacking. However, in common with other glaciated landscapes, repeated sequences of channel reach type progression determined by valley steps were evident. The S-A analysis successfully discriminated 87.2% of alluvial and 91.4% of bedrock reaches despite the variable land use and glacial modification. Discrimination of the full range of channel types using S, Ω, or the S-A framework was poor however. Notably, a third of the transport alluvial reaches were located in the bedrock S-A domain, and the majority of mixed reaches were widely distributed mostly within the bedrock domain and not close to the critical slope (Sc). In comparison to other regions, the Sc above which Qc > Qs and bedrock reaches dominate, was notably higher. We hypothesise that a drier climate and the higher entrainment threshold of coarse, granite-dominated bed materials create a higher Sc.

  10. Selectivity Mechanism of the Voltage-gated Proton Channel, HV1

    NASA Astrophysics Data System (ADS)

    Dudev, Todor; Musset, Boris; Morgan, Deri; Cherny, Vladimir V.; Smith, Susan M. E.; Mazmanian, Karine; Decoursey, Thomas E.; Lim, Carmay

    2015-05-01

    Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O+ protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na+ or Cl- was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH0-H2O0-Arg+ interactions with hydronium but unfavorable Asp--X-/X+-Arg+ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.

  11. Poorly selective cation channels in the apical membrane of A6 cells.

    PubMed

    Van Driessche, W; De Smet, P; de Smedt, H

    1994-03-01

    This paper describes a Ca(2+)-blockable, poorly selective cation pathway in the apical membrane of A6 epithelia. This pathway has properties that resemble the cation-selective channels in the toad urinary bladder and frog skin. Transepithelial short circuit currents (Isc) and power density spectra (PDS) of the fluctuations in current were recorded. The basolateral surface of the tissues was exposed to Cl- or SO4(2-) solutions with Na+ as the major cation. Ca(2+)-blockable inward oriented currents and Lorentzian noise were recorded with isotonic (215 mosmol/kg) mucosal Cl- and hypotonic (144 mos-mol/kg serosal SO4(2-) solution with Na+, K+, Rb+ or Cs+ as the major mucosal cation. Experiments with mucosal K+ demonstrated that the cation-selective channel was markedly activated by serosal hypotonicity. Effects of an increased electrical driving force were excluded on the basis of the results obtained with microelectrode experiments and transepithelial voltage clamping. Cell volume expansion induced by isotonic replacements of serosal sucrose by glycerol or urea also activated the cation-selective pathway. Furthermore, the presence of Cl- in the mucosal solution was a prerequisite for a sustained response to hypotonicity or replacements of the organic compounds. Moreover, we found that the cation-selective channels are mainly expressed in the cells during the early period of epithelial growth.

  12. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

    PubMed Central

    Kiyonaka, Shigeki; Kato, Kenta; Nishida, Motohiro; Mio, Kazuhiro; Numaga, Takuro; Sawaguchi, Yuichi; Yoshida, Takashi; Wakamori, Minoru; Mori, Emiko; Numata, Tomohiro; Ishii, Masakazu; Takemoto, Hiroki; Ojida, Akio; Watanabe, Kenta; Uemura, Aya; Kurose, Hitoshi; Morii, Takashi; Kobayashi, Tsutomu; Sato, Yoji; Sato, Chikara; Hamachi, Itaru; Mori, Yasuo

    2009-01-01

    Canonical transient receptor potential (TRPC) channels control influxes of Ca2+ and other cations that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a pyrazole compound (Pyr3), which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In DT40 B lymphocytes, Pyr3 potently eliminated the Ca2+ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptor-induced Ca2+ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca2+-dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3-selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy. PMID:19289841

  13. Control of ionic selectivity by a pore helix residue in the Kv1.2 channel.

    PubMed

    Chao, Chia-Chia; Huang, Chieh-Chen; Kuo, Chang-Shin; Leung, Yuk-Man

    2010-11-01

    Interaction between the selectivity filter and the adjacent pore helix of voltage-gated K(+) (Kv) channels controls pore stability during K(+) conduction. Kv channels, having their selectivity filter destabilized during depolarization, are said to undergo C-type inactivation. We examined the functionality of a residue at the pore helix of the Kv1.2 channel (V370), which reportedly affects C-type inactivation. A mutation into glycine (V370G) caused a shift in reversal potential from around -72 to -9 mV. The permeability ratios (P(Na)/P(K)) of the wild type and V370G mutant are 0.04 and 0.76, respectively. In the wild-type, P(Rb)/P(K), P(Cs)/P(K) and P(Li)/P(K) are 0.78, 0.10 and 0.05, respectively. Kv1.2 V370G channels had enhanced permeability to Rb(+) and Cs(+) (P(Rb)/P(K) and P(Cs)/P(K) are 1.63 and 1.18, respectively); however, Li(+) permeability was not significantly augmented (P(Li)/P(K) is 0.13). Therefore, in addition to its known effect on pore stability, V370 of Kv1.2 is also crucial in controlling ion selectivity.

  14. Stochastic relevance analysis of epileptic EEG signals for channel selection and classification.

    PubMed

    Duque-Muñoz, L; Guerrero-Mosquera, C; Castellanos-Dominguez, G

    2013-01-01

    Time-frequency decompositions (TFDs) are well known techniques that permit to extract useful information or features from EEG signals, being necessary to distinguish between irrelevant information and the features effectively representing the subjacent physiological phenomena, according to some evaluation measure. This work introduces a new method to obtain relevant features extracted from time-frequency plane for epileptic EEG signals. Particularly, EEG features are extracted by common spectral methods such as short time Fourier transform (STFT), wavelets transform and Empirical Mode Decomposition (EMD). Then, each method is evaluated by Stochastic Relevance Analysis (SRA) that is further used for EEG classification and channel selection. The classification measures are carried out based on the performance of the k-NN classifier, while the channels selected are validated by visual inspection and topographic scalp map. The study uses real and multi-channel EEG data and all the experiments have been supervised by an expert neurologist. Results obtained in this paper show that SRA is a good alternative for automatic seizure detection and also opens the possibility of formulating new criteria to select, classify or analyze abnormal EEG channels.

  15. Sequence-function analysis of the K+-selective family of ion channels using a comprehensive alignment and the KcsA channel structure.

    PubMed

    Shealy, Robin T; Murphy, Anuradha D; Ramarathnam, Rampriya; Jakobsson, Eric; Subramaniam, Shankar

    2003-05-01

    Sequence-function analysis of K(+)-selective channels was carried out in the context of the 3.2 A crystal structure of a K(+) channel (KcsA) from Streptomyces lividans (Doyle et al., 1998). The first step was the construction of an alignment of a comprehensive set of K(+)-selective channel sequences forming the putative permeation path. This pathway consists of two transmembrane segments plus an extracellular linker. Included in the alignment are channels from the eight major classes of K(+)-selective channels from a wide variety of species, displaying varied rectification, gating, and activation properties. Segments of the alignment were assigned to structural motifs based on the KcsA structure. The alignment's accuracy was verified by two observations on these motifs: 1), the most variability is shown in the turret region, which functionally is strongly implicated in susceptibility to toxin binding; and 2), the selectivity filter and pore helix are the most highly conserved regions. This alignment combined with the KcsA structure was used to assess whether clusters of contiguous residues linked by hydrophobic or electrostatic interactions in KcsA are conserved in the K(+)-selective channel family. Analysis of sequence conservation patterns in the alignment suggests that a cluster of conserved residues is critical for determining the degree of K(+) selectivity. The alignment also supports the near-universality of the "glycine hinge" mechanism at the center of the inner helix for opening K channels. This mechanism has been suggested by the recent crystallization of a K channel in the open state. Further, the alignment reveals a second highly conserved glycine near the extracellular end of the inner helix, which may be important in minimizing deformation of the extracellular vestibule as the channel opens. These and other sequence-function relationships found in this analysis suggest that much of the permeation path architecture in KcsA is present in most K(+)-selective

  16. EMG feature assessment for myoelectric pattern recognition and channel selection: a study with incomplete spinal cord injury.

    PubMed

    Liu, Jie; Li, Xiaoyan; Li, Guanglin; Zhou, Ping

    2014-07-01

    Myoelectric pattern recognition with a large number of electromyogram (EMG) channels provides an approach to assessing motor control information available from the recorded muscles. In order to develop a practical myoelectric control system, a feature dependent channel reduction method was developed in this study to determine a small number of EMG channels for myoelectric pattern recognition analysis. The method selects appropriate raw EMG features for classification of different movements, using the minimum Redundancy Maximum Relevance (mRMR) and the Markov random field (MRF) methods to rank a large number of EMG features, respectively. A k-nearest neighbor (KNN) classifier was used to evaluate the performance of the selected features in terms of classification accuracy. The method was tested using 57 channels' surface EMG signals recorded from forearm and hand muscles of individuals with incomplete spinal cord injury (SCI). Our results demonstrate that appropriate selection of a small number of raw EMG features from different recording channels resulted in similar high classification accuracies as achieved by using all the EMG channels or features. Compared with the conventional sequential forward selection (SFS) method, the feature dependent method does not require repeated classifier implementation. It can effectively reduce redundant information not only cross different channels, but also cross different features in the same channel. Such hybrid feature-channel selection from a large number of EMG recording channels can reduce computational cost for implementation of a myoelectric pattern recognition based control system.

  17. An efficient selective-repeat ARQ scheme for satellite channels and its throughput analysis

    NASA Astrophysics Data System (ADS)

    Yu, P. S.; Lin, S.

    1981-03-01

    A selective-repeat automatic repeat request (ARQ) scheme which operates with a finite receiver buffer and a finite range of sequence numbers is investigated. The throughput performance of the proposed scheme is analyzed and simulated based on the assumption that the channel errors are randomly distributed and the return channel is noiseless. Both analytical and simulation results show that it significantly outperforms the go-back-N ARQ scheme, particularly for channels with large roundtrip delay and high data rate. It provides high throughput efficiency over a wide range of bit error rates. The throughput remains in a usable range even for very high error rate conditions. The proposed scheme is capable of handling data and/or acknowledgment loss. Furthermore, when buffer overflow occurs at the receiver, the transmitter is capable of detecting it and backs up to the proper location of the input queue to retransmit the correct data blocks.

  18. Phencyclidine in low doses selectively blocks a presynaptic voltage-regulated potassium channel in rat brain.

    PubMed Central

    Bartschat, D K; Blaustein, M P

    1986-01-01

    Phencylidine (PCP) is a major drug of abuse in the United States. It produces a toxic confusional psychosis in man. We show here that nanomolar to micromolar concentrations of PCP and behaviorally active congeners selectively block voltage-regulated noninactivating (or very slowly inactivating) presynaptic K channels in the brain. The rank order of potency for blockage of these K channels parallels both the relative ability of these agents to produce characteristic behavioral deficits in rats and their ability to displace [3H]PCP from its high-affinity binding sites in brain. In view of the enhanced voltage-gated Ca influx that would be expected to accompany blockage of presynaptic K channels, this mechanism could explain the excessive neurotransmitter release that is characteristic of PCP intoxication. PMID:2417237

  19. Selective T-Type Calcium Channel Blockade Alleviates Hyperalgesia in ob/ob Mice

    PubMed Central

    Latham, Janelle R.; Pathirathna, Sriyani; Jagodic, Miljen M.; Joo Choe, Won; Levin, Michaela E.; Nelson, Michael T.; Yong Lee, Woo; Krishnan, Kathiresan; Covey, Douglas F.; Todorovic, Slobodan M.; Jevtovic-Todorovic, Vesna

    2009-01-01

    OBJECTIVE Morbid obesity may be accompanied by diabetes and painful diabetic neuropathy, a poorly understood condition that is manifested by mechanical or thermal allodynia and hyperalgesia. Recent studies have highlighted the importance of T-type calcium channels (T-channels) in peripheral nociception; therefore, our goal was to examine the function of these channels in the pathophysiology and development of painful diabetic neuropathy. RESEARCH DESIGN AND METHODS In vivo testing of mechanical and thermal sensation, morphometric peripheral nerve studies, and electrophysiological and biochemical measurements were used to characterize the role of T-channels and the development of painful diabetic neuropathy in leptin-deficient (ob/ob) mice. RESULTS We found that ob/ob mice developed significant mechanical and thermal hypersensitivity early in life that coincided with hyperglycemia and was readily reversed with insulin therapy. These disturbances were accompanied by significant biophysical and biochemical modulation of T-channels in dorsal root ganglion neurons as measured by a large increase in the amplitude of T-currents and the expression of mRNA. The most prevalent subtype, α1H (Cav3.2), was most strongly affected. Moreover, (3β,5α,17β)-17-hydroxyestrane-3-carbonitrile (ECN), a novel neuroactive steroid and selective T-channel antagonist, provided dose-dependent alleviation of neuropathic thermal and mechanical hypersensitivity in diabetic ob/ob mice. CONCLUSIONS Our results indicate that pharmacological antagonism of T-channels is potentially an important novel therapeutic approach for the management of painful diabetic neuropathy. PMID:19651818

  20. Pentaquarks and doubly heavy exotic mesons

    NASA Astrophysics Data System (ADS)

    Karliner, Marek

    2016-11-01

    I discuss the experimental evidence for and theoretical interpretation of the new mesons and baryons with two heavy quarks. These include doubly-heavy baryons, exotic hadronic quarkonia and most recently a manifestly exotic pentaquark-like doubly heavy baryon with a minimal quark content uudc¯ discovered by LHCb, whose mass, decay mode and width are in agreement with a prediction based on a physical picture of a deuteron-like Σc D¯* "hadronic molecule".

  1. Doubly special relativity and Finsler geometry

    SciTech Connect

    Mignemi, S.

    2007-08-15

    We discuss the recent proposal of implementing doubly special relativity in configuration space by means of Finsler geometry. Although this formalism leads to a consistent description of the dynamics of a particle, it does not seem to give a complete description of the physics. In particular, the Finsler line element is not invariant under the deformed Lorentz transformations of doubly special relativity. We study in detail some simple applications of the formalism.

  2. Different ionic selectivities for connexins 26 and 32 produce rectifying gap junction channels.

    PubMed Central

    Suchyna, T M; Nitsche, J M; Chilton, M; Harris, A L; Veenstra, R D; Nicholson, B J

    1999-01-01

    The functional diversity of gap junction intercellular channels arising from the large number of connexin isoforms is significantly increased by heterotypic interactions between members of this family. This is particularly evident in the rectifying behavior of Cx26/Cx32 heterotypic channels (. Proc. Natl. Acad. Sci. USA. 88:8410-8414). The channel properties responsible for producing the rectifying current observed for Cx26/Cx32 heterotypic gap junction channels were determined in transfected mouse neuroblastoma 2A (N2A) cells. Transfectants revealed maximum unitary conductances (gamma(j)) of 135 pS for Cx26 and 53 pS for Cx32 homotypic channels in 120 mM KCl. Anionic substitution of glutamate for Cl indicated that Cx26 channels favored cations by 2.6:1, whereas Cx32 channels were relatively nonselective with respect to charge. In Cx26/Cx32 heterotypic cell pairs, the macroscopic fast rectification of the current-voltage relationship was fully explained at the single-channel level by a rectifying gamma(j) that increased by a factor of 2.9 as the transjunctional voltage (V(j)) changed from -100 to +100 mV with the Cx26 cell as the positive pole. A model of electrodiffusion of ions through the gap junction pore based on Nernst-Planck equations for ion concentrations and the Poisson equation for the electrical potential within the junction is developed. Selectivity characteristics are ascribed to each hemichannel based on either pore features (treated as uniform along the length of the hemichannel) or entrance effects unique to each connexin. Both analytical GHK approximations and full numerical solutions predict rectifying characteristics for Cx32/Cx26 heterotypic channels, although not to the full extent seen empirically. The model predicts that asymmetries in the conductance/permeability properties of the hemichannels (also cast as Donnan potentials) will produce either an accumulation or a depletion of ions within the channel, depending on voltage polarity, that

  3. EEG channel selection using particle swarm optimization for the classification of auditory event-related potentials.

    PubMed

    Gonzalez, Alejandro; Nambu, Isao; Hokari, Haruhide; Wada, Yasuhiro

    2014-01-01

    Brain-machine interfaces (BMI) rely on the accurate classification of event-related potentials (ERPs) and their performance greatly depends on the appropriate selection of classifier parameters and features from dense-array electroencephalography (EEG) signals. Moreover, in order to achieve a portable and more compact BMI for practical applications, it is also desirable to use a system capable of accurate classification using information from as few EEG channels as possible. In the present work, we propose a method for classifying P300 ERPs using a combination of Fisher Discriminant Analysis (FDA) and a multiobjective hybrid real-binary Particle Swarm Optimization (MHPSO) algorithm. Specifically, the algorithm searches for the set of EEG channels and classifier parameters that simultaneously maximize the classification accuracy and minimize the number of used channels. The performance of the method is assessed through offline analyses on datasets of auditory ERPs from sound discrimination experiments. The proposed method achieved a higher classification accuracy than that achieved by traditional methods while also using fewer channels. It was also found that the number of channels used for classification can be significantly reduced without greatly compromising the classification accuracy.

  4. Ionic selectivity and thermal adaptations within the voltage-gated sodium channel family of alkaliphilic Bacillus.

    PubMed

    DeCaen, Paul G; Takahashi, Yuka; Krulwich, Terry A; Ito, Masahiro; Clapham, David E

    2014-11-11

    Entry and extrusion of cations are essential processes in living cells. In alkaliphilic prokaryotes, high external pH activates voltage-gated sodium channels (Nav), which allows Na(+) to enter and be used as substrate for cation/proton antiporters responsible for cytoplasmic pH homeostasis. Here, we describe a new member of the prokaryotic voltage-gated Na(+) channel family (NsvBa; Non-selective voltage-gated, Bacillus alcalophilus) that is nonselective among Na(+), Ca(2+) and K(+) ions. Mutations in NsvBa can convert the nonselective filter into one that discriminates for Na(+) or divalent cations. Gain-of-function experiments demonstrate the portability of ion selectivity with filter mutations to other Bacillus Nav channels. Increasing pH and temperature shifts their activation threshold towards their native resting membrane potential. Furthermore, we find drugs that target Bacillus Nav channels also block the growth of the bacteria. This work identifies some of the adaptations to achieve ion discrimination and gating in Bacillus Nav channels.

  5. Transient Receptor Potential Canonical 7 (TRPC7): A Diacylglycerol-Activated Non-Selective Cation Channel

    PubMed Central

    Zhang, Xuexin

    2016-01-01

    Transient receptor potential canonical 7 (TRPC7) channel is the seventh member of the mammalian TRPC channel family. TRPC7 mRNA, protein and channel activity have been detected in many tissues and organs from mouse, rat and human. TRPC7 has high sequence homology with TRPC3 and TRPC6 and all three channels are activated by membrane receptors that couple to isoforms of phospholipase C (PLC) and mediate non-selective cation currents. TRPC7, along with TRPC3 and TRPC6 can be activated by direct exogenous application of diacylglycerol (DAG) analogs and by pharmacological maneuvers that increase endogenous DAG in cells. TRPC7 shows distinct properties of activation, such as constitutive activity, susceptibility to negative regulation by extracellular Ca2+ and by protein kinase C. TRPC7 can form heteromultimers with TRPC3 and TRPC6. Although TRPC7 remains one of the least studied TRPC channel, its role in various cell types and physiological and pathophysiological conditions is begining to emerge. PMID:24756707

  6. EEG Channel Selection Using Particle Swarm Optimization for the Classification of Auditory Event-Related Potentials

    PubMed Central

    Hokari, Haruhide

    2014-01-01

    Brain-machine interfaces (BMI) rely on the accurate classification of event-related potentials (ERPs) and their performance greatly depends on the appropriate selection of classifier parameters and features from dense-array electroencephalography (EEG) signals. Moreover, in order to achieve a portable and more compact BMI for practical applications, it is also desirable to use a system capable of accurate classification using information from as few EEG channels as possible. In the present work, we propose a method for classifying P300 ERPs using a combination of Fisher Discriminant Analysis (FDA) and a multiobjective hybrid real-binary Particle Swarm Optimization (MHPSO) algorithm. Specifically, the algorithm searches for the set of EEG channels and classifier parameters that simultaneously maximize the classification accuracy and minimize the number of used channels. The performance of the method is assessed through offline analyses on datasets of auditory ERPs from sound discrimination experiments. The proposed method achieved a higher classification accuracy than that achieved by traditional methods while also using fewer channels. It was also found that the number of channels used for classification can be significantly reduced without greatly compromising the classification accuracy. PMID:24982944

  7. Non-Selective Cation Channels Mediate Chloroquine-Induced Relaxation in Precontracted Mouse Airway Smooth Muscle

    PubMed Central

    Li, Wen-Er; Ma, Yun-Fei; Chen, Weiwei; Zhai, Kui; Qin, Gangjian; Guo, Donglin; Zheng, Yun-Min; Wang, Yong-Xiao; Shen, Jin-Hua; Ji, Guangju; Liu, Qing-Hua

    2014-01-01

    Bitter tastants can induce relaxation in precontracted airway smooth muscle by activating big-conductance potassium channels (BKs) or by inactivating voltage-dependent L-type Ca2+ channels (VDLCCs). In this study, a new pathway for bitter tastant-induced relaxation was defined and investigated. We found nifedipine-insensitive and bitter tastant chloroquine-sensitive relaxation in epithelium-denuded mouse tracheal rings (TRs) precontracted with acetylcholine (ACH). In the presence of nifedipine (10 µM), ACH induced cytosolic Ca2+ elevation and cell shortening in single airway smooth muscle cells (ASMCs), and these changes were inhibited by chloroquine. In TRs, ACH triggered a transient contraction under Ca2+-free conditions, and, following a restoration of Ca2+, a strong contraction occurred, which was inhibited by chloroquine. Moreover, the ACH-activated whole-cell and single channel currents of non-selective cation channels (NSCCs) were blocked by chloroquine. Pyrazole 3 (Pyr3), an inhibitor of transient receptor potential C3 (TRPC3) channels, partially inhibited ACH-induced contraction, intracellular Ca2+ elevation, and NSCC currents. These results demonstrate that NSCCs play a role in bitter tastant-induced relaxation in precontracted airway smooth muscle. PMID:24992312

  8. Barium ions selectively activate BK channels via the Ca2+-bowl site

    PubMed Central

    Zhou, Yu; Zeng, Xu-Hui; Lingle, Christopher J.

    2012-01-01

    Activation of Ca2+-dependent BK channels is increased via binding of micromolar Ca2+ to two distinct high-affinity sites per BK α-subunit. One site, termed the Ca2+ bowl, is embedded within the second RCK domain (RCK2; regulator of conductance for potassium) of each α-subunit, while oxygen-containing residues in the first RCK domain (RCK1) have been linked to a separate Ca2+ ligation site. Although both sites are activated by Ca2+ and Sr2+, Cd2+ selectively favors activation via the RCK1 site. Divalent cations of larger ionic radius than Sr2+ are thought to be ineffective at activating BK channels. Here we show that Ba2+, better known as a blocker of K+ channels, activates BK channels and that this effect arises exclusively from binding at the Ca2+-bowl site. Compared with previous estimates for Ca2+ bowl–mediated activation by Ca2+, the affinity of Ba2+ to the Ca2+ bowl is reduced about fivefold, and coupling of binding to activation is reduced from ∼3.6 for Ca2+ to about ∼2.8 for Ba2+. These results support the idea that ionic radius is an important determinant of selectivity differences among different divalent cations observed for each Ca2+-binding site. PMID:22733762

  9. Barium ions selectively activate BK channels via the Ca2+-bowl site.

    PubMed

    Zhou, Yu; Zeng, Xu-Hui; Lingle, Christopher J

    2012-07-10

    Activation of Ca(2+)-dependent BK channels is increased via binding of micromolar Ca(2+) to two distinct high-affinity sites per BK α-subunit. One site, termed the Ca(2+) bowl, is embedded within the second RCK domain (RCK2; regulator of conductance for potassium) of each α-subunit, while oxygen-containing residues in the first RCK domain (RCK1) have been linked to a separate Ca(2+) ligation site. Although both sites are activated by Ca(2+) and Sr(2+), Cd(2+) selectively favors activation via the RCK1 site. Divalent cations of larger ionic radius than Sr(2+) are thought to be ineffective at activating BK channels. Here we show that Ba(2+), better known as a blocker of K(+) channels, activates BK channels and that this effect arises exclusively from binding at the Ca(2+)-bowl site. Compared with previous estimates for Ca(2+) bowl-mediated activation by Ca(2+), the affinity of Ba(2+) to the Ca(2+) bowl is reduced about fivefold, and coupling of binding to activation is reduced from ∼3.6 for Ca(2+) to about ∼2.8 for Ba(2+). These results support the idea that ionic radius is an important determinant of selectivity differences among different divalent cations observed for each Ca(2+)-binding site.

  10. Channels

    NASA Image and Video Library

    2015-11-20

    Today's VIS image shows a number of unnamed channels located on the northeastern margin of Terra Sabaea. Orbit Number: 61049 Latitude: 33.5036 Longitude: 58.6967 Instrument: VIS Captured: 2015-09-18 12:54 http://photojournal.jpl.nasa.gov/catalog/PIA20097

  11. A general method for selecting quantum channel for bidirectional controlled state teleportation and other schemes of controlled quantum communication

    NASA Astrophysics Data System (ADS)

    Thapliyal, Kishore; Verma, Amit; Pathak, Anirban

    2015-12-01

    Recently, a large number of protocols for bidirectional controlled state teleportation (BCST) have been proposed using n-qubit entangled states (nin {5,6,7}) as quantum channel. Here, we propose a general method of selecting multiqubit (n>4) quantum channels suitable for BCST and show that all the channels used in the existing protocols of BCST can be obtained using the proposed method. Further, it is shown that the quantum channels used in the existing protocols of BCST form only a negligibly small subset of the set of all the quantum channels that can be constructed using the proposed method to implement BCST. It is also noted that all these quantum channels are also suitable for controlled bidirectional remote state preparation. Following the same logic, methods for selecting quantum channels for other controlled quantum communication tasks, such as controlled bidirectional joint remote state preparation and controlled quantum dialogue, are also provided.

  12. Determinants of ligand selectivity in a cyclic nucleotide-regulated potassium channel.

    PubMed

    Pessoa, João; Fonseca, Fátima; Furini, Simone; Morais-Cabral, João H

    2014-07-01

    Cyclic nucleotide-binding (CNB) domains regulate the activity of channels, kinases, exchange factors, and transcription factors. These proteins are highly variable in their ligand selectivity; some are highly selective for either cAMP or cGMP, whereas others are not. Several molecular determinants of ligand selectivity in CNB domains have been defined, but these do not provide a complete view of the selectivity mechanism. We performed a thorough analysis of the ligand-binding properties of mutants of the CNB domain from the MlotiK1 potassium channel. In particular, we defined which residues specifically favor cGMP or cAMP. Inversion of ligand selectivity, from favoring cAMP to favoring cGMP, was only achieved through a combination of three mutations in the ligand-binding pocket. We determined the x-ray structure of the triple mutant bound to cGMP and performed molecular dynamics simulations and a biochemical analysis of the effect of the mutations. We concluded that the increase in cGMP affinity and selectivity does not result simply from direct interactions between the nucleotide base and the amino acids introduced in the ligand-binding pocket residues. Rather, tighter cGMP binding over cAMP results from the polar chemical character of the mutations, from greater accessibility of water molecules to the ligand in the bound state, and from an increase in the structural flexibility of the mutated binding pocket. © 2014 Pessoa et al.

  13. Adaptive real time selection for quantum key distribution in lossy and turbulent free-space channels

    NASA Astrophysics Data System (ADS)

    Vallone, Giuseppe; Marangon, Davide G.; Canale, Matteo; Savorgnan, Ilaria; Bacco, Davide; Barbieri, Mauro; Calimani, Simon; Barbieri, Cesare; Laurenti, Nicola; Villoresi, Paolo

    2015-04-01

    The unconditional security in the creation of cryptographic keys obtained by quantum key distribution (QKD) protocols will induce a quantum leap in free-space communication privacy in the same way that we are beginning to realize secure optical fiber connections. However, free-space channels, in particular those with long links and the presence of atmospheric turbulence, are affected by losses, fluctuating transmissivity, and background light that impair the conditions for secure QKD. Here we introduce a method to contrast the atmospheric turbulence in QKD experiments. Our adaptive real time selection (ARTS) technique at the receiver is based on the selection of the intervals with higher channel transmissivity. We demonstrate, using data from the Canary Island 143-km free-space link, that conditions with unacceptable average quantum bit error rate which would prevent the generation of a secure key can be used once parsed according to the instantaneous scintillation using the ARTS technique.

  14. An Efficient P300-based BCI Using Wavelet Features and IBPSO-based Channel Selection

    PubMed Central

    Perseh, Bahram; Sharafat, Ahmad R.

    2012-01-01

    We present a novel and efficient scheme that selects a minimal set of effective features and channels for detecting the P300 component of the event-related potential in the brain–computer interface (BCI) paradigm. For obtaining a minimal set of effective features, we take the truncated coefficients of discrete Daubechies 4 wavelet, and for selecting the effective electroencephalogram channels, we utilize an improved binary particle swarm optimization algorithm together with the Bhattacharyya criterion. We tested our proposed scheme on dataset IIb of BCI competition 2005 and achieved 97.5% and 74.5% accuracy in 15 and 5 trials, respectively, using a simple classification algorithm based on Bayesian linear discriminant analysis. We also tested our proposed scheme on Hoffmann's dataset for eight subjects, and achieved similar results. PMID:23717804

  15. Importance of Hydration and Dynamics on the Selectivity of the KcsA and NaK Channels

    PubMed Central

    Noskov, Sergei Yu.; Roux, Benoît

    2007-01-01

    Fundamental concepts governing ion selectivity in narrow pores are reviewed and the microscopic factors responsible for the lack of selectivity of the NaK channel, which is structurally similar to the K+-selective KcsA channel, are elucidated on the basis of all-atom molecular dynamics free energy simulations. The results on NaK are contrasted and compared with previous studies of the KcsA channel. Analysis indicates that differences in hydration of the cation in the pore of NaK is at the origin of the lack of selectivity of NaK. PMID:17227917

  16. Importance of hydration and dynamics on the selectivity of the KcsA and NaK channels.

    PubMed

    Noskov, Sergei Yu; Roux, Benoît

    2007-02-01

    Fundamental concepts governing ion selectivity in narrow pores are reviewed and the microscopic factors responsible for the lack of selectivity of the NaK channel, which is structurally similar to the K+-selective KcsA channel, are elucidated on the basis of all-atom molecular dynamics free energy simulations. The results on NaK are contrasted and compared with previous studies of the KcsA channel. Analysis indicates that differences in hydration of the cation in the pore of NaK is at the origin of the lack of selectivity of NaK.

  17. On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel.

    PubMed Central

    Favre, I; Moczydlowski, E; Schild, L

    1996-01-01

    Voltage-sensitive sodium channels and calcium channels are homologous proteins with distinctly different selectivity for permeation of inorganic cations. This difference in function is specified by amino acid residues located within P-region segments that link presumed transmembrane elements S5 and S6 in each of four repetitive Domains I, II, III, and IV. By analyzing the selective permeability of Na+, K+, and Ca2+ in various mutants of the mu 1 rat muscle sodium channel, the results in this paper support the concept that a conserved motif of four residues contributed by each of the Domains I-IV, termed the DEKA locus in sodium channels and the EEEE locus in calcium channels, determines the ionic selectivity of these channels. Furthermore, the results indicate that the Lys residue in Domain III of the sodium channel is the critical determinant that specifies both the impermeability of Ca2+ and the selective permeability of Na+ over K+. We propose that the alkylammonium ion of the Lys(III) residue acts as an endogenous cation within the ion binding site/selectivity filter of the sodium channel to tune the kinetics and affinity of inorganic cation binding within the pore in a manner analogous to ion-ion interactions that occur in the process of multi-ion channel conduction. PMID:8968582

  18. EMG Feature Assessment for Myoelectric Pattern Recognition and Channel Selection: A Study with Incomplete Spinal Cord Injury

    PubMed Central

    Liu, Jie; Li, Xiaoyan; Li, Guanglin; Zhou, Ping

    2014-01-01

    Myoelectric pattern recognition with a large number of electromyogram (EMG) channels provides an approach to assessing motor control information available from the recorded muscles. In order to develop a practical myoelectric control system, a feature dependent channel reduction method was developed in this study to determine a small number of EMG channels for myoelectric pattern recognition analysis. The method selects appropriate raw EMG features for classification of different movements, using the minimum Redundancy Maximum Relevance (mRMR) and the Markov random field (MRF) methods to rank a large number of EMG features, respectively. A k-nearest neighbor (KNN) classifier was used to evaluate the performance of the selected features in terms of classification accuracy. The method was tested using 57 channels’ surface EMG signals recorded from forearm and hand muscles of individuals with incomplete spinal cord injury (SCI). Our results demonstrate that appropriate selection of a small number of raw EMG features from different recording channels resulted in similar high classification accuracies as achieved by using all the EMG channels or features. Compared with the conventional sequential forward selection (SFS) method, the feature dependent method does not require repeated classifier implementation. It can effectively reduce redundant information not only cross different channels, but also cross different features in the same channel. Such hybrid feature-channel selection from a large number of EMG recording channels can reduce computational cost for implementation of a myoelectric pattern recognition based control system. PMID:24844608

  19. Ion Selectivity Mechanism in a Bacterial Pentameric Ligand-Gated Ion Channel

    SciTech Connect

    Fritsch, Sebastian M; Ivanov, Ivaylo N; Wang, Hailong; Cheng, Xiaolin

    2011-01-01

    The proton-gated ion channel from Gloeobacter violaceus (GLIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. Recent emergence of a high resolution crystal structure of GLIC captured in a potentially open state allowed detailed, atomic-level insight into ion conduction and selectivity mechanisms in these channels. Herein, we have examined the barriers to ion conduction and origins of ion selectivity in the GLIC channel by the construction of potential of mean force (PMF) profiles for sodium and chloride ions inside the transmembrane region. Our calculations reveal that the GLIC channel is open for a sodium ion to transport, but presents a ~10 kcal/mol free energy barrier for a chloride ion, which arises primarily from the unfavorable interactions with a ring of negatively charged glutamate residues (E-2 ) at the intracellular end and a ring of hydrophobic residues (I9 ) in the middle of the transmembrane domain. Our collective findings further suggest that the charge selection mechanism can, to a large extent, be attributed to the narrow intracellular end and a ring of glutamate residues in this position their strong negative electrostatics and ability to bind cations. By contrast, E19 at the extracellular entrance only plays a minor role in ion selectivity of GLIC. In addition to electrostatics, both ion hydration and protein dynamics are found to be crucial for ion conduction as well, which explains why a chloride ion experiences a much greater barrier than a sodium ion in the hydrophobic region of the pore.

  20. Structure, dynamics and selectivity of the sodium channel blocker µ-conotoxin SIIIA†,‡

    PubMed Central

    Yao, Shenggen; Zhang, Minmin; Yoshikami, Doju; Azam, Layla; Olivera, Baldomero M.; Bulaj, Grzegorz; Norton, Raymond S.

    2014-01-01

    µ-SIIIA, a novel µ-conotoxin from Conus striatus, appeared to be a selective blocker of tetrodotoxin-sensitive sodium channels in frog preparations. It also exhibited potent analgesic activity in mice, although its selectivity profile against mammalian sodium channels remained unknown. We have determined the structure of µ-SIIIA in aqueous solution and characterized its backbone dynamics by NMR and its functional properties electrophysiologically. Consistent with the absence of hydroxyprolines, µ-SIIIA adopts a single conformation with all peptide bonds in the trans conformation. The C-terminal region contains a well-defined helix encompassing residues 11–16, while residues 3–5 in the N-terminal region form a helix-like turn resembling 310 helix. The Trp12 and His16 side chains are in close proximity, as in the related conotoxin µ-SmIIIA, but Asn2 is further away. Dynamics measurements show that the N-terminus and Ser9 have larger magnitude motions on the sub-ns timescale, while the C-terminus is more rigid. Cys4, Trp12 and Cys13 undergo significant conformational exchange on µs - ms timescales. µ-SIIIA is a potent, nearly irreversible blocker of NaV1.2, but also blocks NaV1.4 and NaV1.6 with submicromolar potency. The selectivity profile of µ-SIIIA, including poor activity against the cardiac sodium channel, NaV1.5, is similar to that of the closely related µ-KIIIA, suggesting that the C-terminal regions of both are critical for blocking neuronal NaV1.2. The structural and functional characterization described in this paper of an analgesic µ-conotoxin that targets neuronal subtypes of mammalian sodium channels provides a basis for the design of novel analogues with an improved selectivity profile. PMID:18798648

  1. Distributed Channel Selection in CRAHNs with Heterogeneous Spectrum Opportunities: A Local Congestion Game Approach

    NASA Astrophysics Data System (ADS)

    Xu, Yuhua; Wu, Qihui; Wang, Jinlong; Min, Neng; Anpalagan, Alagan

    This letter investigates the problem of distributed channel selection in cognitive radio ad hoc networks (CRAHNs) with heterogeneous spectrum opportunities. Firstly, we formulate this problem as a local congestion game, which is proved to be an exact potential game. Then, we propose a spatial best response dynamic (SBRD) to rapidly achieve Nash equilibrium via local information exchange. Moreover, the potential function of the game reflects the network collision level and can be used to achieve higher throughput.

  2. Mechanisms Underlying Atrial-Selective Block of Sodium Channels by Wenxin Keli: Experimental and Theoretical Analysis

    PubMed Central

    Hu, Dan; Barajas-Martínez, Hector; Burashnikov, Alexander; Panama, Brian K.; Cordeiro, Jonathan M.; Antzelevitch, Charles

    2016-01-01

    Introduction Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. Methods Whole cell INa was recorded at rroom temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. Results Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. Conclusion Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation. PMID:26820362

  3. The selectivity filter of the tandem pore potassium channel TASK-1 and its pH-sensitivity and ionic selectivity.

    PubMed

    Yuill, K; Ashmole, I; Stanfield, P R

    2004-04-01

    We have studied pH sensitivity and ionic selectivity of the tandem pore K(+) channel TASK-1 heterologously expressed in Xenopus oocytes. We fit pH sensitivity assuming that only one of the two residues H98 need be protonated for channels to be shut. The effect of protons was weakly voltage dependent with a p K(a) of 6.02 at +40 mV. Replacement of His (H98D, H98N) reduced pH sensitivity but did not abolish it. Use of a concatameric channel permitted replacement of one His residue only; this concatamer was fully pH-sensitive. Increasing the number of His residues to 4 (mutant D204H) abolished pH sensitivity over the physiological range. The implication that D204 plays a role in pH-sensitivity was confirmed by the finding that pH sensitivity over the physiological range was also abolished in the mutant D204N. Ionic selectivity was also altered in D204H, D204N and H98D mutants. P(Rb)/ P(K) was increased from 0.80+/-0.04 (n=19) in wild type to 1.06+/-0.04 (n=19) in D204H. H98D, D204H and D204N were permeable to Na(+) with P(Na)/ P(K)=0.39+/-0.03 (n=14) in H98D, 0.64+/-0.04 (n=18) in D204H and 0.33+/-0.07 (n=3) in D204N. Thus, the arrangement of ring of residues HDHD appears to optimise both pH sensitivity and ionic selectivity.

  4. Ion permeation through a Cl[superscript -]-selective channel designed from a CLC Cl[superscript -]/H[superscript +] exchanger

    SciTech Connect

    Jayaram, Hariharan; Accardi, Alessio; Wu, Fang; Williams, Carole; Miller, Christopher

    2008-09-03

    The CLC family of Cl{sup -}-transporting proteins includes both Cl{sup -} channels and Cl{sup -}/H{sup +} exchange transporters. CLC-ec1, a structurally known bacterial homolog of the transporter subclass, exchanges two Cl{sup -} ions per proton with strict, obligatory stoichiometry. Point mutations at two residues, Glu{sup 148} and Tyr{sup 445}, are known to impair H{sup +} movement while preserving Cl{sup -} transport. In the x-ray crystal structure of CLC-ec1, these residues form putative 'gates' flanking an ion-binding region. In mutants with both of the gate-forming side chains reduced in size, H{sup +} transport is abolished, and unitary Cl{sup -} transport rates are greatly increased, well above values expected for transporter mechanisms. Cl{sup -} transport rates increase as side-chain volume at these positions is decreased. The crystal structure of a doubly ungated mutant shows a narrow conduit traversing the entire protein transmembrane width. These characteristics suggest that Cl{sup -} flux through uncoupled, ungated CLC-ec1 occurs via a channel-like electrodiffusion mechanism rather than an alternating-exposure conformational cycle that has been rendered proton-independent by the gate mutations.

  5. Further analysis of counterion permeation through anion-selective glycine receptor channels.

    PubMed

    Barry, Peter H; Sugiharto, Silas; Lewis, Trevor M; Moorhouse, Andrew J

    2010-01-01

    The functional role of ion channels, which allow counterion permeation, depends critically on their relative anion-cation relative selectivity. From whole-cell patch clamp reversal potential measurements under dilution potential conditions, we have already shown that anion-cation permeabilities of anion-selective wild-type (WT) and mutant (with larger pore diameter) glycine receptor (GlyR) channels in the presence of Li(+), Na(+) and Cs(+) counterions, were inversely correlated with the equivalent hydration diameter of the counterion, with chloride-cation permeability increasing as counterion equivalent hydration diameter increased with respect to the channel minimum pore diameter. Corrected for liquid junction potentials (LJPs; using ion activities), the previous chloride-cation permeabilities for the alkali cations were 23.4 (Li(+)), 10.9 (Na(+)) and 5.0 (Cs(+)) for the smaller WT channel. Further analysis to incorporate an initial offset potential correction, to fully allow for slight differences between internal cell composition and external control salt solution, changed the above permeability ratios to 30.6 (Li(+)), 11.8 (Na(+)) and 5.0 (Cs(+)), adding enhanced support for the inverse correlation between anion-to-counterion permeability ratio and equivalent hydrated counterion diameter relative to channel pore diameter (erroneously ignoring LJPs reduces each permeability ratio to about 4). Also, new direct measurements of LJPs (for NaCl and LiCl salt dilutions) using a 3M KCl-agar reference salt bridge (with freshly-cut end for each solution composition change) have shown excellent agreement with calculated LJPs (using ion activities), validating calculated LJP values. We continue to suggest that counterion cations permeate with chloride ions as neutral pairs.

  6. Cation selectivity by the CorA Mg2+ channel requires a fully hydrated cation.

    PubMed

    Moomaw, Andrea S; Maguire, Michael E

    2010-07-27

    The CorA Mg(2+) channel is the primary uptake system in about half of all bacteria and archaea. However, the basis for its Mg(2+) selectivity is unknown. Previous data suggested that CorA binds a fully hydrated Mg(2+) ion, unlike other ion channels. The crystal structure of Thermotoga maritima CorA shows a homopentamer with two transmembrane segments per monomer connected by a short periplasmic loop. This highly conserved loop, (281)EFMPELKWS(289) in Salmonella enterica serovar Typhimurium CorA, is the only portion of the channel outside of the cell, suggesting a role in cation selectivity. Mutation of charged residues in the loop, E281 and K287, to any of several amino acids had little effect, demonstrating that despite conservation electrostatic interactions with these residues are not essential. While mutation of the universally conserved E285 gave a minimally functional channel, E285A and E285K mutants were the most functional, again indicating that the negative charge at this position is not a determining factor. Several mutations at K287 and W288 behaved anomalously in a transport assay. Analysis indicated that mutation of K287 and W288 disrupts cooperative interactions between distinct Mg(2+) binding sites. Overall, these results are not compatible with electrostatic interaction of the Mg(2+) ion with the periplasmic loop. Instead, the loop appears to form an initial binding site for hydrated Mg(2+), not for the dehydrated cation. The loop residues may function to accelerate dehydration of the before entry of Mg(2+) into the pore of the channel.

  7. Selective alteration of sodium channel gating by Australian funnel-web spider toxins.

    PubMed

    Nicholson, G M; Little, M J; Tyler, M; Narahashi, T

    1996-01-01

    The actions of potent mammalian neurotoxins isolated from the venom of two Australian funnel-web spiders were investigated using both electrophysiological and neurochemical techniques. Whole-cell patch clamp recording of sodium currents in rat dorsal root ganglion neurons revealed that versutoxin (VTX), isolated from the venom of Hadronyche versuta, produced a concentration-dependent slowing or removal of tetrodotoxin-sensitive (TTX-S) sodium current inactivation and a reduction in peak TTX-S sodium current. In contrast, VTX had no effect on tetrodotoxin-resistant (TTX-R) sodium currents or potassium currents. VTX also shifted the voltage dependence of sodium channel activation in the hyperpolarizing direction and increased the rate of recovery from inactivation. Ion flux studies performed in rat brain synaptosomes also revealed that robustoxin (RTX), from the venom of Atrax robustus, and VTX both produced a partial activation of 22Na+ flux and an inhibition of batrachotoxin-activated 22Na+ flux. This inhibition of flux through batrachotoxin-activated channels was not due to an interaction with neurotoxin receptor site 1 since [3H]saxitoxin binding was unaffected. In addition, the partial activation of 22Na+ flux was not enhanced in the presence of alpha-scorpion toxin and further experiments suggest that VTX also enhances [3H]batrachotoxin binding. These selective actions of funnel-web spider toxins on sodium channel function are comparable to those of alpha-scorpion and sea anemone toxins which bind to neurotoxin receptor site 3 on the channel to slow channel inactivation profoundly. Also, these modifications of sodium channel gating and kinetics are consistent with actions of the spider toxins to produce repetitive firing of action potentials.

  8. A calcium-permeable non-selective cation channel in the thick ascending limb apical membrane of the mouse kidney.

    PubMed

    Guinamard, Romain; Paulais, Marc; Lourdel, Stéphane; Teulon, Jacques

    2012-05-01

    Non-selective cation channels have been described in the basolateral membrane of the renal tubule, but little is known about functional channels on the apical side. Apical membranes of microdissected fragments of mouse cortical thick ascending limbs were searched for ion channels using the cell-free configuration of the patch-clamp technique. A cation channel with a linear current-voltage relationship (19pS) that was permeable both to monovalent cations [P(NH4)(1.7)>P(Na) (1.0)=P(K) (1.0)] and to Ca(2+) (P(Ca)/P(Na)≈0.3) was detected. Unlike the basolateral TRPM4 Ca(2+)-impermeable non-selective cation channel, this non-selective cation channel was insensitive to internal Ca(2+), pH and ATP. The channel was already active after patch excision, and its activity increased after reduced pressure was applied via the pipette. External gadolinium (10(-5)M) decreased the channel-open probability by 70% in outside-out patches, whereas external amiloride (10(-4)M) had no effect. Internal flufenamic acid (10(-4)M) inhibited the channel in inside-out patches. Its properties suggest that the current might be supported by the TRPM7 protein that is expressed in the loop of Henle. The conduction properties of the channel suggest that it could be involved in Ca(2+) signaling. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Mechanism for phosphoinositide selectivity and activation of TRPV1 ion channels

    PubMed Central

    Ufret-Vincenty, Carmen A.; Klein, Rebecca M.; Collins, Marcus D.; Rosasco, Mario G.; Martinez, Gilbert Q.

    2015-01-01

    Although PI(4,5)P2 is believed to play an essential role in regulating the activity of numerous ion channels and transporters, the mechanisms by which it does so are unknown. Here, we used the ability of the TRPV1 ion channel to discriminate between PI(4,5)P2 and PI(4)P to localize the region of TRPV1 sequence that interacts directly with the phosphoinositide. We identified a point mutation in the proximal C-terminal region after the TRP box, R721A, that inverted the selectivity of TRPV1. Although the R721A mutation produced only a 30% increase in the EC50 for activation by PI(4,5)P2, it decreased the EC50 for activation by PI(4)P by more than two orders of magnitude. We used chemically induced and voltage-activated phosphatases to determine that PI(4)P continued to support TRPV1 activity even after depletion of PI(4,5)P2 from the plasma membrane. Our data cannot be explained by a purely electrostatic mechanism for interaction between the phosphoinositide and the protein, similar to that of the MARCKS (myristoylated alanine-rich C kinase substrate) effector domain or the EGF receptor. Rather, conversion of a PI(4,5)P2-selective channel to a PI(4)P-selective channel indicates that a structured phosphoinositide-binding site mediates the regulation of TRPV1 activity and that the amino acid at position 721 likely interacts directly with the moiety at the 5′ position of the phosphoinositide. PMID:25918361

  10. Regulatory Evolution and Voltage-Gated Ion Channel Expression in Squid Axon: Selection-Mutation Balance and Fitness Cliffs

    PubMed Central

    MacCarthy, Thomas; Rosati, Barbara; McKinnon, David

    2015-01-01

    It has been suggested that optimization of either axonal conduction velocity or the energy efficiency of action potential conduction predominates in the selection of voltage-gated sodium conductance levels in the squid axon. A population genetics model of channel gene regulatory function was used to examine the role of these and other evolutionary forces on the selection of both sodium and potassium channel expression levels. In this model, the accumulating effects of mutations result in degradation of gene regulatory function, causing channel gene expression to fall to near-zero in the absence of positive selection. In the presence of positive selection, channel expression levels fall to the lowest values consistent with the selection criteria, thereby establishing a selection-mutation balance. Within the parameter space of sodium and potassium conductance values, the physiological performance of the squid axon model showed marked discontinuities associated with conduction failure and excitability. These discontinuities in physiological function may produce fitness cliffs. A fitness cliff associated with conduction failure, combined with the effects of phenotypic noise, can account for the selection of sodium conductance levels, without considering either conduction velocity or metabolic cost. A fitness cliff associated with a transition in axonal excitability, combined with phenotypic noise, can explain the selection of potassium channel expression levels. The results suggest that voltage-gated ion channel expression will fall to low levels, consistent with key functional constraints, even in the absence of positive selection for energy efficiency. Channel expression levels and individual variation in channel expression within the population can be explained by regulatory evolution in combination with genetic variation in regulatory function and phenotypic noise, without resorting to more complex mechanisms, such as activity-dependent homeostasis. Only a

  11. Regulatory evolution and voltage-gated ion channel expression in squid axon: selection-mutation balance and fitness cliffs.

    PubMed

    Kim, Min; McKinnon, Don; MacCarthy, Thomas; Rosati, Barbara; McKinnon, David

    2015-01-01

    It has been suggested that optimization of either axonal conduction velocity or the energy efficiency of action potential conduction predominates in the selection of voltage-gated sodium conductance levels in the squid axon. A population genetics model of channel gene regulatory function was used to examine the role of these and other evolutionary forces on the selection of both sodium and potassium channel expression levels. In this model, the accumulating effects of mutations result in degradation of gene regulatory function, causing channel gene expression to fall to near-zero in the absence of positive selection. In the presence of positive selection, channel expression levels fall to the lowest values consistent with the selection criteria, thereby establishing a selection-mutation balance. Within the parameter space of sodium and potassium conductance values, the physiological performance of the squid axon model showed marked discontinuities associated with conduction failure and excitability. These discontinuities in physiological function may produce fitness cliffs. A fitness cliff associated with conduction failure, combined with the effects of phenotypic noise, can account for the selection of sodium conductance levels, without considering either conduction velocity or metabolic cost. A fitness cliff associated with a transition in axonal excitability, combined with phenotypic noise, can explain the selection of potassium channel expression levels. The results suggest that voltage-gated ion channel expression will fall to low levels, consistent with key functional constraints, even in the absence of positive selection for energy efficiency. Channel expression levels and individual variation in channel expression within the population can be explained by regulatory evolution in combination with genetic variation in regulatory function and phenotypic noise, without resorting to more complex mechanisms, such as activity-dependent homeostasis. Only a

  12. Dimethyl sulfoxide at high concentrations inhibits non-selective cation channels in human erythrocytes.

    PubMed

    Nardid, Oleg A; Schetinskey, Miroslav I; Kucherenko, Yuliya V

    2013-03-01

    Dimethyl sulfoxide (DMSO), a by-product of the pulping industry, is widely used in biological research, cryobiology and medicine. On cellular level DMSO was shown to suppress NMDA-AMPA channels activation, blocks Na+ channel activation and attenuates Ca2+ influx (Lu and Mattson 2001). In the present study we explored the whole-cell patch-clamp to examine the acute effect of high concentrations of DMSO (0.1-2 mol/l) on cation channels activity in human erythrocytes. Acute application of DMSO (0.1-2 mol/l) dissolved in Cl--containing saline buffer solution significantly inhibited cation conductance in human erythrocytes. Inhibition was concentration-dependent and had an exponential decay profile. DMSO (2 mol/l) induced cation inhibition in Cl-- containing saline solutions of: 40.3 ± 3.9% for K+, 35.4 ± 3.1% for Ca2+ and 47.4 ± 1.9% for NMDG+. Substitution of Cl- with gluconate- increased the inhibitory effect of DMSO on the Na+ current. Inhibitory effect of DMSO was neither due to high permeability of erythrocytes to DMSO nor to an increased tonicity of the bath media since no effect was observed in 2 mol/l glycerol solution. In conclusion, we have shown that high concentrations of DMSO inhibit the non-selective cation channels in human erythrocytes and thus protect the cells against Na+ and Ca2+ overload. Possible mechanisms of DMSO effect on cation conductance are discussed.

  13. Recent (circa 1998 to 2011) channel-migration rates of selected streams in Indiana

    USGS Publications Warehouse

    Robinson, Bret A.

    2013-01-01

    An investigation was completed to document recent (circa 1998 to 2011) channel-migration rates at 970 meander bends along 38 of the largest streams in Indiana. Data collection was completed by using the Google Earth™ platform and, for each selected site, identifying two images with capture dates separated by multiple years. Within each image, the position of the meander-bend cutbank was measured relative to a fixed local landscape feature visible in both images, and an average channel-migration rate was calculated at the point of maximum cutbank displacement. From these data it was determined that 65 percent of the measured sites have recently been migrating at a rate less than 1 ft/yr, 75 percent of the sites have been migrating at a rate less than 10 ft/yr, and while some sites are migrating in excess of 20 ft/yr, these occurrences are rare. In addition, it is shown that recent channel-migration activity is not evenly distributed across Indiana. For the stream reaches studied, far northern and much of far southern Indiana are drained by streams that recently have been relatively stationary. At the same time, this study shows that most of the largest streams in west-central Indiana and many of the largest streams in east-central Indiana have shown significant channel-migration activity during the recent past. It is anticipated that these results will support several fluvial-erosion-hazard mitigation activities currently being undertaken in Indiana.

  14. Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain.

    PubMed

    Shcherbatko, Anatoly; Rossi, Andrea; Foletti, Davide; Zhu, Guoyun; Bogin, Oren; Galindo Casas, Meritxell; Rickert, Mathias; Hasa-Moreno, Adela; Bartsevich, Victor; Crameri, Andreas; Steiner, Alexander R; Henningsen, Robert; Gill, Avinash; Pons, Jaume; Shelton, David L; Rajpal, Arvind; Strop, Pavel

    2016-07-01

    The prominent role of voltage-gated sodium channel 1.7 (Nav1.7) in nociception was revealed by remarkable human clinical and genetic evidence. Development of potent and subtype-selective inhibitors of this ion channel is crucial for obtaining therapeutically useful analgesic compounds. Microproteins isolated from animal venoms have been identified as promising therapeutic leads for ion channels, because they naturally evolved to be potent ion channel blockers. Here, we report the engineering of highly potent and selective inhibitors of the Nav1.7 channel based on tarantula ceratotoxin-1 (CcoTx1). We utilized a combination of directed evolution, saturation mutagenesis, chemical modification, and rational drug design to obtain higher potency and selectivity to the Nav1.7 channel. The resulting microproteins are highly potent (IC50 to Nav1.7 of 2.5 nm) and selective. We achieved 80- and 20-fold selectivity over the closely related Nav1.2 and Nav1.6 channels, respectively, and the IC50 on skeletal (Nav1.4) and cardiac (Nav1.5) sodium channels is above 3000 nm The lead molecules have the potential for future clinical development as novel therapeutics in the treatment of pain.

  15. Protein interactions central to stabilizing the K[superscript +] channel selectivity filter in a four-sited configuration for selective K[superscript +] permeation

    SciTech Connect

    Sauer, David B.; Zeng, Weizhong; Raghunathan, Srinivasan; Jiang, Youxing

    2011-11-18

    The structural and functional conversion of the nonselective NaK channel to a K{sup +} selective channel (NaK2K) allows us to identify two key residues, Tyr and Asp in the filter sequence of TVGYGD, that participate in interactions central to stabilizing the K{sup +} channel selectivity filter. By using protein crystallography and channel electrophysiology, we demonstrate that the K{sup +} channel filter exists as an energetically strained structure and requires these key protein interactions working in concert to hold the filter in the precisely defined four-sited configuration that is essential for selective K{sup +} permeation. Disruption of either interaction, as tested on both the NaK2K and eukaryotic K{sub v}1.6 channels, can reduce or completely abolish K{sup +} selectivity and in some cases may also lead to channel inactivation due to conformational changes at the filter. Additionally, on the scaffold of NaK we recapitulate the protein interactions found in the filter of the Kir channel family, which uses a distinct interaction network to achieve similar stabilization of the filter.

  16. Evolutionary insights into T-type Ca(2+) channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue.

    PubMed

    Smith, Carolyn L; Abdallah, Salsabil; Wong, Yuen Yan; Le, Phuong; Harracksingh, Alicia N; Artinian, Liana; Tamvacakis, Arianna N; Rehder, Vincent; Reese, Thomas S; Senatore, Adriano

    2017-04-03

    Four-domain voltage-gated Ca(2+) (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCav3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCav3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCav3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Cav3 family. We also characterize the channel's cation permeation properties and find that its pore is less selective for Ca(2+) over Na(+) compared with the human homologue Cav3.1, yet it exhibits a similar potent block of inward Na(+) current by low external Ca(2+) concentrations (i.e., the Ca(2+) block effect). A comparison of the permeability features of TCav3 with other cloned channels suggests that Ca(2+) block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca(2+) block and higher Ca(2+) selectivity. TCav3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Cav3 channel structure-function properties, ion selectivity, and cellular physiology.

  17. Ion selectivity of porcine skeletal muscle Ca2+ release channels is unaffected by the Arg615 to Cys615 mutation.

    PubMed Central

    Shomer, N H; Mickelson, J R; Louis, C F

    1994-01-01

    The Arg615 to Cys615 mutation of the sarcoplasmic reticulum (SR) Ca2+ release channel of malignant hyperthermia susceptible (MHS) pigs results in a decreased sensitivity of the channel to inhibitory Ca2+ concentrations. To investigate whether this mutation also affects the ion selectivity filter of the channel, the monovalent cation conductances and ion permeability ratios of single Ca2+ release channels incorporated into planar lipid bilayers were compared. Monovalent cation conductances in symmetrical solutions were: Li+, 183 pS +/- 3 (n = 21); Na+, 474 pS +/- 6 (n = 29); K+, 771 pS +/- 7 (n = 29); Rb+, 502 pS +/- 10 (n = 22); and Cs+, 527 pS +/- 5 (n = 16). The single-channel conductances of MHS and normal Ca2+ release channel were not significantly different for any of the monovalent cations tested. Permeability ratios measured under biionic conditions had the permeability sequence Ca2+ >> Li+ > Na+ > K+ > or Rb+ > Cs+, with no significant difference noted between MHS and normal channels. This systematic examination of the conduction properties of the pig skeletal muscle Ca2+ release channel indicated a higher Ca2+ selectivity (PCa2+:Pk+ approximately 15.5) than the sixfold Ca2+ selectivity previously reported for rabbit skeletal (Smith et al., 1988) or sheep cardiac muscle (Tinker et al., 1992) Ca2+ release channels. These results also indicate that although Ca2+ regulation of Ca2+ release channel activity is altered, the Arg615 to Cys615 mutation of the porcine Ca2+ release channel does not affect the conductance or ion selectivity properties of the channel. PMID:7948678

  18. Differential binding of monovalent cations to KcsA: Deciphering the mechanisms of potassium channel selectivity.

    PubMed

    Montoya, Estefanía; Lourdes Renart, M; Marcela Giudici, A; Poveda, José A; Fernández, Asia M; Morales, Andrés; González-Ros, José M

    2017-05-01

    This work explores whether the ion selectivity and permeation properties of a model potassium channel, KcsA, could be explained based on ion binding features. Non-permeant Na(+) or Li(+) bind with low affinity (millimolar KD's) to a single set of sites contributed by the S1 and S4 sites seen at the selectivity filter in the KcsA crystal structure. Conversely, permeant K(+), Rb(+), Tl(+) and even Cs(+) bind to two different sets of sites as their concentration increases, consistent with crystallographic evidence on the ability of permeant species to induce concentration-dependent transitions between conformational states (non-conductive and conductive) of the channel's selectivity filter. The first set of such sites, assigned also to the crystallographic S1 and S4 sites, shows similarly high affinities for all permeant species (micromolar KD's), thus, securing displacement of potentially competing non-permeant cations. The second set of sites, available only to permeant cations upon the transition to the conductive filter conformation, shows low affinity (millimolar KD's), thus, favoring cation dissociation and permeation and results from the contribution of all S1 through S4 crystallographic sites. The differences in affinities between permeant and non-permeant cations and the similarities in binding behavior within each of these two groups, correlate fully with their permeabilities relative to K(+), suggesting that binding is an important determinant of the channel's ion selectivity. Conversely, the complexity observed in permeation features cannot be explained just in terms of binding and likely relates to reported differences in the occupancy of the S2 and S3 sites by the permeant cations.

  19. Isospin Splittings of Doubly Heavy Baryons

    SciTech Connect

    Brodsky, Stanley J.; Guo, Feng-Kun; Hanhart, Christoph; Meissner, Ulf-G.; /Julich, Forschungszentrum /JCHP, Julich /IAS, Julich /Bonn U., HISKP /Bonn U.

    2011-08-18

    The SELEX Collaboration has reported a very large isospin splitting of doubly charmed baryons. We show that this effect would imply that the doubly charmed baryons are very compact. One intriguing possibility is that such baryons have a linear geometry Q-q-Q where the light quark q oscillates between the two heavy quarks Q, analogous to a linear molecule such as carbon dioxide. However, using conventional arguments, the size of a heavy-light hadron is expected to be around 0.5 fm, much larger than the size needed to explain the observed large isospin splitting. Assuming the distance between two heavy quarks is much smaller than that between the light quark and a heavy one, the doubly heavy baryons are related to the heavy mesons via heavy quark-diquark symmetry. Based on this symmetry, we predict the isospin splittings for doubly heavy baryons including {Xi}{sub cc}, {Xi}{sub bb} and {Xi}{sub bc}. The prediction for the {Xi}{sub cc} is much smaller than the SELEX value. On the other hand, the {Xi}{sub bb} baryons are predicted to have an isospin splitting as large as (6.3 {+-} 1.7) MeV. An experimental study of doubly bottomed baryons is therefore very important to better understand the structure of baryons with heavy quarks.

  20. Nonlinear and asymmetric open channel characteristics of an ion-selective porin in planar membranes.

    PubMed Central

    Mathes, A; Engelhardt, H

    1998-01-01

    The open channel characteristics of the bacterial porin Omp32 from Comamonas acidovorans were investigated by means of conductance measurements in planar lipid bilayers of the Montal-Mueller type. Particularly at low salt conditions (< or = 30 mM KCl) Omp32 exhibited some unusual asymmetric and nonlinear functional properties. Current-voltage relationship measurements showed that conductance depends on the orientation of porin molecules and is a nonlinear function of the applied membrane potential. Conductance also depends on the salt concentration in a manner not common to porins and the salt concentration modulates the nonlinearity of conductance-voltage relationships. Omp32 is strongly anion-selective. The nonlinear and asymmetric conductance of the open channel is a new observation in porins. PMID:9726928

  1. Discrimination of correlated and entangling quantum channels with selective process tomography

    DOE PAGES

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-10

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hiddenmore » sources of noise. Lastly, our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.« less

  2. Discrimination of correlated and entangling quantum channels with selective process tomography

    SciTech Connect

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-10

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hidden sources of noise. Lastly, our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.

  3. Discrimination of correlated and entangling quantum channels with selective process tomography

    NASA Astrophysics Data System (ADS)

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-01

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hidden sources of noise. Our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.

  4. Discrimination of correlated and entangling quantum channels with selective process tomography

    SciTech Connect

    Dumitrescu, Eugene; Humble, Travis S.

    2016-10-10

    The accurate and reliable characterization of quantum dynamical processes underlies efforts to validate quantum technologies, where discrimination between competing models of observed behaviors inform efforts to fabricate and operate qubit devices. We present a protocol for quantum channel discrimination that leverages advances in direct characterization of quantum dynamics (DCQD) codes. We demonstrate that DCQD codes enable selective process tomography to improve discrimination between entangling and correlated quantum dynamics. Numerical simulations show selective process tomography requires only a few measurement configurations to achieve a low false alarm rate and that the DCQD encoding improves the resilience of the protocol to hidden sources of noise. Lastly, our results show that selective process tomography with DCQD codes is useful for efficiently distinguishing sources of correlated crosstalk from uncorrelated noise in current and future experimental platforms.

  5. Enhancement of the NMSU Channel Error Simulator to Provide User-Selectable Link Delays

    NASA Technical Reports Server (NTRS)

    Horan, Stephen; Wang, Ru-Hai

    2000-01-01

    This is the third in a continuing series of reports describing the development of the Space-to-Ground Link Simulator (SGLS) to be used for testing data transfers under simulated space channel conditions. The SGLS is based upon Virtual Instrument (VI) software techniques for managing the error generation, link data rate configuration, and, now, selection of the link delay value. In this report we detail the changes that needed to be made to the SGLS VI configuration to permit link delays to be added to the basic error generation and link data rate control capabilities. This was accomplished by modifying the rate-splitting VIs to include a buffer the hold the incoming data for the duration selected by the user to emulate the channel link delay. In sample tests of this configuration, the TCP/IP(sub ftp) service and the SCPS(sub fp) service were used to transmit 10-KB data files using both symmetric (both forward and return links set to 115200 bps) and unsymmetric (forward link set at 2400 bps and a return link set at 115200 bps) link configurations. Transmission times were recorded at bit error rates of 0 through 10(exp -5) to give an indication of the link performance. In these tests. we noted separate timings for the protocol setup time to initiate the file transfer and the variation in the actual file transfer time caused by channel errors. Both protocols showed similar performance to that seen earlier for the symmetric and unsymmetric channels. This time, the delays in establishing the file protocol also showed that these delays could double the transmission time and need to be accounted for in mission planning. Both protocols also showed a difficulty in transmitting large data files over large link delays. In these tests, there was no clear favorite between the TCP/IP(sub ftp) and the SCPS(sub fp). Based upon these tests, further testing is recommended to extend the results to different file transfer configurations.

  6. New Positive Ca2+-Activated K+ Channel Gating Modulators with Selectivity for KCa3.1

    PubMed Central

    Coleman, Nichole; Brown, Brandon M.; Oliván-Viguera, Aida; Singh, Vikrant; Olmstead, Marilyn M.; Valero, Marta Sofia; Köhler, Ralf

    2014-01-01

    Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate KCa2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV1.5, and NaV1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1−/− mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation. PMID:24958817

  7. Putative resolution of the EEEE selectivity paradox in L-type Ca2+ and bacterial Na+ biological ion channels

    NASA Astrophysics Data System (ADS)

    Kaufman, I. Kh; Luchinsky, D. G.; Gibby, W. A. T.; McClintock, P. V. E.; Eisenberg, R. S.

    2016-05-01

    The highly selective permeation of ions through biological ion channels can be described and explained in terms of fluctuational dynamics under the influence of powerful electrostatic forces. Hence valence selectivity, e.g. between Ca2+ and Na+ in calcium and sodium channels, can be described in terms of ionic Coulomb blockade, which gives rise to distinct conduction bands and stop-bands as the fixed negative charge Q f at the selectivity filter of the channel is varied. This picture accounts successfully for a wide range of conduction phenomena in a diversity of ion channels. A disturbing anomaly, however, is that what appears to be the same electrostatic charge and structure (the so-called EEEE motif) seems to select Na+ conduction in bacterial channels but Ca2+ conduction in mammalian channels. As a possible resolution of this paradox it is hypothesised that an additional charged protein residue on the permeation path of the mammalian channel increases |{{Q}f}| by e, thereby altering the selectivity from Na+ to Ca2+. Experiments are proposed that will enable the hypothesis to be tested.

  8. Wavelet Packet Feature Assessment for High-Density Myoelectric Pattern Recognition and Channel Selection toward Stroke Rehabilitation

    PubMed Central

    Wang, Dongqing; Zhang, Xu; Gao, Xiaoping; Chen, Xiang; Zhou, Ping

    2016-01-01

    This study presents wavelet packet feature assessment of neural control information in paretic upper limb muscles of stroke survivors for myoelectric pattern recognition, taking advantage of high-resolution time–frequency representations of surface electromyogram (EMG) signals. On this basis, a novel channel selection method was developed by combining the Fisher’s class separability index and the sequential feedforward selection analyses, in order to determine a small number of appropriate EMG channels from original high-density EMG electrode array. The advantages of the wavelet packet features and the channel selection analyses were further illustrated by comparing with previous conventional approaches, in terms of classification performance when identifying 20 functional arm/hand movements implemented by 12 stroke survivors. This study offers a practical approach including paretic EMG feature extraction and channel selection that enables active myoelectric control of multiple degrees of freedom with paretic muscles. All these efforts will facilitate upper limb dexterity restoration and improved stroke rehabilitation. PMID:27917149

  9. Evolutionary insights into T-type Ca2+ channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue

    PubMed Central

    Smith, Carolyn L.; Abdallah, Salsabil; Le, Phuong; Harracksingh, Alicia N.; Artinian, Liana; Tamvacakis, Arianna N.; Rehder, Vincent; Reese, Thomas S.

    2017-01-01

    Four-domain voltage-gated Ca2+ (Cav) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Cav channels, Cav1 (L-type), Cav2 (P/Q-, N- and R-type) and Cav3 (T-type), Cav3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Cav3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCav3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCav3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCav3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Cav3 family. We also characterize the channel’s cation permeation properties and find that its pore is less selective for Ca2+ over Na+ compared with the human homologue Cav3.1, yet it exhibits a similar potent block of inward Na+ current by low external Ca2+ concentrations (i.e., the Ca2+ block effect). A comparison of the permeability features of TCav3 with other cloned channels suggests that Ca2+ block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca2+ block and higher Ca2+ selectivity. TCav3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Cav3 channel structure–function properties, ion selectivity, and cellular physiology. PMID:28330839

  10. Masses of doubly and triply charmed baryons

    NASA Astrophysics Data System (ADS)

    Wei, Ke-Wei; Chen, Bing; Guo, Xin-Heng

    2015-10-01

    Until now, the first reported doubly charmed baryon Ξcc +(3520 ) is still a puzzle. It was discovered and confirmed by SELEX collaboration, but not confirmed by LHCb, BABAR, BELLE, FOCUS, or any other collaboration. In the present paper, by employing Regge phenomenology, we first express the mass of the ground state (L =0 ) doubly charmed baryon Ωcc *+ as a function of masses of the well established light baryons and singly charmed baryons. Inserting the recent experimental data, the mass of Ωcc *+ is given to be 3809 ±36 MeV , which is independent of any unobservable parameters. Then, with the quadratic mass relations, we calculate the masses of the ground state triply charmed baryon Ωcc c ++ and doubly charmed baryons Ξcc (*)++, Ξcc (*)+ , and Ωcc + [the mass of Ξcc + is determined as 3520-40+41 MeV , which agrees with the mass of Ξcc +(3520 ) ]. The isospin splitting MΞcc ++-MΞcc +=0.4 ±0.3 MeV . After that, masses of the orbitally excited (L =1 , 2, 3) doubly and triply charmed baryons are estimated. The results are reasonable comparing with those extracted in many other approaches. We suggest more efforts to study doubly and triply charmed baryons both theoretically and experimentally, not only for the abundance of baryon spectra, but also for numerically examining whether the linear mass relations or the quadratic mass relations are realized in nature. Our predictions are useful for the discovery of unobserved doubly and triply charmed baryon states and the JP assignment of these states.

  11. Doubly fed machine review: agenda. Conference report, Washington, DC

    SciTech Connect

    Not Available

    1982-09-01

    The visual aids presented at the doubly fed machine review are presented. The doubly fed machine is a generating system either for wind turbines or hydro systems. Conceptual design and trade-offs are included, as well as testing. (LEW)

  12. Performance of the IEEE 802.11a Wireless Lan Standard Over Frequency-Selective, Slow, Ricean Fading Channels

    DTIC Science & Technology

    2002-09-01

    modeled as a random variable. Typical models are the Rayleigh , Ricean, and Nakagami - m distributions. In this thesis, two widely used models for...and [2], frequency-selective, Rayleigh fading channels [3], and frequency-selective, slow, Nakagami channels [4]. Unlike the above referenced work...signal component where i qM M M = × ; therefore, the probability of symbol error for rectangular QAM can be expressed as ( )error on error on . i q i

  13. Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels

    PubMed Central

    Stephens, Robert F.; Guan, W.; Zhorov, Boris S.; Spafford, J. David

    2015-01-01

    How nature discriminates sodium from calcium ions in eukaryotic channels has been difficult to resolve because they contain four homologous, but markedly different repeat domains. We glean clues from analyzing the changing pore region in sodium, calcium and NALCN channels, from single-cell eukaryotes to mammals. Alternative splicing in invertebrate homologs provides insights into different structural features underlying calcium and sodium selectivity. NALCN generates alternative ion selectivity with splicing that changes the high field strength (HFS) site at the narrowest level of the hourglass shaped pore where the selectivity filter is located. Alternative splicing creates NALCN isoforms, in which the HFS site has a ring of glutamates contributed by all four repeat domains (EEEE), or three glutamates and a lysine residue in the third (EEKE) or second (EKEE) position. Alternative splicing provides sodium and/or calcium selectivity in T-type channels with extracellular loops between S5 and P-helices (S5P) of different lengths that contain three or five cysteines. All eukaryotic channels have a set of eight core cysteines in extracellular regions, but the T-type channels have an infusion of 4–12 extra cysteines in extracellular regions. The pattern of conservation suggests a possible pairing of long loops in Domains I and III, which are bridged with core cysteines in NALCN, Cav, and Nav channels, and pairing of shorter loops in Domains II and IV in T-type channel through disulfide bonds involving T-type specific cysteines. Extracellular turrets of increasing lengths in potassium channels (Kir2.2, hERG, and K2P1) contribute to a changing landscape above the pore selectivity filter that can limit drug access and serve as an ion pre-filter before ions reach the pore selectivity filter below. Pairing of extended loops likely contributes to the large extracellular appendage as seen in single particle electron cryo-microscopy images of the eel Nav1 channel. PMID

  14. Wavenumber selection for small-wavelength Goertler vortices in curved channel flows

    NASA Technical Reports Server (NTRS)

    Dando, Andrew; Hall, Philip

    1995-01-01

    The problem of wavenumber selection for fully nonlinear, small-wavelength Goertler vortices in a curved channel flow is considered. These types of Goertler vortices were first considered by Hall & Lakin (1988) for an external boundary layer flow. They proved particularly amenable to asymptotic description, it was possible to consider vortices large enough so that the mean flow correction driven by them is as large as the basic state, and this prompted the authors to consider them in a curved channel flow as an initial application of the phase-equation approach to Goertler vortices. This involves the assumption that the phase variable of these Goertler vortices varies on slow spanwise and time scales, then an analysis of both inside and outside the core region, to which vortex activity is restricted, leads to a system of partial differential equations which can be solved numerically for the wavenumber. The authors consider in particular the effect on the wavenumber of the outer channel wall varying on the same slow spanwise scale as the phase variable.

  15. GATING OF HCN CHANNELS BY CYCLIC NUCLEOTIDES: RESIDUE CONTACTS THAT UNDERLIE LIGAND BINDING, SELECTIVITY AND EFFICACY

    PubMed Central

    Zhou, Lei; Siegelbaum, Steven A.

    2007-01-01

    SUMMARY Cyclic nucleotides regulate the activity of various proteins by interacting with a conserved cyclic nucleotide-binding domain (CNBD). Although X-ray crystallographic studies have revealed the structures of several CNBDs, the residues responsible for generating the high efficacy with which ligand binding leads to protein activation remain unknown. Here we combine molecular dynamics simulations with mutagenesis to identify ligand contacts important for the regulation of the hyperpolarization-activated HCN2 channel by cyclic nucleotides. Surprisingly, out of seven residues that make strong contacts with ligand, only R632 in the C-helix of the CNBD is essential for high ligand efficacy, due to its selective stabilization of cNMP binding to the open state of the channel. Principle component analysis suggests that a local movement of the C-helix upon ligand binding propagates through the CNBD of one subunit to the C-linker of a neighboring subunit to apply force to the gate of the channel. PMID:17562313

  16. Selective pressure modulation of synaptic voltage-dependent calcium channels-involvement in HPNS mechanism.

    PubMed

    Aviner, Ben; Gradwohl, Gideon; Bliznyuk, Alice; Grossman, Yoram

    2016-10-01

    Exposure to hyperbaric pressure (HP) exceeding 100 msw (1.1 MPa) is known to cause a constellation of motor and cognitive impairments named high-pressure neurological syndrome (HPNS), considered to be the result of synaptic transmission alteration. Long periods of repetitive HP exposure could be an occupational risk for professional deep-sea divers. Previous studies have indicated the modulation of presynaptic Ca(2+) currents based on synaptic activity modified by HP. We have recently demonstrated that currents in genetically identified cellular voltage-dependent Ca(2+) channels (VDCCs), CaV 1.2 and CaV 3.2 are selectively affected by HP. This work further elucidates the HPNS mechanism by examining HP effect on Ca(2+) currents in neuronal VDCCs, CaV 2.2 and CaV 2.1, which are prevalent in presynaptic terminals, expressed in Xenopus oocytes. HP augmented the CaV 2.2 current amplitude, much less so in a channel variation containing an additional modulatory subunit, and had almost no effect on the CaV 2.1 currents. HP differentially affected the channels' kinetics. It is, therefore, suggested that HPNS signs and symptoms arise, at least in part, from pressure modulation of various VDCCs. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  17. A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective[C][W

    PubMed Central

    Maierhofer, Tobias; Lind, Christof; Hüttl, Stefanie; Scherzer, Sönke; Papenfuß, Melanie; Simon, Judy; Al-Rasheid, Khaled A.S.; Ache, Peter; Rennenberg, Heinz; Hedrich, Rainer; Müller, Thomas D.; Geiger, Dietmar

    2014-01-01

    In contrast to animal cells, plants use nitrate as a major source of nitrogen. Following the uptake of nitrate, this major macronutrient is fed into the vasculature for long-distance transport. The Arabidopsis thaliana shoot expresses the anion channel SLOW ANION CHANNEL1 (SLAC1) and its homolog SLAC1 HOMOLOGOUS3 (SLAH3), which prefer nitrate as substrate but cannot exclude chloride ions. By contrast, we identified SLAH2 as a nitrate-specific channel that is impermeable for chloride. To understand the molecular basis for nitrate selection in the SLAH2 channel, SLAC1 and SLAH2 were modeled to the structure of HiTehA, a distantly related bacterial member. Structure-guided site-directed mutations converted SLAC1 into a SLAH2-like nitrate-specific anion channel and vice versa. Our findings indicate that two pore-occluding phenylalanines constrict the pore. The selectivity filter of SLAC/SLAH anion channels is determined by the polarity of pore-lining residues located on alpha helix 3. Changing the polar character of a single amino acid side chain (Ser-228) to a nonpolar residue turned the nitrate-selective SLAH2 into a chloride/nitrate-permeable anion channel. Thus, the molecular basis of the anion specificity of SLAC/SLAH anion channels seems to be determined by the presence and constellation of polar side chains that act in concert with the two pore-occluding phenylalanines. PMID:24938289

  18. Centrifugal sedimentation for selectively packing channels with silica microbeads in three-dimensional micro/nanofluidic devices.

    PubMed

    Gong, Maojun; Bohn, Paul W; Sweedler, Jonathan V

    2009-03-01

    Incorporation of nanofluidic elements into microfluidic channels is one approach for adding filtration and partition functionality to planar microfluidic devices, as well as providing enhanced biomolecular separations. Here we introduce a strategy to pack microfluidic channels with silica nanoparticles and microbeads, thereby indirectly producing functional nanostructures; the method allows selected channels to be packed, here demonstrated so that a separation channel is packed while keeping an injection channel unpacked. A nanocapillary array membrane is integrated between two patterned microfluidic channels that cross each other in vertically separated layers. The membrane serves both as a frit for bead packing and as a fluid communication conduit between microfluidic channels. Centrifugal force-assisted sedimentation is then used to selectively pack the microfluidic channels using an aqueous silica bead suspension loaded into the appropriate inlet reservoirs. This packing approach may be used to simultaneously pack multiple channels with silica microbeads having different sizes and surface properties. The chip design and packing method introduced here are suitable for packing silica particles in sizes ranging from nanometers to micrometers and allow rapid (approximately 10 min) packing with high quality. The liquid/analyte transport characteristics of these packed micro/nanofluidic devices have potential utility in a wide range of applications, including electroosmotic pumping, liquid chromatographic separations, and electrochromatography.

  19. Modification of the conductance, selectivity and concentration-dependent saturation of Pseudomonas aeruginosa protein P channels by chemical acetylation.

    PubMed

    Hancock, R E; Poole, K; Gimple, M; Benz, R

    1983-10-26

    Protein P, an anion-specific channel-forming protein from the outer membrane of Pseudomonas aeruginosa was chemically modified by acetylation and syccinylation of its accessible amino groups. The chemically modified protein retained its ability to form oligomers on sodium dodecyl sulfate polyacrylamide gels, whereas only the acetylated protein formed channels in reconstitution experiments with lipid bilayers. Acetylated protein P demonstrated a substantially reduced mean single channel conductance (25 pS at 1 M KCl) compared to the native protein P channels (250 pS at 1 M KCl) when reconstituted into black lipid bilayer membranes. The homogeneous size distribution of single-channel conductances suggested that all of the protein P molecules had been acetylated. Zero-current potential measurements demonstrated that the acetylated protein P channel was only weakly selective for anions and allowed the permeation of cations, in contrast to the native protein P channels, which were more than 100-fold selective for anions over cations. The dependence of conductance on salt concentration was changed upon acetylation, in that acetylated protein P demonstrated a linear concentration-conductance relationship, whereas native protein P channels became saturated at high salt concentrations. These data strongly suggested that the basis of anion selectivity for native protein P channels is fixed amino groups. In agreement with this, we could demonstrate a 2.5-fold decrease in single-channel conductance between pH 7 and pH 9, between which pH values the epsilon-amino groups of amino acids would start to become deprotonated. Two alternative schemes for the topography of the protein P channel and localization of the fixed amino groups are presented and discussed.

  20. Mechanisms of Selectivity in Channels and Enzymes Studied with Interactive Molecular Dynamics

    PubMed Central

    Grayson, Paul; Tajkhorshid, Emad; Schulten, Klaus

    2003-01-01

    Interactive molecular dynamics, a new modeling tool for rapid investigation of the physical mechanisms of biological processes at the atomic level, is applied to study selectivity and regulation of the membrane channel protein GlpF and the enzyme glycerol kinase. These proteins facilitate the first two steps of Escherichia coli glycerol metabolism. Despite their different function and architecture the proteins are found to employ common mechanisms for substrate selectivity: an induced geometrical fit by structurally homologous binding sites and an induced rapid dipole moment reversal. Competition for hydrogen bonding sites with water in both proteins is critical for substrate motion. In glycerol kinase, it is shown that the proposed domain motion prevents competition with water, in turn regulating the binding of glycerol. PMID:12829462

  1. Drainage basins, channels, and flow characteristics of selected streams in central Pennsylvania

    USGS Publications Warehouse

    Brush, Lucien M.

    1961-01-01

    The hydraulic, basin, and geologic characteristics of 16 selected streams in central Pennsylvania were measured for the purpose of studying the relations among these general characteristics and their process of development. The basic parameters which were measured include bankfull width and depth, channel slope, bed material size and shape, length of stream from drainage divide, and size of drainage area. The kinds of bedrock over which the streams flow were noted. In these streams the bankfull channel is filled by flows approximating the 2.3-year flood. By measuring the breadth and mean depth of the channel, it was possible to compute the bankfull mean velocity for each of the 119 sampling stations. These data were then used to compute the downstream changes in hydraulic geometry of the streams studied. This method has been called an indirect computation of the hydraulic geometry. The results obtained by the indirect method are similar to those of the direct method of other workers. The basins were studied by examining the relations of drainage area, discharge, and length of stream from drainage divide. For the streams investigated, excellent correlations were found to exist between drainage area and the 2.3-year flood, as well as between length of stream from the basin divide and drainage area. From these correlations it is possible to predict the discharge for the 2.3-year flood at any arbitrary point along the length of the stream. The long, intermediate, and short axes of pebbles sampled from the bed of the stream were recorded to study both size and sphericity changes along individual streams and among the streams studied. No systematic downstream changes in sphericity were found. Particle size changes are erratic and show no consistent relation to channel slope. Particle size decreases downstream in many streams but remains constant or increases in others. Addition of material by tributaries is one factor affecting particle size and another is the parent

  2. An embryo of protocells: The capsule of graphene with selective ion channels

    SciTech Connect

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-05-19

    In this study, the synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.

  3. An embryo of protocells: The capsule of graphene with selective ion channels

    DOE PAGES

    Li, Zhan; Wang, Chunmei; Tian, Longlong; ...

    2015-05-19

    In this study, the synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into amore » secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.« less

  4. Kinetic approach with ab initio MO method on ionic selectivity and size in sodium channel.

    PubMed

    Tani, S; Imamura, A; Kanda, K

    1989-10-23

    Three kinds of models for ionic selectivity and size of the filter in sodium channel have been treated by using ab initio molecular orbital (MO) calculations with MINI-3 and MIDI-3* basis sets. A three-components system, HCO2M-H2O (M = Li+, Na+ or K+), is acceptable for describing experimental facts well. Thermochemical parameters obtained from harmonic vibrational analysis with MINI-3 basis sets, for the translocation of the permeant metal cations in the HCO2M-H2O system, are that the activation enthalpies for Li+, Na+ and K+ are 7.0, 6.4 and 23.4 kJ/mol, and also the free energies of activation are 10.6, 1.5 and 19.0 kJ/mol, respectively. These results are qualitatively in good correspondence with experimental facts of the ion selectivity of the channel. One of water molecule was found to have a key role in the translocation of the permeant cations.

  5. Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

    PubMed Central

    Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

    2016-01-01

    Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

  6. An embryo of protocells: The capsule of graphene with selective ion channels

    NASA Astrophysics Data System (ADS)

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-05-01

    The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.

  7. An embryo of protocells: The capsule of graphene with selective ion channels.

    PubMed

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-05-19

    The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused (84)Kr(25+), has a high selectivity for permeation of the monovalent metal ions ( Rb(+) > K(+) > Cs(+) > Na(+) > Li(+), based on permeation concentration), but does not allow Cl(-) go through. It is similar to K(+) channels, which would cause an influx of K(+) into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.

  8. Channel selection in the modulation domain for improved speech intelligibility in noise

    PubMed Central

    Wójcicki, Kamil K.; Loizou, Philipos C.

    2012-01-01

    Background noise reduces the depth of the low-frequency envelope modulations known to be important for speech intelligibility. The relative strength of the target and masker envelope modulations can be quantified using a modulation signal-to-noise ratio, (S/N)mod, measure. Such a measure can be used in noise-suppression algorithms to extract target-relevant modulations from the corrupted (target + masker) envelopes for potential improvement in speech intelligibility. In the present study, envelopes are decomposed in the modulation spectral domain into a number of channels spanning the range of 0–30 Hz. Target-dominant modulations are identified and retained in each channel based on the (S/N)mod selection criterion, while modulations which potentially interfere with perception of the target (i.e., those dominated by the masker) are discarded. The impact of modulation-selective processing on the speech-reception threshold for sentences in noise is assessed with normal-hearing listeners. Results indicate that the intelligibility of noise-masked speech can be improved by as much as 13 dB when preserving target-dominant modulations, present up to a modulation frequency of 18 Hz, while discarding masker-dominant modulations from the mixture envelopes. PMID:22501068

  9. An embryo of protocells: The capsule of graphene with selective ion channels

    PubMed Central

    Li, Zhan; Wang, Chunmei; Tian, Longlong; Bai, Jing; Yao, Huijun; Zhao, Yang; Zhang, Xin; Cao, Shiwei; Qi, Wei; Wang, Suomin; Shi, Keliang; Xu, Youwen; Mingliang, Zhang; Liu, Bo; Qiu, Hongdeng; Liu, Jie; Wu, Wangsuo; Wang, Xiaoli; Wenzhen, An

    2015-01-01

    The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life. PMID:25989440

  10. A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels.

    PubMed

    Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

    2015-07-07

    Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K(+) channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na(+), Cs(+), and dimethylammonium (DMA(+)), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels.

  11. A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels

    PubMed Central

    Napolitano, Luisa Maria Rosaria; Bisha, Ina; De March, Matteo; Marchesi, Arin; Arcangeletti, Manuel; Demitri, Nicola; Mazzolini, Monica; Rodriguez, Alex; Magistrato, Alessandra; Onesti, Silvia; Laio, Alessandro; Torre, Vincent

    2015-01-01

    Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K+ channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na+, Cs+, and dimethylammonium (DMA+), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels. PMID:26100907

  12. The depressant scorpion neurotoxin LqqIT2 selectively modulates the insect voltage-gated sodium channel.

    PubMed

    Bosmans, Frank; Martin-Eauclaire, Marie-France; Tytgat, Jan

    2005-03-15

    LqqIT2 is a depressant neurotoxin present in the venom of the Leiurus quinquestriatus quinquestriatus scorpion, one of the world's most dangerous scorpions endemic to dry habitats in Africa and Asia. In order to determine its efficacy, potency and selectivity, LqqIT2 was subjected for the first time to an electrophysiological and pharmacological comparison between two different cloned sodium channels expressed in Xenopus laevis oocytes. Aside from typical beta-toxin effects, LqqIT2 also affected the inactivation process and ion selectivity of the insect voltage-gated sodium channel. The most interesting feature of LqqIT2 is its total insect-selectivity. At a concentration of 1 microM, the insect-voltage-gated sodium channel, para, was profoundly modulated while its mammalian counterpart, the rat brain Na(v)1.2 channel, was not affected. This trait offers excellent prospects for the development of novel insecticides.

  13. The voltage-dependent gate in MthK potassium channels is located at the selectivity filter

    PubMed Central

    Posson, David J.; McCoy, Jason G.; Nimigean, Crina M.

    2012-01-01

    Understanding how ion channels open and close their pores is crucial for understanding their physiological roles. We used intracellular quaternary ammonium blockers to locate the voltage-dependent gate in MthK potassium channels from Methanobacterium thermoautotrophicum with electrophysiology and X-ray crystallography. Blockers bind in an aqueous cavity between two putative gates, an intracellular gate and the selectivity filter. Thus, these blockers directly probe gate location: an intracellular gate will prevent binding when closed, whereas a selectivity filter gate will always allow binding. A kinetic analysis of tetrabutylammonium block of single MthK channels combined with X-ray crystallographic analysis of the pore with tetrabutylantimony unequivocally determined that the voltage-dependent gate, like the C-type inactivation gate in eukaryotic channels, is located at the selectivity filter. State-dependent binding kinetics suggests that MthK inactivation leads to conformational changes within the cavity and intracellular pore entrance. PMID:23262489

  14. The voltage-dependent gate in MthK potassium channels is located at the selectivity filter.

    PubMed

    Posson, David J; McCoy, Jason G; Nimigean, Crina M

    2013-02-01

    Understanding how ion channels open and close their pores is crucial for comprehending their physiological roles. We used intracellular quaternary ammonium blockers, electrophysiology and X-ray crystallography to locate the voltage-dependent gate in MthK potassium channels from Methanobacterium thermoautotrophicum. Blockers bind in an aqueous cavity between two putative gates: an intracellular gate and the selectivity filter. Thus, these blockers directly probe gate location--an intracellular gate will prevent binding when closed, whereas a selectivity filter gate will always allow binding. Kinetic analysis of tetrabutylammonium block of single MthK channels combined with X-ray crystallographic analysis of the pore with tetrabutyl antimony unequivocally determined that the voltage-dependent gate, like the C-type inactivation gate in eukaryotic channels, is located at the selectivity filter. State-dependent binding kinetics suggest that MthK inactivation leads to conformational changes within the cavity and intracellular pore entrance.

  15. Observation of the doubly strange b baryon Omegab-.

    PubMed

    Abazov, V M; Abbott, B; Abolins, M; Acharya, B S; Adams, M; Adams, T; Aguilo, E; Ahsan, M; Alexeev, G D; Alkhazov, G; Alton, A; Alverson, G; Alves, G A; Anastasoaie, M; Ancu, L S; Andeen, T; Andrieu, B; Anzelc, M S; Aoki, M; Arnoud, Y; Arov, M; Arthaud, M; Askew, A; Asman, B; Assis Jesus, A C S; Atramentov, O; Avila, C; Badaud, F; Bagby, L; Baldin, B; Bandurin, D V; Banerjee, P; Banerjee, S; Barberis, E; Barfuss, A-F; Bargassa, P; Baringer, P; Barreto, J; Bartlett, J F; Bassler, U; Bauer, D; Beale, S; Bean, A; Begalli, M; Begel, M; Belanger-Champagne, C; Bellantoni, L; Bellavance, A; Benitez, J A; Beri, S B; Bernardi, G; Bernhard, R; Bertram, I; Besançon, M; Beuselinck, R; Bezzubov, V A; Bhat, P C; Bhatnagar, V; Biscarat, C; Blazey, G; Blekman, F; Blessing, S; Bloom, K; Boehnlein, A; Boline, D; Bolton, T A; Boos, E E; Borissov, G; Bose, T; Brandt, A; Brock, R; Brooijmans, G; Bross, A; Brown, D; Bu, X B; Buchanan, N J; Buchholz, D; Buehler, M; Buescher, V; Bunichev, V; Burdin, S; Burnett, T H; Buszello, C P; Butler, J M; Calfayan, P; Calvet, S; Cammin, J; Carrera, E; Carvalho, W; Casey, B C K; Castilla-Valdez, H; Chakrabarti, S; Chakraborty, D; Chan, K M; Chandra, A; Cheu, E; Chevallier, F; Cho, D K; Choi, S; Choudhary, B; Christofek, L; Christoudias, T; Cihangir, S; Claes, D; Clutter, J; Cooke, M; Cooper, W E; Corcoran, M; Couderc, F; Cousinou, M-C; Crépé-Renaudin, S; Cuplov, V; Cutts, D; Cwiok, M; da Motta, H; Das, A; Davies, G; De, K; de Jong, S J; De La Cruz-Burelo, E; De Oliveira Martins, C; DeVaughan, K; Degenhardt, J D; Déliot, F; Demarteau, M; Demina, R; Denisov, D; Denisov, S P; Desai, S; Diehl, H T; Diesburg, M; Dominguez, A; Dong, H; Dorland, T; Dubey, A; Dudko, L V; Duflot, L; Dugad, S R; Duggan, D; Duperrin, A; Dyer, J; Dyshkant, A; Eads, M; Edmunds, D; Ellison, J; Elvira, V D; Enari, Y; Eno, S; Ermolov, P; Evans, H; Evdokimov, A; Evdokimov, V N; Ferapontov, A V; Ferbel, T; Fiedler, F; Filthaut, F; Fisher, W; Fisk, H E; Fortner, M; Fox, H; Fu, S; Fuess, S; Gadfort, T; Galea, C F; Garcia, C; Garcia-Bellido, A; Gavrilov, V; Gay, P; Geist, W; Geng, W; Gerber, C E; Gershtein, Y; Gillberg, D; Ginther, G; Gollub, N; Gómez, B; Goussiou, A; Grannis, P D; Greenlee, H; Greenwood, Z D; Gregores, E M; Grenier, G; Gris, Ph; Grivaz, J-F; Grohsjean, A; Grünendahl, S; Grünewald, M W; Guo, F; Guo, J; Gutierrez, G; Gutierrez, P; Haas, A; Hadley, N J; Haefner, P; Hagopian, S; Haley, J; Hall, I; Hall, R E; Han, L; Harder, K; Harel, A; Hauptman, J M; Hays, J; Hebbeker, T; Hedin, D; Hegeman, J G; Heinson, A P; Heintz, U; Hensel, C; Herner, K; Hesketh, G; Hildreth, M D; Hirosky, R; Hobbs, J D; Hoeneisen, B; Hoeth, H; Hohlfeld, M; Hossain, S; Houben, P; Hu, Y; Hubacek, Z; Hynek, V; Iashvili, I; Illingworth, R; Ito, A S; Jabeen, S; Jaffré, M; Jain, S; Jakobs, K; Jarvis, C; Jesik, R; Johns, K; Johnson, C; Johnson, M; Johnston, D; Jonckheere, A; Jonsson, P; Juste, A; Kajfasz, E; Kalk, J M; Karmanov, D; Kasper, P A; Katsanos, I; Kau, D; Kaushik, V; Kehoe, R; Kermiche, S; Khalatyan, N; Khanov, A; Kharchilava, A; Kharzheev, Y M; Khatidze, D; Kim, T J; Kirby, M H; Kirsch, M; Klima, B; Kohli, J M; Komissarov, E V; Konrath, J-P; Kozelov, A V; Kraus, J; Kuhl, T; Kumar, A; Kupco, A; Kurca, T; Kuzmin, V A; Kvita, J; Lacroix, F; Lam, D; Lammers, S; Landsberg, G; Lebrun, P; Lee, W M; Leflat, A; Lellouch, J; Li, J; Li, L; Li, Q Z; Lietti, S M; Lim, J K; Lima, J G R; Lincoln, D; Linnemann, J; Lipaev, V V; Lipton, R; Liu, Y; Liu, Z; Lobodenko, A; Lokajicek, M; Love, P; Lubatti, H J; Luna, R; Lyon, A L; Maciel, A K A; Mackin, D; Madaras, R J; Mättig, P; Magass, C; Magerkurth, A; Mal, P K; Malbouisson, H B; Malik, S; Malyshev, V L; Maravin, Y; Martin, B; McCarthy, R; Melnitchouk, A; Mendoza, L; Mercadante, P G; Merekov, Y P; Merkin, M; Merritt, K W; Meyer, A; Meyer, J; Mitrevski, J; Mommsen, R K; Mondal, N K; Moore, R W; Moulik, T; Muanza, G S; Mulhearn, M; Mundal, O; Mundim, L; Nagy, E; Naimuddin, M; Narain, M; Naumann, N A; Neal, H A; Negret, J P; Neustroev, P; Nilsen, H; Nogima, H; Novaes, S F; Nunnemann, T; O'Dell, V; O'Neil, D C; Obrant, G; Ochando, C; Onoprienko, D; Orduna, J; Oshima, N; Osman, N; Osta, J; Otec, R; Otero y Garzón, G J; Owen, M; Padley, P; Pangilinan, M; Parashar, N; Park, S-J; Park, S K; Parsons, J; Partridge, R; Parua, N; Patwa, A; Pawloski, G; Penning, B; Perfilov, M; Peters, K; Peters, Y; Pétroff, P; Petteni, M; Piegaia, R; Piper, J; Pleier, M-A; Podesta-Lerma, P L M; Podstavkov, V M; Pogorelov, Y; Pol, M-E; Polozov, P; Pope, B G; Popov, A V; Potter, C; Prado da Silva, W L; Prosper, H B; Protopopescu, S; Qian, J; Quadt, A; Quinn, B; Rakitine, A; Rangel, M S; Ranjan, K; Ratoff, P N; Renkel, P; Rich, P; Rieger, J; Rijssenbeek, M; Ripp-Baudot, I; Rizatdinova, F; Robinson, S; Rodrigues, R F; Rominsky, M; Royon, C; Rozhdestvenski, A; Rubinov, P; Ruchti, R; Safronov, G; Sajot, G; Sánchez-Hernández, A; Sanders, M P; Sanghi, B; Savage, G; Sawyer, L; Scanlon, T; Schaile, D; Schamberger, R D; Scheglov, Y; Schellman, H; Schliephake, T; Schlobohm, S; Schwanenberger, C; Schwartzman, A; Schwienhorst, R; Sekaric, J; Severini, H; Shabalina, E; Shamim, M; Shary, V; Shchukin, A A; Shivpuri, R K; Siccardi, V; Simak, V; Sirotenko, V; Skubic, P; Slattery, P; Smirnov, D; Snow, G R; Snow, J; Snyder, S; Söldner-Rembold, S; Sonnenschein, L; Sopczak, A; Sosebee, M; Soustruznik, K; Spurlock, B; Stark, J; Steele, J; Stolin, V; Stoyanova, D A; Strandberg, J; Strandberg, S; Strang, M A; Strauss, E; Strauss, M; Ströhmer, R; Strom, D; Stutte, L; Sumowidagdo, S; Svoisky, P; Sznajder, A; Tamburello, P; Tanasijczuk, A; Taylor, W; Tiller, B; Tissandier, F; Titov, M; Tokmenin, V V; Torchiani, I; Tsybychev, D; Tuchming, B; Tully, C; Tuts, P M; Unalan, R; Uvarov, L; Uvarov, S; Uzunyan, S; Vachon, B; van den Berg, P J; Van Kooten, R; van Leeuwen, W M; Varelas, N; Varnes, E W; Vasilyev, I A; Verdier, P; Vertogradov, L S; Vertogradova, Y; Verzocchi, M; Vilanova, D; Villeneuve-Seguier, F; Vint, P; Vokac, P; Voutilainen, M; Wagner, R; Wahl, H D; Wang, M H L S; Warchol, J; Watts, G; Wayne, M; Weber, G; Weber, M; Welty-Rieger, L; Wenger, A; Wermes, N; Wetstein, M; White, A; Wicke, D; Williams, M; Wilson, G W; Wimpenny, S J; Wobisch, M; Wood, D R; Wyatt, T R; Xie, Y; Yacoob, S; Yamada, R; Yang, W-C; Yasuda, T; Yatsunenko, Y A; Yin, H; Yip, K; Yoo, H D; Youn, S W; Yu, J; Zeitnitz, C; Zelitch, S; Zhao, T; Zhou, B; Zhu, J; Zielinski, M; Zieminska, D; Zieminski, A; Zivkovic, L; Zutshi, V; Zverev, E G

    2008-12-05

    We report the observation of the doubly strange b baryon Omegab- in the decay channel Omegab(-)-->J/psiOmega-, with J/psi-->mu+mu(-) and Omega(-)-->LambdaK(-)-->(ppi-)K-, in pp collisions at sqrt[s]=1.96 TeV. Using approximately 1.3 fb(-1) of data collected with the D0 detector at the Fermilab Tevatron Collider, we observe 17.8+/-4.9(stat)+/-0.8(syst) Omegab- signal events at a mass of 6.165+/-0.010(stat)+/-0.013(syst) GeV. The significance of the observed signal is 5.4sigma, corresponding to a probability of 6.7 x 10(-8) of it arising from a background fluctuation.

  16. Molecular Determinant for Specific Ca/Ba Selectivity Profiles of Low and High Threshold Ca2+ Channels

    PubMed Central

    Cens, Thierry; Rousset, Matthieu; Kajava, Andrey; Charnet, Pierre

    2007-01-01

    Voltage-gated Ca2+ channels (VGCC) play a key role in many physiological functions by their high selectivity for Ca2+ over other divalent and monovalent cations in physiological situations. Divalent/monovalent selection is shared by all VGCC and is satisfactorily explained by the existence, within the pore, of a set of four conserved glutamate/aspartate residues (EEEE locus) coordinating Ca2+ ions. This locus however does not explain either the choice of Ca2+ among other divalent cations or the specific conductances encountered in the different VGCC. Our systematic analysis of high- and low-threshold VGCC currents in the presence of Ca2+ and Ba2+ reveals highly specific selectivity profiles. Sequence analysis, molecular modeling, and mutational studies identify a set of nonconserved charged residues responsible for these profiles. In HVA (high voltage activated) channels, mutations of this set modify divalent cation selectivity and channel conductance without change in divalent/monovalent selection, activation, inactivation, and kinetics properties. The CaV2.1 selectivity profile is transferred to CaV2.3 when exchanging their residues at this location. Numerical simulations suggest modification in an external Ca2+ binding site in the channel pore directly involved in the choice of Ca2+, among other divalent physiological cations, as the main permeant cation for VGCC. In LVA (low voltage activated) channels, this locus (called DCS for divalent cation selectivity) also influences divalent cation selection, but our results suggest the existence of additional determinants to fully recapitulate all the differences encountered among LVA channels. These data therefore attribute to the DCS a unique role in the specific shaping of the Ca2+ influx between the different HVA channels. PMID:17893194

  17. Temperature tuned doubly resonant OPO: Peculiarities

    NASA Astrophysics Data System (ADS)

    Jarutis, Vygandas; Jurkus, Karolis; Smilgevičius, Valerijus

    2017-01-01

    We show experimentally and theoretically that under some circumstances the doubly resonant OPO's output energy and spectrum periodically depend on the nonlinear crystal temperature. We explain these phenomena using a simple matrix formalism, and interpret them as oscillations between two states of light in the DRO cavity.

  18. On doubly stochastic rarefaction of renewal processes

    NASA Astrophysics Data System (ADS)

    Korolev, V. Yu.; Korchagin, A. Yu.; Zeifman, A. I.

    2017-07-01

    In the paper, the concepts of π-mixed geometric and π-mixed binomial distributions are introduced within the setting of Bernoulli trials with a random probability of success. A generalization of the Rényi theorem concerning the asymptotic behavior of rarefied renewal processes is proved for doubly stochastic rarefaction resulting in that the limit process is mixed Poisson.

  19. Doubly perturbed neutral stochastic functional equations

    NASA Astrophysics Data System (ADS)

    Hu, Lanying; Ren, Yong

    2009-09-01

    In this paper, we prove the existence and uniqueness of the solution to a class of doubly perturbed neutral stochastic functional equations (DPNSFEs in short) under some non-Lipschitz conditions. The solution is constructed by successive approximation. Furthermore, we give the continuous dependence of the solution on the initial value by means of the corollary of Bihari inequality.

  20. Binding and selectivity in L-type calcium channels: a mean spherical approximation.

    PubMed Central

    Nonner, W; Catacuzzeno, L; Eisenberg, B

    2000-01-01

    L-type calcium channels are Ca(2+) binding proteins of great biological importance. They generate an essential intracellular signal of living cells by allowing Ca(2+) ions to move across the lipid membrane into the cell, thereby selecting an ion that is in low extracellular abundance. Their mechanism of selection involves four carboxylate groups, containing eight oxygen ions, that belong to the side chains of the "EEEE" locus of the channel protein, a setting similar to that found in many Ca(2+)-chelating molecules. This study examines the hypothesis that selectivity in this locus is determined by mutual electrostatic screening and volume exclusion between ions and carboxylate oxygens of finite diameters. In this model, the eight half-charged oxygens of the tethered carboxylate groups of the protein are confined to a subvolume of the pore (the "filter"), but interact spontaneously with their mobile counterions as ions interact in concentrated bulk solutions. The mean spherical approximation (MSA) is used to predict ion-specific excess chemical potentials in the filter and baths. The theory is calibrated using a single experimental observation, concerning the apparent dissociation constant of Ca(2+) in the presence of a physiological concentration of NaCl. When ions are assigned their independently known crystal diameters and the carboxylate oxygens are constrained, e.g., to a volume of 0.375 nm(3) in an environment with an effective dielectric coefficient of 63.5, the hypothesized selectivity filter produces the shape of the calcium binding curves observed in experiment, and it predicts Ba(2+)/Ca(2+) and Na(+)/Li(+) competition, and Cl(-) exclusion as observed. The selectivities for Na(+), Ca(2+), Ba(2+), other alkali metal ions, and Cl(-) thus can be predicted by volume exclusion and electrostatic screening alone. Spontaneous coordination of ions and carboxylates can produce a wide range of Ca(2+) selectivities, depending on the volume density of carboxylate

  1. Molecular dynamics - potential of mean force calculations as a tool for understanding ion permeation and selectivity in narrow channels.

    PubMed

    Allen, Toby W; Andersen, Olaf S; Roux, Benoit

    2006-12-01

    Ion channels catalyze the permeation of charged molecules across cell membranes and are essential for many vital physiological functions, including nerve and muscle activity. To understand better the mechanisms underlying ion conduction and valence selectivity of narrow ion channels, we have employed free energy techniques to calculate the potential of mean force (PMF) for ion movement through the prototypical gramicidin A channel. Employing modern all-atom molecular dynamics (MD) force fields with umbrella sampling methods that incorporate one hundred 1-2 ns trajectories, we find that it is possible to achieve semi-quantitative agreement with experimental binding and conductance measurements. We also examine the sensitivity of the MD-PMF results to the choice of MD force field and compare PMFs for potassium, calcium and chloride ions to explore the basis for the valence selectivity of this narrow and uncharged ion channel. A large central barrier is observed for both anions and divalent ions, consistent with lack of experimental conductance. Neither anion or divalent cation is seen to be stabilized inside the channel relative to the bulk electrolyte and each leads to large disruptions to the protein and membrane structure when held deep inside the channel. Weak binding of calcium ions outside the channel corresponds to a free energy well that is too shallow to demonstrate channel blocking. Our findings emphasize the success of the MD-PMF approach and the sensitivity of ion energetics to the choice of biomolecular force field.

  2. Recombinant pICln Forms Highly Cation-selective Channels when Reconstituted into Artificial and Biological Membranes

    PubMed Central

    Li, Canhui; Breton, Sylvie; Morrison, Rebecca; Cannon, Carolyn L.; Emma, Francesco; Sanchez-Olea, Roberto; Bear, Christine; Strange, Kevin

    1998-01-01

    pICln has been proposed to be the swelling-activated anion channel responsible for ICl, swell, or a channel regulator. We tested the anion channel hypothesis by reconstituting recombinant pICln into artificial and biological membranes. Single channels were observed when pICln was reconstituted into planar lipid bilayers. In the presence of symmetrical 300 mM KCl, the channels had a high open probability and a slope conductance of 48 pS, and were outwardly rectifying. Reduction of trans KCl to 50 mM shifted the reversal potential by −31.2 ± 0.06 mV, demonstrating that the channel is at least seven times more selective for cations than for anions. Consistent with this finding, channel conductance was unaffected by substitution of Cl− with glutamate, but was undetectable when K+ was replaced by N-methyl-d-glucamine. Reconstitution of pICln into liposomes increased 86Rb+ uptake by three- to fourfold, but had no effect on 36Cl− uptake. Phosphorylation of pICln with casein kinase II or mutation of G54, G56, and G58 to alanine decreased channel open probability and 86Rb+ uptake. When added to the external medium bathing Sf9 cells, pICln inserted into the plasma membrane and increased cell cation permeability. Taken together, these observations demonstrate that channel activity is due to pICln and not minor contaminant proteins. However, these findings do not support the hypothesis that pICln is the anion-selective ICl, swell channel. The observed cation channel activity may reflect an as yet to be defined physiological function of pICln, or may be a consequence of in vitro reconstitution of purified, recombinant protein. PMID:9834142

  3. α-SNAP regulates dynamic, on-site assembly and calcium selectivity of Orai1 channels

    PubMed Central

    Li, Peiyao; Miao, Yong; Dani, Adish; Vig, Monika

    2016-01-01

    Orai1 forms a highly calcium-selective pore of the calcium release activated channel, and α-SNAP is necessary for its function. Here we show that α-SNAP regulates on-site assembly of Orai1 dimers into calcium-selective multimers. We find that Orai1 is a dimer in resting primary mouse embryonic fibroblasts but displays variable stoichiometry in the plasma membrane of store-depleted cells. Remarkably, α-SNAP depletion induces formation of higher-order Orai1 oligomers, which permeate significant levels of sodium via Orai1 channels. Sodium permeation in α-SNAP–deficient cells cannot be corrected by tethering multiple Stim1 domains to Orai1 C-terminal tail, demonstrating that α-SNAP regulates functional assembly and calcium selectivity of Orai1 multimers independently of Stim1 levels. Fluorescence nanoscopy reveals sustained coassociation of α-SNAP with Stim1 and Orai1, and α-SNAP–depleted cells show faster and less constrained mobility of Orai1 within ER-PM junctions, suggesting Orai1 and Stim1 coentrapment without stable contacts. Furthermore, α-SNAP depletion significantly reduces fluorescence resonance energy transfer between Stim1 and Orai1 N-terminus but not C-terminus. Taken together, these data reveal a unique role of α-SNAP in the on-site functional assembly of Orai1 subunits and suggest that this process may, in part, involve enabling crucial low-affinity interactions between Orai1 N-terminus and Stim1. PMID:27335124

  4. Applied-field molecular dynamics study of a model calcium channel selectivity filter

    NASA Astrophysics Data System (ADS)

    Yang, Yan; Henderson, Douglas; Busath, David

    2003-03-01

    The calcium channel is thought to have a short selectivity filter containing charged glutamate side chains. This filter was modeled using an atomistic cylinder of length 10 Å in which were confined eight half-charged oxygen anions representing glutamate carboxylate oxygens. Current flow through the filter was computed using applied field nonequilibrium molecular dynamics simulations at various mole fractions of Na+ and Ca2+ in 2 M chloride solutions with simple point charge/extended model water. The filter was cation selective and had conductances in the range of those extrapolated from experimental results. For this model, unlike implicit solvent models at lower voltages and concentrations, the mole fraction behavior was not anomalous and cation binding was nonselective at 2.2 V. Perturbations of filter diameter and confined charge resulted in similar behaviors. At physiological voltages, mole fraction conductance behavior could not be reliably simulated in 100 ns runs, but nonselective cation binding persisted. Nevertheless, it is of interest that ion entry into the confinement region was limited by an energy barrier and at least, in the case of Ca2+, led to an increase in the energy of the other Ca2+ ion in the confinement region and prompt exit of one of them. The filter was most commonly occupied by 2 or 3 Na+ ions in pure Na+ solutions or 1 or 2 Ca2+ ions in pure Ca2+ solutions. For CaCl2 solution, the additional ion, if present, was most commonly stalled behind the entry barrier, i.e., within the channel filter but not yet having entered the confinement region. Thus, the simulations demonstrate the concept that entry of a new mobile Ca2+ ion into the selectivity filter serves to release the prior occupant that was tightly bound.

  5. Ca(2+)-dependent non-selective cation and potassium channels activated by bradykinin in pig coronary artery endothelial cells.

    PubMed Central

    Baron, A; Frieden, M; Chabaud, F; Bény, J L

    1996-01-01

    1. Using the cell-attached and inside-out modes of the patch-clamp technique, we studied the Ca(2+)-dependent ionic channels activated by bradykinin in cultured pig coronary artery endothelial cells to further understand electrophysiological events underlying cellular activation. 2. In the cell-attached mode, bradykinin (94 nM) activated two types of Ca(2+)-dependent channels: a high conductance K+ channel (285 pS in high symmetrical K+), whose open state probability was increased by depolarization, and a lower conductance inwardly rectifying non-selective cation channel (44 pS in high symmetrical K+). 3. The 285 pS K+ channel was half-maximally activated by cytosolic Ca2+ levels of 1.6 and 4.5 microM at +10 and -30 mV, respectively. Such local concentrations should be reached in the presence of bradykinin, which induces a mean maximal cytosolic Ca2+ rise of 1.3 microM. 4. The 285 pS K+ channel was inhibited by d-tubocurarine, which acted by reducing the mean open time duration (flickering pattern), finally reducing the channel conductance. 5. Divalent cations such as Ca2+ could flow through the 44 pS non-selective cation channel, with nearly the same permeability (P) as monovalent cations (PK: PNa: PCa = 1:1:0.7). 6. The cation channel appeared to be more sensitive to Ca2+ than the K+ channel, with a half-maximal open probability induced by 0.7 microM Ca2+ on the intracellular side of the membrane. 7. In contrast to the K+ channel, the cation channel mean open time was clearly increased by bradykinin. This effect was delayed compared with the increase in the channel open state probability and was rapidly lost in the inside-out configuration. Caffeine also activated the cation channel but more transiently than bradykinin and without any effect on the open duration. 8. In the absence of extracellular Ca2+, the bradykinin-induced increase in cytosolic free Ca2+ was shortened temporally by 52% and reduced in amplitude by 88%, whereas the bradykinin

  6. On the classical vibrational coherence of carbonyl groups in the selectivity filter backbone of the KcsA ion channel.

    PubMed

    Salari, V; Sajadi, M; Bassereh, H; Rezania, V; Alaei, M; Tuszynski, J A

    2015-06-01

    It has been suggested that quantum coherence in the selectivity filter of ion channel may play a key role in fast conduction and selectivity of ions. However, it has not been clearly elucidated yet why classical coherence is not sufficient for this purpose. In this paper, we investigate the classical vibrational coherence between carbonyl groups oscillations in the selectivity filter of KcsA ion channels based on the data obtained from molecular dynamics simulations. Our results show that classical coherence plays no effective role in fast ionic conduction.

  7. Selectivity of Ca2+ channel blockers in inhibiting muscular and nerve activities in isolated colon.

    PubMed Central

    Lecchini, S.; Marcoli, M.; De Ponti, F.; Castelletti, C. A.; Frigo, G. M.

    1991-01-01

    1. Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea-pig isolated distal colon. Both the neuronal and muscular effects of Ca2+ channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+ channels. 2. Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration-dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+ channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+ concentration, and completely abolished by Bay K 8644. 3. By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1285398

  8. Tackling the combined effects of reverberation and masking noise using ideal channel selection

    PubMed Central

    Hazrati, Oldooz

    2012-01-01

    Purpose A new signal processing algorithm is proposed and evaluated in this study for the suppression of the combined effects of reverberation and noise. Method The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a signal-to-reverberant ratio (SRR) criterion. The construction of this criterion assumes access to a priori knowledge of the target (anechoic) signal and the aim of the present study is to assess the full potential of the proposed channel-selection algorithm assuming that this criterion can be estimated accurately. Listening tests were conducted with normal-hearing listeners to assess the performance of the proposed algorithm in highly reverberant conditions (T60 = 1.0 s) which included additive noise at 0 and 5 dB SNR. Results A substantial gain in intelligibility was obtained in both reverberant and combined reverberant and noise conditions. The mean intelligibility scores improved by 44 and 33 percentage points at 0 and 5 dB SNR reverberant+noise conditions. Feature analysis of the consonant confusion matrices revealed that the transmission of voicing information was most negatively affected, followed by manner and place of articulation. Conclusions The proposed algorithm was found to produce substantial gains in intelligibility, and this benefit was attributed to the ability of the proposed SRR criterion to accurately detect voiced/unvoiced boundaries. Detection of those boundaries is postulated to be critical for better perception of voicing information and manner of articulation. PMID:22232411

  9. Serum factor induces selective increase in Na-channel expression in cultured skeletal muscle

    SciTech Connect

    Brodie, C.; Sampson, S.R. )

    1991-07-01

    The authors have examined effects of horse serum (HS) and various fractions (1 million-1M, 300K, 100K, and 30K nominal molecular weight limit) obtained by ultrafiltration on expression of TTX-sensitive Na-channels and on activities of the Na-K pump and glucose transport systems in cultured myotubes obtained from 1-2-day-old neonatal rat pups. Five-day-old cells were transferred to serum-free medium with no hormone or growth factor supplements (DMEM) for 24 hr and then treated with the various serum fractions for 48 hr. Measurements were made of specific (3H)-saxitoxin (STX) binding, action potential properties, 86Rb-uptake and 2-deoxyglucose (2-DG) uptake. HS significantly increased all parameters compared to DMEM (increases in STX-binding, 69%; Rb-uptake, 65%; 2-DG uptake, 93%). Results of treatment with the separate fractions showed that the 300K fraction caused a significantly greater increase in STX-binding than either HS or the other fractions. In contrast, the increases in Rb and 2-DG uptakes induced by the different fractions were not different from that obtained with HS. They conclude that serum contains a factor that selectively increases expression of TTX-sensitive Na-channels in skeletal muscle.

  10. Frequency channel-dependent selectivity for temporal call characteristics in gray treefrogs, Hyla versicolor.

    PubMed

    Reichert, Michael S; Höbel, Gerlinde

    2017-04-01

    Sensory receptors transmit information on multiple stimulus dimensions. Much remains to be understood about how the processing of different signal characteristics is partitioned and integrated in different areas of the nervous system. Amphibian hearing involves two morphologically distinct inner-ear organs that process different components of the frequency spectrum. Many anuran signals contain two frequency peaks, each one matching the sensitivity of one of these two organs. We hypothesized that the processing of temporal characteristics of acoustic signals would differ in these two frequency channels, perhaps because of differences in the response properties of the two inner-ear organs. We tested this hypothesis in the gray treefrog, Hyla versicolor; male advertisement calls of this species contain a bimodal frequency spectrum. We generated synthetic male advertisement calls in which we independently manipulated the pattern of amplitude modulation in the low-frequency peak or the high-frequency peak and measured the attractiveness of these stimuli to females in single-speaker and two-speaker phonotaxis tests. We obtained multiple lines of evidence that females were more selective for fine-temporal characteristics in the high-frequency peak. We discuss the potential implications of frequency channel-dependent temporal processing for signal evolution and suggest that additional neurophysiological investigations of the anuran auditory periphery will give important insights into how the nervous system partitions the encoding of multiple characteristics of complex signals. © 2017. Published by The Company of Biologists Ltd.

  11. Osteoinduction of porous Ti implants with a channel structure fabricated by selective laser melting.

    PubMed

    Fukuda, A; Takemoto, M; Saito, T; Fujibayashi, S; Neo, M; Pattanayak, Deepak K; Matsushita, T; Sasaki, K; Nishida, N; Kokubo, T; Nakamura, T

    2011-05-01

    Many studies have shown that certain biomaterials with specific porous structures can induce bone formation in non-osseous sites without the need for osteoinductive biomolecules, however, the mechanisms responsible for this phenomenon (intrinsic osteoinduction of biomaterials) remain unclear. In particular, to our knowledge the type of pore structure suitable for osteoinduction has not been reported in detail. In the present study we investigated the effects of interconnective pore size on osteoinductivity and the bone formation processes during osteoinduction. Selective laser melting was employed to fabricate porous Ti implants (diameter 3.3mm, length 15 mm) with a channel structure comprising four longitudinal square channels, representing pores, of different diagonal widths, 500, 600, 900, and 1200 μm (termed p500, p600, p900, and p1200, respectively). These were then subjected to chemical and heat treatments to induce bioactivity. Significant osteoinduction was observed in p500 and p600, with the highest observed osteoinduction occurring at 5mm from the end of the implants. A distance of 5mm probably provides a favorable balance between blood circulation and fluid movement. Thus, the simple architecture of the implants allowed effective investigation of the influence of the interconnective pore size on osteoinduction, as well as the relationship between bone quantity and its location for different pore sizes.

  12. Selective trapping and concentration of nanoparticles and viruses in dual-height nanofluidic channels.

    PubMed

    Hamblin, Mark N; Xuan, Jie; Maynes, Daniel; Tolley, H Dennis; Belnap, David M; Woolley, Adam T; Lee, Milton L; Hawkins, Aaron R

    2010-01-21

    Nanofluidic systems offer advantages for chemical analysis, including small sample volumes, size-selective particle trapping, sample concentration and the ability to separate and detect single molecules. Such systems can be fabricated using planar nanochannels, which rely on standard photolithographic techniques. Nanochannel fluid flow can be driven by capillary action, which benefits from simple injection and reasonably high flow rates. We demonstrate an analysis chip fabricated with planar nanochannels that consist of two adjoining segments of different heights. When nano-analytes elute through the channel, they become physically trapped when the channel dimensions shrink below the size of the particles. We demonstrate the capability of these devices to trap and concentrate by using the following: 120-nm polymer beads, 30-nm polymer beads, Herpes simplex virus 1 capsids, and hepatitis B virus capsids. Each species was fluorescently labeled and its resulting fluorescent signal was detected using a cooled CCD camera. We show how the signal-to-noise ratio of trapped analyte intensity varies linearly with analyte concentration. The goal of this work is to eventually perform size-based fractionation of a variety of nanoparticles, including biomolecules such as proteins.

  13. Role of fluctuations in a snug-fit mechanism of KcsA channel selectivity.

    PubMed

    Asthagiri, D; Pratt, Lawrence R; Paulaitis, Michael E

    2006-07-14

    The thermodynamic exclusion of Na+ relative to K+ in potassium channels is examined by calculating the distribution of binding energies for Na+ and K+ in a model of the selectivity filter of the KcsA potassium channel. These distributions are observed to take a surprisingly simple form: Gaussian with a slight positive skewness that is insignificant in the present context. Complications that might be anticipated from these distributions are not problematic here. Na+ occupies the filter with a mean binding energy substantially lower than that of K+. The difference is comparable to the difference in hydration free energies of Na+ and K+ in bulk aqueous solution. Thus, the average energies of binding to the filter do not discriminate Na+ from K+ when measured from a baseline of the difference in bulk hydration free energies. The strong binding of Na+ constricts the filter, consistent with a negative partial molar volume of Na+ in water in contrast with a positive partial molar volume of K+ in water. Discrimination in favor of K+)can be attributed to the scarcity of favorable binding configurations for Na+ compared to K+. That relative scarcity is quantified as enhanced binding energy fluctuations, which reflects both the energetically stronger binding of Na+ and the constriction of the filter induced by Na+ binding.

  14. X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel.

    PubMed

    Baconguis, Isabelle; Bohlen, Christopher J; Goehring, April; Julius, David; Gouaux, Eric

    2014-02-13

    Acid-sensing ion channels (ASICs) detect extracellular protons produced during inflammation or ischemic injury and belong to the superfamily of degenerin/epithelial sodium channels. Here, we determine the cocrystal structure of chicken ASIC1a with MitTx, a pain-inducing toxin from the Texas coral snake, to define the structure of the open state of ASIC1a. In the MitTx-bound open state and in the previously determined low-pH desensitized state, TM2 is a discontinuous α helix in which the Gly-Ala-Ser selectivity filter adopts an extended, belt-like conformation, swapping the cytoplasmic one-third of TM2 with an adjacent subunit. Gly 443 residues of the selectivity filter provide a ring of three carbonyl oxygen atoms with a radius of ∼3.6 Å, presenting an energetic barrier for hydrated ions. The ASIC1a-MitTx complex illuminates the mechanism of MitTx action, defines the structure of the selectivity filter of voltage-independent, sodium-selective ion channels, and captures the open state of an ASIC. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. X-ray structure of acid-sensing ion channel 1–snake toxin complex reveals open state of a Na+-selective channel

    PubMed Central

    Baconguis, Isabelle; Bohlen, Christopher J.; Goehring, April; Julius, David; Gouaux, Eric

    2014-01-01

    Summary Acid sensing ion channels (ASICs) detect extracellular protons produced during inflammation or ischemic injury and belong to the super family of degenerin/epithelial sodium channels. Here, we determine the cocrystal structure of chicken ASIC1a with MitTx, a pain-inducing toxin from the Texas coral snake, to define the structure of the open state of ASIC1a. In the MitTx-bound open state and in the previously determined low pH desensitized state, TM2 is a discontinuous α-helix in which the Gly-Ala-Ser selectivity filter adopts an extended, belt-like conformation, swapping the cytoplasmic one-third of TM2 with an adjacent subunit. Gly 443 residues of the selectivity filter provide a ring of 3 carbonyl oxygen atoms with a radius of ~3.6 Å, presenting an energetic barrier for hydrated ions. The ASIC1a-MitTx complex illuminates the mechanism of MitTx action, defines the structure of the selectivity filter of voltage-independent, sodium-selective ion channels and captures the open state of an ASIC. PMID:24507937

  16. Single-Tap Precoders and Decoders for Multiuser MIMO FBMC-OQAM Under Strong Channel Frequency Selectivity

    NASA Astrophysics Data System (ADS)

    Rottenberg, Francois; Mestre, Xavier; Horlin, Francois; Louveaux, Jerome

    2017-02-01

    The design of linear precoders or decoders for multiuser (MU) multiple-input multiple-output (MIMO) filterbank multicarrier (FBMC) modulations in the case of strong channel frequency selectivity is presented. The users and the base station (BS) communicate using space division multiple access (SDMA). The low complexity proposed solution is based on a single tap per-subcarrier precoding/decoding matrix at the base station (BS) in the downlink/uplink. As opposed to classical approaches that assume flat channel frequency selectivity at the subcarrier level, the BS does not make this assumption and takes into account the distortion caused by channel frequency selectivity. The expression of the FBMC asymptotic mean squared error (MSE) in the case of strong channel selectivity derived in earlier works is developed and extended. The linear precoders and decoders are found by optimizing the MSE formula under two design criteria, namely zero forcing (ZF) or minimum mean squared error (MMSE). Finally, simulation results demonstrate the performance of the optimized design. As long as the number of BS antennas is larger than the number of users, it is shown that those extra degrees of freedom can be used to compensate for the channel frequency selectivity.

  17. A novel selective and orally bioavailable Nav1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability

    PubMed Central

    Payne, Claire Elizabeth; Brown, Adam R; Theile, Jonathon W; Loucif, Alexandre J C; Alexandrou, Aristos J; Fuller, Mathew D; Mahoney, John H; Antonio, Brett M; Gerlach, Aaron C; Printzenhoff, David M; Prime, Rebecca L; Stockbridge, Gillian; Kirkup, Anthony J; Bannon, Anthony W; England, Steve; Chapman, Mark L; Bagal, Sharan; Roeloffs, Rosemarie; Anand, Uma; Anand, Praveen; Bungay, Peter J; Kemp, Mark; Butt, Richard P; Stevens, Edward B

    2015-01-01

    Background and Purpose NaV1.8 ion channels have been highlighted as important molecular targets for the design of low MW blockers for the treatment of chronic pain. Here, we describe the effects of PF-01247324, a new generation, selective, orally bioavailable Nav1.8 channel blocker of novel chemotype. Experimental Approach The inhibition of Nav1.8 channels by PF-01247324 was studied using in vitro patch-clamp electrophysiology and the oral bioavailability and antinociceptive effects demonstrated using in vivo rodent models of inflammatory and neuropathic pain. Key Results PF-01247324 inhibited native tetrodotoxin-resistant (TTX-R) currents in human dorsal root ganglion (DRG) neurons (IC50: 331 nM) and in recombinantly expressed h Nav1.8 channels (IC50: 196 nM), with 50-fold selectivity over recombinantly expressed TTX-R hNav1.5 channels (IC50: ∼10 μM) and 65–100-fold selectivity over TTX-sensitive (TTX-S) channels (IC50: ∼10–18 μM). Native TTX-R currents in small-diameter rodent DRG neurons were inhibited with an IC50 448 nM, and the block of both human recombinant Nav1.8 channels and TTX-R from rat DRG neurons was both frequency and state dependent. In vitro current clamp showed that PF-01247324 reduced excitability in both rat and human DRG neurons and also altered the waveform of the action potential. In vivo experiments n rodents demonstrated efficacy in both inflammatory and neuropathic pain models. Conclusions and Implications Using PF-01247324, we have confirmed a role for Nav1.8 channels in both inflammatory and neuropathic pain. We have also demonstrated a key role for Nav1.8 channels in action potential upstroke and repetitive firing of rat and human DRG neurons. PMID:25625641

  18. Gating-pore currents demonstrate selective and specific modulation of individual sodium channel voltage-sensors by biological toxins.

    PubMed

    Xiao, Yucheng; Blumenthal, Kenneth; Cummins, Theodore R

    2014-08-01

    Voltage-gated sodium channels are critical determinants of nerve and muscle excitability. Although numerous toxins and small molecules target sodium channels, identifying the mechanisms of action is challenging. Here we used gating-pore currents selectively generated in each of the voltage-sensors from the four α-subunit domains (DI-DIV) to monitor the activity of individual voltage-sensors and to investigate the molecular determinants of sodium channel pharmacology. The tarantula toxin huwentoxin-IV (HWTX-IV), which inhibits sodium channel current, exclusively enhanced inward gating-pore currents through the DII voltage-sensor. By contrast, the tarantula toxin ProTx-II, which also inhibits sodium channel currents, altered the gating-pore currents in multiple voltage-sensors in a complex manner. Thus, whereas HWTX-IV inhibits central-pore currents by selectively trapping the DII voltage-sensor in the resting configuration, ProTx-II seems to inhibit central-pore currents by differentially altering the configuration of multiple voltage-sensors. The sea anemone toxin anthopleurin B, which impairs open-channel inactivation, exclusively enhanced inward gating-pore currents through the DIV voltage-sensor. This indicates that trapping the DIV voltage-sensor in the resting configuration selectively impairs open-channel inactivation. Furthermore, these data indicate that although activation of all four voltage-sensors is not required for central-pore current generation, activation of the DII voltage-sensor is crucial. Overall, our data demonstrate that gating-pore currents can determine the mechanism of action for sodium channel gating modifiers with high precision. We propose this approach could be adapted to identify the molecular mechanisms of action for gating modifiers of various voltage-gated ion channels. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins

    PubMed Central

    Xiao, Yucheng; Blumenthal, Kenneth

    2014-01-01

    Voltage-gated sodium channels are critical determinants of nerve and muscle excitability. Although numerous toxins and small molecules target sodium channels, identifying the mechanisms of action is challenging. Here we used gating-pore currents selectively generated in each of the voltage-sensors from the four α-subunit domains (DI–DIV) to monitor the activity of individual voltage-sensors and to investigate the molecular determinants of sodium channel pharmacology. The tarantula toxin huwentoxin-IV (HWTX-IV), which inhibits sodium channel current, exclusively enhanced inward gating-pore currents through the DII voltage-sensor. By contrast, the tarantula toxin ProTx-II, which also inhibits sodium channel currents, altered the gating-pore currents in multiple voltage-sensors in a complex manner. Thus, whereas HWTX-IV inhibits central-pore currents by selectively trapping the DII voltage-sensor in the resting configuration, ProTx-II seems to inhibit central-pore currents by differentially altering the configuration of multiple voltage-sensors. The sea anemone toxin anthopleurin B, which impairs open-channel inactivation, exclusively enhanced inward gating-pore currents through the DIV voltage-sensor. This indicates that trapping the DIV voltage-sensor in the resting configuration selectively impairs open-channel inactivation. Furthermore, these data indicate that although activation of all four voltage-sensors is not required for central-pore current generation, activation of the DII voltage-sensor is crucial. Overall, our data demonstrate that gating-pore currents can determine the mechanism of action for sodium channel gating modifiers with high precision. We propose this approach could be adapted to identify the molecular mechanisms of action for gating modifiers of various voltage-gated ion channels. PMID:24898004

  20. Attentional selection of superimposed surfaces cannot be explained by modulation of the gain of color channels.

    PubMed

    Mitchell, Jude F; Stoner, Gene R; Fallah, Mazyar; Reynolds, John H

    2003-06-01

    When two differently colored, superimposed patterns of dots rotate in opposite directions, this yields the percept of two superimposed transparent surfaces. If observers are cued to attend to one set of dots, they are impaired in making judgments about the other set. Since the two sets of dots are overlapping, the cueing effect cannot be explained by spatial attention. This has led to the interpretation that the impairment reflects surface-based attentional selection. However, recent single-unit recording studies in monkeys have found that attention can modulate the gain of neurons tuned for features such as color. Thus, rather than reflecting the selection of a surface, the behavioral effects might simply reflect a reduction in the gain of color channels selective for the color of the uncued set of dots (feature-based attention), as if viewing the surfaces through a colored filter. If so, then the impairment should be eliminated when the two surfaces are made the same color. Instead, we find that the impairment persists with no reduction in strength. Our findings thus rule out the color gain explanation.

  1. High-Flip-Angle slice-selective parallel RF transmission with 8 channels at 7 Tesla

    PubMed Central

    Setsompop, Kawin; Alagappan, Vijayanand; Zelinski, Adam C.; Potthast, Andreas; Fontius, Ulrich; Hebrank, Franz; Schmitt, Franz; Wald, Lawrence L.; Adalsteinsson, Elfar

    2008-01-01

    At high magnetic field, B1+ non-uniformity causes undesired inhomogeneity in SNR and image contrast. Parallel RF transmission using tailored 3D k-space trajectory design has been shown to correct for this problem and produce highly uniform in-plane magnetization with good slice selection profile within a relatively short excitation duration. However, at large flip angles the excitation k-space based design method fails. Consequently, several large-flip-angle parallel transmission designs have recently been suggested. In this work, we propose and demonstrate a large-flip-angle parallel excitation design for 90° and 180° spin-echo slice-selective excitations that mitigate severe B1+ inhomogeneity. The method was validated on an 8-channel transmit array at 7T using a water phantom with B1+ inhomogeneity similar to that seen in human brain in vivo. Slice-selective excitations with parallel RF systems offer means to implement conventional high-flip excitation sequences without a severe pulse-duration penalty, even at very high B0 field strengths where large B1+ inhomogeneity is present. PMID:18799336

  2. Contribution of a leucine residue in the first transmembrane segment to the selectivity filter region in the CFTR chloride channel.

    PubMed

    Negoda, Alexander; El Hiani, Yassine; Cowley, Elizabeth A; Linsdell, Paul

    2017-05-01

    The anion selectivity and conductance of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are determined predominantly by interactions between permeant anions and the narrow region of the channel pore. This narrow region has therefore been described as functioning as the "selectivity filter" of the channel. Multiple pore-lining transmembrane segments (TMs) have previously been shown to contribute to the selectivity filter region. However, little is known about the three-dimensional organization of this region, or how multiple TMs combine to determine its functional properties. In the present study we have used patch clamp recording to identify changes in channel function associated with the formation of disulfide cross-links between cysteine residues introduced into different TMs within the selectivity filter. Cysteine introduced at position L102 in TM1 was able to form disulfide bonds with F337C and T338C in TM6, two positions that are known to play key roles in determining anion permeation properties. Consistent with this proximal arrangement of L102, F337 and T338, different mutations at L102 altered anion selectivity and conductance properties in a way that suggests that this residue plays an important role in determining selectivity filter function, albeit a much lesser role than that of F337. These results suggest an asymmetric three-dimensional arrangement of the key selectivity filter region of the pore, as well as having important implications regarding the molecular mechanism of anion permeation.

  3. Efficient selective repeat ARQ strategies for very noisy and fluctuating channels

    NASA Astrophysics Data System (ADS)

    Metzner, J. J.; Chang, D.

    1985-05-01

    Memory and selective repeat ARQ techniques, when channels in both directions are very noisy are investigated, demonstrating that a difficulty arises when memory ARQ is used in these situations, and proposing a remedy, the similarity test. The paper considers a combination of both memory ARQ techniques where an unacknowledged block is retransmitted exactly as before, and modified memory ARQ where alternate transmissions together form a rate 1/2 code. The following items are featured: (1) discussion and analysis of the similarity test, (2) a memory ARQ technique which employs double null zone reception and 3 bits of past-information storage per binary digit, and (3) for modified memory ARQ procedures, a discussion of how to resolve problems of confusing the identity of the two halves of the rate 1/2 code used.

  4. Enterobacter aerogenes OmpX, a cation-selective channel mar- and osmo-regulated.

    PubMed

    Dupont, Myrielle; Dé, Emmanuelle; Chollet, Renaud; Chevalier, Jacqueline; Pagès, Jean-Marie

    2004-07-02

    The ompX gene of Enterobacter aerogenes was cloned. Its overexpression induced a decrease in the major porin Omp36 production and consequently a beta-lactam resistance was noted. Purified outer membrane protein X (OmpX) was reconstituted into artificial membranes and formed ion channels with a conductance of 20 pS in 1 M NaCl and a cationic selectivity. Both MarA expression and high osmolarity induced a noticeable increase of the OmpX synthesis in the E. aerogenes ATCC 13048 strain. In addition, OmpX synthesis increased under conditions in which the expression of the E. aerogenes major non-specific porins, Omp36 and Omp35, decreased.

  5. Spatial filter and feature selection optimization based on EA for multi-channel EEG.

    PubMed

    Wang, Yubo; Mohanarangam, Krithikaa; Mallipeddi, Rammohan; Veluvolu, K C

    2015-01-01

    The EEG signals employed for BCI systems are generally band-limited. The band-limited multiple Fourier linear combiner (BMFLC) with Kalman filter was developed to obtain amplitude estimates of the EEG signal in a pre-fixed frequency band in real-time. However, the high-dimensionality of the feature vector caused by the application of BMFLC to multi-channel EEG based BCI deteriorates the performance of the classifier. In this work, we apply evolutionary algorithm (EA) to tackle this problem. The real-valued EA encodes both the spatial filter and the feature selection into its solution and optimizes it with respect to the classification error. Three BMFLC based BCI configurations are proposed. Our results show that the BMFLC-KF with covariance matrix adaptation evolution strategy (CMAES) has the best overall performance.

  6. Channel selection and feature projection for cognitive load estimation using ambulatory EEG.

    PubMed

    Lan, Tian; Erdogmus, Deniz; Adami, Andre; Mathan, Santosh; Pavel, Misha

    2007-01-01

    We present an ambulatory cognitive state classification system to assess the subject's mental load based on EEG measurements. The ambulatory cognitive state estimator is utilized in the context of a real-time augmented cognition (AugCog) system that aims to enhance the cognitive performance of a human user through computer-mediated assistance based on assessments of cognitive states using physiological signals including, but not limited to, EEG. This paper focuses particularly on the offline channel selection and feature projection phases of the design and aims to present mutual-information-based techniques that use a simple sample estimator for this quantity. Analyses conducted on data collected from 3 subjects performing 2 tasks (n-back/Larson) at 2 difficulty levels (low/high) demonstrate that the proposed mutual-information-based dimensionality reduction scheme can achieve up to 94% cognitive load estimation accuracy.

  7. Multilevel Concatenated Block Modulation Codes for the Frequency Non-selective Rayleigh Fading Channel

    NASA Technical Reports Server (NTRS)

    Lin, Shu; Rhee, Dojun

    1996-01-01

    This paper is concerned with construction of multilevel concatenated block modulation codes using a multi-level concatenation scheme for the frequency non-selective Rayleigh fading channel. In the construction of multilevel concatenated modulation code, block modulation codes are used as the inner codes. Various types of codes (block or convolutional, binary or nonbinary) are being considered as the outer codes. In particular, we focus on the special case for which Reed-Solomon (RS) codes are used as the outer codes. For this special case, a systematic algebraic technique for constructing q-level concatenated block modulation codes is proposed. Codes have been constructed for certain specific values of q and compared with the single-level concatenated block modulation codes using the same inner codes. A multilevel closest coset decoding scheme for these codes is proposed.

  8. Maitotoxin Is a Potential Selective Activator of the Endogenous Transient Receptor Potential Canonical Type 1 Channel in Xenopus laevis Oocytes.

    PubMed

    Flores, Pedro L; Rodríguez, Emma; Zapata, Estrella; Carbó, Roxana; Farías, José María; Martínez, Martín

    2017-06-25

    Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels.

  9. Charged Residues Distribution Modulates Selectivity of the Open State of Human Isoforms of the Voltage Dependent Anion-Selective Channel

    PubMed Central

    Messina, Angela; De Pinto, Vito; Ceccarelli, Matteo

    2014-01-01

    Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the ‘unstructured’ conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10′ to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl−/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities. PMID:25084457

  10. Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel.

    PubMed

    Amodeo, Giuseppe Federico; Scorciapino, Mariano Andrea; Messina, Angela; De Pinto, Vito; Ceccarelli, Matteo

    2014-01-01

    Voltage Dependent Anion-selective Channels (VDACs) are pore-forming proteins located in the outer mitochondrial membrane. They are responsible for the access of ions and energetic metabolites into the inner membrane transport systems. Three VDAC isoforms exist in mammalian, but their specific role is unknown. In this work we have performed extensive (overall ∼5 µs) Molecular Dynamics (MD) simulations of the human VDAC isoforms to detect structural and conformational variations among them, possibly related to specific functional roles of these proteins. Secondary structure analysis of the N-terminal domain shows a high similarity among the three human isoforms of VDAC but with a different plasticity. In particular, the N-terminal domain of the hVDAC1 is characterized by a higher plasticity, with a ∼20% occurrence for the 'unstructured' conformation throughout the folded segment, while hVDAC2, containing a peculiar extension of 11 amino acids at the N-terminal end, presents an additional 310-helical folded portion comprising residues 10' to 3, adhering to the barrel wall. The N-terminal sequences of hVDAC isoforms are predicted to have a low flexibility, with possible consequences in the dynamics of the human VDACs. Clear differences were found between hVDAC1 and hVDAC3 against hVDAC2: a significantly modified dynamics with possible important consequence on the voltage-gating mechanism. Charge distribution inside and at the mouth of the pore is responsible for a different preferential localization of ions with opposite charge and provide a valuable rationale for hVDAC1 and hVDAC3 having a Cl-/K+ selectivity ratio of 1.8, whereas hVDAC2 of 1.4. Our conclusion is that hVDAC isoforms, despite sharing a similar scaffold, have modified working features and a biological work is now requested to give evidence to the described dissimilarities.

  11. Multi-ion free energy landscapes underscore the microscopic mechanism of ion selectivity in the KcsA channel.

    PubMed

    Medovoy, David; Perozo, Eduardo; Roux, Benoît

    2016-07-01

    Potassium (K(+)) channels are transmembrane proteins that passively and selectively allow K(+) ions to flow through them, after opening in response to an external stimulus. One of the most critical functional aspects of their function is their ability to remain very selective for K(+) over Na(+) while allowing high-throughput ion conduction at a rate close to the diffusion limit. Classically, it is assumed that the free energy difference between K(+) and Na(+) in the pore relative to the bulk solution is the critical quantity at the origin of selectivity. This is the thermodynamic view of ion selectivity. An alternative view assumes that kinetic factors play the dominant role. Recent results from a number of studies have also highlighted the great importance of the multi-ion single file on the selectivity of K(+) channels. The data indicate that having multiple K(+) ions bound simultaneously is required for selective K(+) conduction, and that a reduction in the number of bound K(+) ions destroys the multi-ion selectivity mechanism utilized by K(+) channels. In the present study, multi-ion potential of mean force molecular dynamics computations are carried out to clarify the mechanism of ion selectivity in the KcsA channel. The computations show that the multi-ion character of the permeation process is a critical element for establishing the selective ion conductivity through K(+)-channels. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. Copyright © 2016. Published by Elsevier B.V.

  12. Diffusion, Exclusion, and Specific Binding in a Large Channel: A Study of OmpF Selectivity Inversion

    PubMed Central

    Alcaraz, Antonio; Nestorovich, Ekaterina M.; López, M. Lidón; García-Giménez, Elena; Bezrukov, Sergey M.; Aguilella, Vicente M.

    2009-01-01

    Abstract We find that moderate cationic selectivity of the general bacterial porin OmpF in sodium and potassium chloride solutions is inversed to anionic selectivity in concentrated solutions of barium, calcium, nickel, and magnesium chlorides. To understand the origin of this phenomenon, we consider several factors, which include the binding of divalent cations, electrostatic and steric exclusion of differently charged and differently sized ions, size-dependent hydrodynamic hindrance, electrokinetic effects, and significant “anionic” diffusion potential for bulk solutions of chlorides of divalent cations. Though all these factors contribute to the measured selectivity of this large channel, the observed selectivity inversion is mostly due to the following two. First, binding divalent cations compensates, or even slightly overcompensates, for the negative charge of the OmpF protein, which is known to be the main cause of cationic selectivity in sodium and potassium chloride solutions. Second, the higher anionic (versus cationic) transport rate expected for bulk solutions of chloride salts of divalent cations is the leading cause of the measured anionic selectivity of the channel. Interestingly, at high concentrations the binding of cations does not show any pronounced specificity within the divalent series because the reversal potentials measured in the series correlate well with the corresponding bulk diffusion potentials. Thus our study shows that, in contrast to the highly selective channels of neurophysiology that employ mostly the exclusion mechanism, quite different factors account for the selectivity of large channels. The elucidation of these factors is essential for understanding large channel selectivity and its regulation in vivo. PMID:19134471

  13. Bias-Exchange Metadynamics Simulations: An Efficient Strategy for the Analysis of Conduction and Selectivity in Ion Channels.

    PubMed

    Domene, Carmen; Barbini, Paolo; Furini, Simone

    2015-04-14

    Conduction through ion channels possesses two interesting features: (i) different ionic species are selected with high-selectivity and (ii) ions travel across the channel with rates approaching free-diffusion. Molecular dynamics simulations have the potential to reveal how these processes take place at the atomic level. However, analysis of conduction and selectivity at atomistic detail is still hampered by the short time scales accessible by computer simulations. Several algorithms have been developed to "accelerate" sampling along the slow degrees of freedom of the process under study and thus to probe longer time scales. In these algorithms, the slow degrees of freedom need to be defined in advance, which is a well-known shortcoming. In the particular case of ion conduction, preliminary assumptions about the number and type of ions participating in the permeation process need to be made. In this study, a novel approach for the analysis of conduction and selectivity based on bias-exchange metadynamics simulations was tested. This approach was compared with umbrella sampling simulations, using a model of a Na(+)-selective channel. Analogous conclusions resulted from both techniques, but the computational cost of bias-exchange simulations was lower. In addition, with bias-exchange metadynamics it was possible to calculate free energy profiles in the presence of a variable number and type of permeating ions. This approach might facilitate the definition of the set of collective variables required to analyze conduction and selectivity in ion channels.

  14. Mechanisms for production of doubly excited states in low energies Iq+-He collisions

    NASA Astrophysics Data System (ADS)

    Harel, C.; Jouin, H.; Pons, B.

    1993-06-01

    We present a theoretical study of the mechanisms leading to the formation of doubly excited states of the series 3l3l' (or 4l') and 2lnl' in N7+, O8+ and C6+-He low energy collisions. The importance of both direct transitions from the entry channel (involving electron-electron interaction couplings) and transitions through a single electron capture channel has been analyzed for a range of impact velocities between 0.2 and 0.6 a.u.

  15. Evidence for the production of the charmed, doubly strange baryon Ω c in e +e - annihilation

    NASA Astrophysics Data System (ADS)

    Albrecht, H.; Cronström, H. I.; Ehrlichmann, H.; Hamacher, T.; Hofmann, R. P.; Kirchhoff, T.; Nau, A.; Nowak, S.; Reidenbach, M.; Reiner, R.; Schröder, H.; Schulz, H. D.; Walter, M.; Wurth, R.; Appuhn, R. D.; Hast, C.; Kolanoski, H.; Lange, A.; Lindner, A.; Mankel, R.; Schieber, M.; Siegmund, T.; Spaan, B.; Thurn, H.; Töpfer, D.; Walther, A.; Wegener, D.; Paulini, M.; Reim, K.; Wegener, H.; Mundt, R.; Oest, T.; Schmidt-Parzefall, W.; Becker, U.; Funk, W.; Stiewe, J.; Werner, S.; Ehret, K.; Hölscher, A.; Hofmann, W.; Hüpper, A.; Kahn, S.; Knöpfle, K. T.; Spengler, J.; Britton, D. I.; Charlesworth, C. E. K.; Edwards, K. W.; Hyatt, E. R. F.; Kapitza, H.; Krieger, P.; Macfarlane, D. B.; Patel, P. M.; Prentice, J. D.; Saull, P. R. B.; Seidel, S. C.; Tzamariudaki, K.; van de Water, R. G.; Yoon, T.-S.; Reßing, D.; Schmidtler, M.; Schneider, M.; Schubert, K. R.; Strahl, K.; Waldi, R.; Weseler, S.; Kernel, G.; Križan, P.; Križnič, E.; Podobnik, T.; Živko, T.; Jönsson, L.; Balagura, V.; Belyaev, I.; Danilov, M.; Droutskoy, A.; Golutvin, A.; Gorelov, I.; Kostina, G.; Lubimov, V.; Murat, P.; Pakhlov, P.; Ratnikov, F.; Semenov, S.; Shibaev, V.; Soloshenko, V.; Tichomirov, I.; Zaitsev, Yu.; Argus Collaboration

    1992-08-01

    Using the detector ARGUS at the storage ring DORIS II of DESY, we have found evidence for the production of the charmed and doubly strange baryon Ω c through its decay channel Ξ -K -π +π +. Its mass has been determined to be ((2719.0±7.0±2.5)MeV/ c2, and the product of production cross section and branching ratio the above channel to be (2.41±0.90±0.30) pb.

  16. Receiver Optimization for Detection in Doubly Spread Communication Channels.

    DTIC Science & Technology

    1984-12-10

    h1T- dt RS T9) -00 aoCHN x [ 0x(t’-T) g*(t’) e j 2 ir ( t ’ - T/ 2 ) dt’ dTd¢ x [ x(t’-T/2) g*(t’+T/2) ej2rot dJ drd4 . (3.2-36) The bracketed terms in...4.3-11) Applying (4.3-11) to (4.3-10) gives IP p . ...................- 66 ff Xx,2+cn(T, RS(T,) dTdO =-f I xgt(T,1)2 RS (T,) drd4 + 2 e ff Re{JXxg...3.2.2 to be given by [0€ EIZ CHNI 2 I f IXx,g(T, ) 2 RSCHN(T,4) drd4 . (3.2-38) If R1 is defined to be the region of the (T,4) plane where the cross

  17. Agonist activation of arachidonate-regulated Ca2+-selective (ARC) channels in murine parotid and pancreatic acinar cells.

    PubMed

    Mignen, Olivier; Thompson, Jill L; Yule, David I; Shuttleworth, Trevor J

    2005-05-01

    ARC channels (arachidonate-regulated Ca(2+)-selective channels) are a novel type of highly Ca(2+)-selective channel that are specifically activated by low concentrations of agonist-induced arachidonic acid. This activation occurs in the absence of any depletion of internal Ca(2+) stores (i.e. they are 'non-capacitative'). Previous studies in HEK293 cells have shown that these channels provide the predominant pathway for the entry of Ca(2+) seen at low agonist concentrations where oscillatory [Ca(2+)](i) signals are typically produced. In contrast, activation of the more widely studied store-operated Ca(2+) channels (e.g. CRAC channels) is only seen at higher agonist concentrations where sustained 'plateau-type'[Ca(2+)](i) responses are observed. We have now demonstrated the presence of ARC channels in both parotid and pancreatic acinar cells and shown that, again, they are specifically activated by the low concentrations of appropriate agonists (carbachol in the parotid, and both carbachol and cholecystokinin in the pancreas) that are associated with oscillatory [Ca(2+)](i) signals in these cells. Uncoupling the receptor-mediated activation of cytosolic phospholipase A(2) (cPLA(2)) with isotetrandrine reduces the activation of the ARC channels by carbachol and, correspondingly, markedly inhibits the [Ca(2+)](i) signals induced by low carbachol concentrations, whilst those signals seen at high agonist concentrations are essentially unaffected. Interestingly, in the pancreatic acinar cells, activation by cholecystokinin induces a current through the ARC channels that is only approximately 60% of that seen with carbachol. This is consistent with previous reports indicating that carbachol-induced [Ca(2+)](i) signals in these cells are much more dependent on Ca(2+) entry than are the cholecystokinin-induced responses.

  18. Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels.

    PubMed

    Taylor-Clark, Thomas E; Undem, Bradley J

    2010-02-01

    Inhalation of ozone is a major health risk in industrialized nations. Ozone can impair lung function and induce respiratory symptoms through sensory neural-mediated pathways, yet the specific interaction of ozone with airway sensory nerves has yet to be elucidated. Here we demonstrate, using a vagally innervated ex vivo tracheal-lung mouse preparation, that ozone selectively and directly evokes action potential discharge in a subset of nociceptive bronchopulmonary nerves, namely slow conducting C-fibres. Sensitivity to ozone correlated with the transient receptor potential (TRP) A1 agonist, cinnamaldehyde, with ozone having no effect on cinnamaldehyde-insensitive fibres. C-fibre responses to ozone were abolished by ruthenium red (TRP inhibitor). Ozone also stimulated a subset of nociceptive sensory neurones isolated from vagal ganglia of wild-type mice, but failed to activate neurones isolated from transient receptor potential ankyrin 1 (TRPA1) knockout mice. Ozone activated HEK293 cells transfected with TRPA1, but failed to activate non-transfected HEK293 or HEK293 transfected with the capsaicin-sensitive transient receptor potential vanilloid 1 (TRPV1) channel. Thus, ozone is not an indiscriminate neuronal activator, but rather it potently and selectively activates a subset of airway C-fibres by directly stimulating TRPA1.

  19. The food dye FD&C Blue No. 1 is a selective inhibitor of the ATP release channel Panx1.

    PubMed

    Wang, Junjie; Jackson, David George; Dahl, Gerhard

    2013-05-01

    The food dye FD&C Blue No. 1 (Brilliant Blue FCF [BB FCF]) is structurally similar to the purinergic receptor antagonist Brilliant Blue G (BBG), which is a well-known inhibitor of the ionotropic P2X7 receptor (P2X7R). The P2X7R functionally interacts with the membrane channel protein pannexin 1 (Panx1) in inflammasome signaling. Intriguingly, ligands to the P2X7R, regardless of whether they are acting as agonists or antagonists at the receptor, inhibit Panx1 channels. Thus, because both P2X7R and Panx1 are inhibited by BBG, the diagnostic value of the drug is limited. Here, we show that the food dye BB FCF is a selective inhibitor of Panx1 channels, with an IC50 of 0.27 µM. No significant effect was observed with concentrations as high as 100 µM of BB FCF on P2X7R. Differing by just one hydroxyl group from BB FCF, the food dye FD&C Green No. 3 exhibited similar selective inhibition of Panx1 channels. A reverse selectivity was observed for the P2X7R antagonist, oxidized ATP, which in contrast to other P2X7R antagonists had no significant inhibitory effect on Panx1 channels. Based on its selective action, BB FCF can be added to the repertoire of drugs to study the physiology of Panx1 channels. Furthermore, because Panx1 channels appear to be involved directly or indirectly through P2X7Rs in several disorders, BB FCF and derivatives of this "safe" food dye should be given serious consideration for pharmacological intervention of conditions such as acute Crohn's disease, stroke, and injuries to the central nervous system.

  20. Double Space Time Transmit Diversity OFDM System with Antenna Shuffling in Spatial Correlated Frequency Selective MIMO Channels

    NASA Astrophysics Data System (ADS)

    Zhou, Liang; Shimizu, Masahiko

    In this paper, we study low complexity transceiver for double space time transmit diversity (DSTTD) and orthogonal frequency division multiplexing (OFDM) system with antenna shuffling. Firstly, we propose a novel antenna shuffling method based on the criterion of minimizing the condition number of channel correlation matrix. The condition number is an indicator about the quality of the channel. By selecting the minimum of condition number which has better channel quality, consequently, a linear detector with respect to this new channel may achieve better performance results. A low complexity variant of the condition number calculation is also proposed, and it is shown that this criterion can be reduced to the minimum mean square error (MMSE) based criterion. Furthermore, the weighted soft decision Viterbi decoding is applied to mitigate noise enhancement inherent to zero forcing (ZF) and MMSE linear receivers and improve error rate performance. Next, we propose an algorithm to reduce the amount of feedback by exploiting the fact that the channel frequency responses across OFDM subcarriers are correlated. In the proposed algorithm, subcarriers are clustered in blocks, which are allocated the same shuffling pattern with the largest number of the shuffling patterns in the cluster. This way, the signaling overhead can be reduced in comparison with each subcarrier based feedback. Extensive simulations show that the proposed techniques for DSTTD-OFDM system outperform other existing techniques under both uncorrelated and highly spatial correlated frequency selective MIMO fading channels.

  1. A Change in the Ion Selectivity of Ligand-Gated Ion Channels Provides a Mechanism to Switch Behavior

    PubMed Central

    Alkema, Mark J.

    2015-01-01

    Behavioral output of neural networks depends on a delicate balance between excitatory and inhibitory synaptic connections. However, it is not known whether network formation and stability is constrained by the sign of synaptic connections between neurons within the network. Here we show that switching the sign of a synapse within a neural circuit can reverse the behavioral output. The inhibitory tyramine-gated chloride channel, LGC-55, induces head relaxation and inhibits forward locomotion during the Caenorhabditis elegans escape response. We switched the ion selectivity of an inhibitory LGC-55 anion channel to an excitatory LGC-55 cation channel. The engineered cation channel is properly trafficked in the native neural circuit and results in behavioral responses that are opposite to those produced by activation of the LGC-55 anion channel. Our findings indicate that switches in ion selectivity of ligand-gated ion channels (LGICs) do not affect network connectivity or stability and may provide an evolutionary and a synthetic mechanism to change behavior. PMID:26348462

  2. Ion Trapping with Fast-Response Ion-Selective Microelectrodes Enhances Detection of Extracellular Ion Channel Gradients

    PubMed Central

    Messerli, Mark A.; Collis, Leon P.; Smith, Peter J.S.

    2009-01-01

    Previously, functional mapping of channels has been achieved by measuring the passage of net charge and of specific ions with electrophysiological and intracellular fluorescence imaging techniques. However, functional mapping of ion channels using extracellular ion-selective microelectrodes has distinct advantages over the former methods. We have developed this method through measurement of extracellular K+ gradients caused by efflux through Ca2+-activated K+ channels expressed in Chinese hamster ovary cells. We report that electrodes constructed with short columns of a mechanically stable K+-selective liquid membrane respond quickly and measure changes in local [K+] consistent with a diffusion model. When used in close proximity to the plasma membrane (<4 μm), the ISMs pose a barrier to simple diffusion, creating an ion trap. The ion trap amplifies the local change in [K+] without dramatically changing the rise or fall time of the [K+] profile. Measurement of extracellular K+ gradients from activated rSlo channels shows that rapid events, 10–55 ms, can be characterized. This method provides a noninvasive means for functional mapping of channel location and density as well as for characterizing the properties of ion channels in the plasma membrane. PMID:19217875

  3. Hydration valve controlled non-selective conduction of Na(+) and K(+) in the NaK channel.

    PubMed

    Shen, Rong; Guo, Wanlin; Zhong, Wenyu

    2010-08-01

    The Na(+) and K(+) channels are essential to neural signaling, but our current knowledge at the atomic level is mainly limited to the conducting mechanism of K(+). Unlike a K(+) channel having four equivalent K(+)-binding sites in its selectivity filter, a NaK channel has a vestibule in the middle part of its selectivity filter, and can conduct both Na(+) and K(+) ions. However, the underlying mechanism for non-selective ion conduction in NaK remains elusive. Here we find four small grottos connecting with the vestibule of the NaK selectivity filter, which form a vestibule-grotto complex perpendicular to the filter pore with a few water molecules within it. It is shown that two or more of the water molecules coming to the vestibule to coordinate the cation are necessary for conducting both Na(+) and K(+) ions, while only one water molecule in the vestibule will obstruct ion permeation. Thus, the complex with the aid of interior water movement forms a dynamic hydration valve which is flexible in conveying different cations through the vestibule. Similar exquisite hydration valve mechanisms are expected to be utilized by other non-selective cation channels, and the results should shed new light on the importance of water in neural signaling. Copyright 2010 Elsevier B.V. All rights reserved.

  4. Structural and biophysical properties of a synthetic channel-forming peptide: Designing a clinically relevant anion selective pore

    PubMed Central

    Bukovnik, U.; Gao, J.; Cook, J.,G.A.; Shank, L.P.; Seabra, M.B.; Schultz, B.D.; Iwamoto, T.; Chen, J.; Tomich, J.M.

    2011-01-01

    The design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the cys-loop superfamily of ligand-gated ion channels are part of an ongoing research focus. Over 300 different sequences have been prepared based on the M2 transmembrane segment of the spinal cord glycine receptor α-subunit. A number of these sequences are water-soluble monomers that readily insert into biological membranes where they undergo supramolecular assembly, yielding channels with a range of selectivities and conductances. Selection of a sequence for further modifications to yield an optimal lead compound came down to a few key biophysical properties: low solution concentrations that yield channel activity, greater ensemble conductance, and enhanced ion selectivity. The sequence NK4-M2GlyR T19R, S22W (KKKKPARVGLGITTVLTMRTQW) addressed these criteria. The structure of this peptide has been analyzed by solution NMR as a monomer in detergent micelles, simulated as five-helix bundles in a membrane environment, modified by cysteine-scanning and studied for insertion efficiency in liposomes of selected lipid compositions. Taken together, these results define the structural and key biophysical properties of this sequence in a membrane. This model provides an initial scaffold from which rational substitutions can be proposed and tested to modulate anion selectivity. PMID:21835162

  5. TRPM4 non-selective cation channels influence action potentials in rabbit Purkinje fibres.

    PubMed

    Hof, Thomas; Sallé, Laurent; Coulbault, Laurent; Richer, Romain; Alexandre, Joachim; Rouet, René; Manrique, Alain; Guinamard, Romain

    2016-01-15

    The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle. TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells. The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells. Transient receptor potential melastatin 4 (TRPM4) Ca(2+)-activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC50 of 32.8 and 36.1×10(-6) mol l(-1), respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na(+) and K(+); sensitivity to voltage, Ca(2+) and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = -0.65 ± 0.15 pA pF(-1); n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate

  6. Motor Imagery EEG Classification for Patients with Amyotrophic Lateral Sclerosis Using Fractal Dimension and Fisher's Criterion-Based Channel Selection.

    PubMed

    Liu, Yi-Hung; Huang, Shiuan; Huang, Yi-De

    2017-07-03

    Motor imagery is based on the volitional modulation of sensorimotor rhythms (SMRs); however, the sensorimotor processes in patients with amyotrophic lateral sclerosis (ALS) are impaired, leading to degenerated motor imagery ability. Thus, motor imagery classification in ALS patients has been considered challenging in the brain-computer interface (BCI) community. In this study, we address this critical issue by introducing the Grassberger-Procaccia and Higuchi's methods to estimate the fractal dimensions (GPFD and HFD, respectively) of the electroencephalography (EEG) signals from ALS patients. Moreover, a Fisher's criterion-based channel selection strategy is proposed to automatically determine the best patient-dependent channel configuration from 30 EEG recording sites. An EEG data collection paradigm is designed to collect the EEG signal of resting state and the imagination of three movements, including right hand grasping (RH), left hand grasping (LH), and left foot stepping (LF). Five late-stage ALS patients without receiving any SMR training participated in this study. Experimental results show that the proposed GPFD feature is not only superior to the previously-used SMR features (mu and beta band powers of EEG from sensorimotor cortex) but also better than HFD. The accuracies achieved by the SMR features are not satisfactory (all lower than 80%) in all binary classification tasks, including RH imagery vs. resting, LH imagery vs. resting, and LF imagery vs. resting. For the discrimination between RH imagery and resting, the average accuracies of GPFD in 30-channel (without channel selection) and top-five-channel configurations are 95.25% and 93.50%, respectively. When using only one channel (the best channel among the 30), a high accuracy of 91.00% can still be achieved by the GPFD feature and a linear discriminant analysis (LDA) classifier. The results also demonstrate that the proposed Fisher's criterion-based channel selection is capable of removing a

  7. K⁺-dependent selectivity and external Ca²⁺ block of Shab K⁺ channels.

    PubMed

    Carrillo, Elisa; Pacheco, Lucero; Balleza, Daniel; Gomez-Lagunas, Froylan

    2015-01-01

    Potassium channels allow the selective flux of K⁺ excluding the smaller, and more abundant in the extracellular solution, Na⁺ ions. Here we show that Shab is a typical K⁺ channel that excludes Na⁺ under bi-ionic, Na(o)/K(i) or Na(o)/Rb(i), conditions. However, when internal K⁺ is replaced by Cs⁺ (Na(o)/Cs(i)), stable inward Na⁺ and outward Cs⁺ currents are observed. These currents show that Shab selectivity is not accounted for by protein structural elements alone, as implicit in the snug-fit model of selectivity. Additionally, here we report the block of Shab channels by external Ca²⁺ ions, and compare the effect that internal K⁺ replacement exerts on both Ca²⁺ and TEA block. Our observations indicate that Ca²⁺ blocks the channels at a site located near the external TEA binding site, and that this pore region changes conformation under conditions that allow Na⁺ permeation. In contrast, the latter ion conditions do not significantly affect the binding of quinidine to the pore central cavity. Based on our observations and the structural information derived from the NaK bacterial channel, we hypothesize that Ca²⁺ is probably coordinated by main chain carbonyls of the pore's first K⁺-binding site.

  8. On the Construction of Orthogonal Spreading Code Groups for MC-CDMA with FDE in a Frequency Selective Channel

    NASA Astrophysics Data System (ADS)

    Adachi, Koichi; Nakagawa, Masao

    The bit error rate (BER) performance of multicode multi-carrier code division multiple access (MC-CDMA) severely degrades due to the inter-code interference (ICI) in a strong frequency-selective channel. Recently a spreading code group construction method was proposed for MC-CDMA. The Walsh-Hadmard (WH) codes are divided into a number of code groups such that the code orthogonality can be maintained within each group even in a strong frequency-selective channel; any code pair taken from different groups is not orthogonal. The number of spreading codes in each group is determined by the maximum time delay difference of the channel. In this paper, we point out that the number of codes in each group is determined by the distribution of time delay differences among the propagation paths of the channel, not the maximum time delay difference. Based on that observation, we show that more orthogonal spreading codes can exist in each code group. The conditional BER is derived taking into account the interference from other code groups and the achievable downlink BER performance using the proposed spreading code group construction is numerically evaluated in a frequency-selective Rayleigh fading channel.

  9. Nickel block of three cloned T-type calcium channels: low concentrations selectively block alpha1H.

    PubMed

    Lee, J H; Gomora, J C; Cribbs, L L; Perez-Reyes, E

    1999-12-01

    Nickel has been proposed to be a selective blocker of low-voltage-activated, T-type calcium channels. However, studies on cloned high-voltage-activated Ca(2+) channels indicated that some subtypes, such as alpha1E, are also blocked by low micromolar concentrations of NiCl(2). There are considerable differences in the sensitivity to Ni(2+) among native T-type currents, leading to the hypothesis that there may be more than one T-type channel. We confirmed part of this hypothesis by cloning three novel Ca(2+) channels, alpha1G, H, and I, whose currents are nearly identical to the biophysical properties of native T-type channels. In this study we examined the nickel block of these cloned T-type channels expressed in both Xenopus oocytes and HEK-293 cells (10 mM Ba(2+)). Only alpha1H currents were sensitive to low micromolar concentrations (IC(50) = 13 microM). Much higher concentrations were required to half-block alpha1I (216 microM) and alpha1G currents (250 microM). Nickel block varied with the test potential, with less block at potentials above -30 mV. Outward currents through the T channels were blocked even less. We show that depolarizations can unblock the channel and that this can occur in the absence of permeating ions. We conclude that Ni(2+) is only a selective blocker of alpha1H currents and that the concentrations required to block alpha1G and alpha1I will also affect high-voltage-activated calcium currents.

  10. Nickel block of three cloned T-type calcium channels: low concentrations selectively block alpha1H.

    PubMed Central

    Lee, J H; Gomora, J C; Cribbs, L L; Perez-Reyes, E

    1999-01-01

    Nickel has been proposed to be a selective blocker of low-voltage-activated, T-type calcium channels. However, studies on cloned high-voltage-activated Ca(2+) channels indicated that some subtypes, such as alpha1E, are also blocked by low micromolar concentrations of NiCl(2). There are considerable differences in the sensitivity to Ni(2+) among native T-type currents, leading to the hypothesis that there may be more than one T-type channel. We confirmed part of this hypothesis by cloning three novel Ca(2+) channels, alpha1G, H, and I, whose currents are nearly identical to the biophysical properties of native T-type channels. In this study we examined the nickel block of these cloned T-type channels expressed in both Xenopus oocytes and HEK-293 cells (10 mM Ba(2+)). Only alpha1H currents were sensitive to low micromolar concentrations (IC(50) = 13 microM). Much higher concentrations were required to half-block alpha1I (216 microM) and alpha1G currents (250 microM). Nickel block varied with the test potential, with less block at potentials above -30 mV. Outward currents through the T channels were blocked even less. We show that depolarizations can unblock the channel and that this can occur in the absence of permeating ions. We conclude that Ni(2+) is only a selective blocker of alpha1H currents and that the concentrations required to block alpha1G and alpha1I will also affect high-voltage-activated calcium currents. PMID:10585925

  11. Main-channel slopes of selected streams in Iowa for estimation of flood-frequency discharges

    USGS Publications Warehouse

    Eash, David A.

    2003-01-01

    This report describes a statewide study conducted to develop main-channel slope (MCS) curves for 138 selected streams in Iowa with drainage areas greater than 100 square miles. MCS values determined from the curves can be used in regression equations for estimating floodfrequency discharges. Multivariable regression equations previously developed for two of the three hydrologic regions defined for Iowa require the measurement of MCS. Main-channel slope is a difficult measurement to obtain for large streams using 1:24,000-scale topographic maps. The curves developed in this report provide a simplified method for determining MCS values for sites located along large streams in Iowa within hydrologic Regions 2 and 3. The curves were developed using MCS values quantified for 2,058 selected sites along 138 selected streams in Iowa. A geographic information system (GIS) technique and 1:24,000-scale topographic data were used to quantify MCS values for the stream sites. The sites were selected at about 5-mile intervals along the streams. River miles were quantified for each stream site using a GIS program. Data points for river-mile and MCS values were plotted and a best-fit curve was developed for each stream. An adjustment was applied to all 138 curves to compensate for differences in MCS values between manual measurements and GIS quantifications. The multivariable equations for Regions 2 and 3 were developed using manual measurements of MCS. A comparison of manual measurements and GIS quantifications of MCS indicates that manual measurements typically produce greater values of MCS compared to GIS quantifications. Median differences between manual measurements and GIS quantifications of MCS are 14.8 and 17.7 percent for Regions 2 and 3, respectively. Comparisons of percentage differences between flood-frequency discharges calculated using MCS values of manual measurements and GIS quantifications indicate that use of GIS values of MCS for Region 3 substantially

  12. Nitric oxide selectively suppresses IH currents mediated by HCN1-containing channels

    PubMed Central

    Kopp-Scheinpflug, Cornelia; Pigott, Beatrice M; Forsythe, Ian D

    2015-01-01

    Key points The superior olivary complex (SOC) exhibits a spectrum of HCN1 and HCN2 subunit expression, which generate IH currents with fast and slow kinetics, respectively. Neuronal nitric oxide synthase (nNOS) was broadly distributed across the SOC. NO hyperpolarizes the half-activation voltage of HCN1-mediated currents and caused a slowing of the IH current kinetics in the respective nuclei (medial and lateral superior olives and superior paraolivary nucleus). This signalling was independent of cGMP. NO also caused a depolarizing shift in the half-activation voltage of HCN2-mediated IH currents, increasing activation at resting potentials; this was cGMP-dependent. Thus, NO signalling suppressed fast HCN1-mediated currents and potentiated slow HCN2-mediated currents, modulating the overall kinetics and magnitude of the endogenous IH. Abstract Hyperpolarization-activated non-specific cation-permeable channels (HCN) mediate IH currents, which are modulated by cGMP and cAMP and by nitric oxide (NO) signalling. Channel properties depend upon subunit composition (HCN1–4 and accessory subunits) as demonstrated in expression systems, but physiological relevance requires investigation in native neurons with intact intracellular signalling. Here we use the superior olivary complex (SOC), which exhibits a distinctive pattern of HCN1 and HCN2 expression, to investigate NO modulation of the respective IH currents, and compare properties in wild-type and HCN1 knockout mice. The medial nucleus of the trapezoid body (MNTB) expresses HCN2 subunits exclusively, and sends inhibitory projections to the medial and lateral superior olives (MSO, LSO) and the superior paraolivary nucleus (SPN). In contrast to the MNTB, these target nuclei possess an IH with fast kinetics, and they express HCN1 subunits. NO is generated in the SOC following synaptic activity and here we show that NO selectively suppresses HCN1, while enhancing IH mediated by HCN2 subunits. NO hyperpolarizes the half

  13. Potent and selective inhibitors of the TASK-1 potassium channel through chemical optimization of a bis-amide scaffold

    PubMed Central

    Flaherty, Daniel P.; Simpson, Denise S.; Miller, Melissa; Maki, Brooks E.; Zou, Beiyan; Shi, Jie; Wu, Meng; McManus, Owen B.; Aubé, Jeffrey; Li, Min; Golden, Jennifer E.

    2014-01-01

    TASK-1 is a two-pore domain potassium channel that is important to modulating cell excitability, most notably in the context of neuronal pathways. In order to leverage TASK-1 for therapeutic benefit, its physiological role needs better characterization; however, designing selective inhibitors that avoid the closely related TASK-3 channel has been challenging. In this study, a series of bis-amide derived compounds were found to demonstrate improved TASK-1 selectivity over TASK-3 compared to reported inhibitors. Optimization of a marginally selective hit led to analog 35 which displays a TASK-1 IC50 = 16 nM with 62-fold selectivity over TASK-3 in an orthogonal electrophysiology assay. PMID:25017033

  14. Monovalent cations contribute to T-type calcium channel (Cav3.1 and Cav3.2) selectivity.

    PubMed

    Delisle, B P; Satin, J

    2003-06-01

    Low voltage-activated (LVA) Ca2+ channels regulate chemical signaling by their ability to select for Ca2+. Whereas Ca2+ is the main permeating species through Ca2+ channels, Ca2+ permeation may be modified by abundant intra- and extracellular monovalent cations. Therefore, we explored monovalent cation regulation of LVA Ca2+ permeation in the cloned T-type Ca2+ channels alpha1G (Cav3.1) and alpha1H (Cav3.2). In physiological [Ca2+], the reversal potential in symmetrical Li+ was 19 mV in alpha1G and 18 mV in alpha1H, in symmetrical Cs+ the reversal potential was 36 mV in alpha1G and 37 mV in alpha1H, and in the bi-ionic condition with Li+ in the bath and Cs+ in the pipette, the reversal potential was 46 mV in both alpha1G and alpha1H. When Cs+ was used in the pipette, replacement of external Cs+ with Li+ (or Na+) shifted the reversal potential positive by 5-6 mV and increased the net inward current in alpha1G. Taken together the data indicate that in physiological [Ca2+], external Li+ (or Na+) permeates more readily than external Cs+, resulting in a positive shift of the reversal potential. We conclude that external monovalent cations dictate T-type Ca2+ channel selectivity by permeating through the channel. Similar to Li+, we previously reported that external [H+] can regulate T-type Ca2+ channel selectivity. Alpha1H's selectivity was more sensitive to external pH changes compared to alpha1G. When Cs+ was used in the pipette and Li+ was used in the bath external acidification from pHo 7.4 to 6.0 caused a negative shift of the reversal by 8 mV in alpha1H. Replacement of internal Cs+ with Li+ reduced the pH-induced shift of the reversal potential to 2 mV. We conclude that, similar to other external monovalent cations, H+ can modify T-type Ca2+ channel selectivity. However, in contrast to external monovalent ions that readily permeate, H+ regulate T-type Ca2+ channel selectivity by increasing the relative permeability of the internal monovalent cation.

  15. Is {sup 276}U a doubly magic nucleus?

    SciTech Connect

    Liliani, N. Sulaksono, A.

    2016-04-19

    We investigate a possible new doubly magic heavy nucleus by using a relativistic mean-field (RMF) model with the addition of a cross interaction term of omega-rho mesons and an electromagnetic exchange term. We propose that {sup 276}U is a doubly magic nucleus. The evidence for {sup 276}U being a doubly magic nucleus is shown through the two-nucleon gaps, the single-particle energies, and the neutron skin thickness of the nucleus. We have also found that the prediction of {sup 276}U as a doubly magic nucleus by the RMF model is not affected by the inclusion of isoscalar-isovector and electromagnetic exchange couplings.

  16. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.

    PubMed

    Chen, Jun; Joshi, Shailen K; DiDomenico, Stanley; Perner, Richard J; Mikusa, Joe P; Gauvin, Donna M; Segreti, Jason A; Han, Ping; Zhang, Xu-Feng; Niforatos, Wende; Bianchi, Bruce R; Baker, Scott J; Zhong, Chengmin; Simler, Gricelda H; McDonald, Heath A; Schmidt, Robert G; McGaraughty, Steve P; Chu, Katharine L; Faltynek, Connie R; Kort, Michael E; Reilly, Regina M; Kym, Philip R

    2011-05-01

    Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  17. Selective activation of heteromeric SK channels contributes to action potential repolarization in mouse atrial myocytes.

    PubMed

    Hancock, Jane M; Weatherall, Kate L; Choisy, Stéphanie C; James, Andrew F; Hancox, Jules C; Marrion, Neil V

    2015-05-01

    Activation of small conductance calcium-activated potassium (SK) channels is proposed to contribute to repolarization of the action potential in atrial myocytes. This role is controversial, as these cardiac SK channels appear to exhibit an uncharacteristic pharmacology. The objectives of this study were to resolve whether activation of SK channels contributes to atrial action potential repolarization and to determine the likely subunit composition of the channel. The effect of 2 SK channel inhibitors was assessed on outward current evoked in voltage clamp and on action potential duration in perforated patch and whole-cell current clamp recording from acutely isolated mouse atrial myocytes. The presence of SK channel subunits was assessed using immunocytochemistry. A significant component of outward current was reduced by the SK channel blockers apamin and UCL1684. Block by apamin displayed a sensitivity indicating that this current was carried by homomeric SK2 channels. Action potential duration was significantly prolonged by UCL1684, but not by apamin. This effect was accompanied by an increase in beat-to-beat variability and action potential triangulation. This pharmacology was matched by that of expressed heteromeric SK2-SK3 channels in HEK293 cells. Immunocytochemistry showed that atrial myocytes express both SK2 and SK3 channels with an overlapping expression pattern. Only proposed heteromeric SK2-SK3 channels are physiologically activated to contribute to action potential repolarization, which is indicated by the difference in pharmacology of evoked outward current and prolongation of atrial action potential duration. The effect of blocking this channel on the action potential suggests that SK channel inhibition during cardiac function has the potential to be proarrhythmic. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  18. Molecular mechanisms, and selective pharmacological rescue, of Rem-inhibited CaV1.2 channels in heart

    PubMed Central

    Xu, Xianghua; Marx, Steven O.; Colecraft, Henry M.

    2010-01-01

    Rationale In heart, Ca2+ entering myocytes via CaV1.2 channels controls essential functions including, excitation-contraction (EC) coupling, action potential duration (APD), and gene expression. RGK GTPases potently inhibit CaV1.2 channels, an effect that may figure prominently in cardiac Ca2+ homeostasis under physiological and disease conditions. Objective To define the mechanisms and molecular determinants underlying Rem GTPase inhibition of CaV1.2 channels in heart, and determine whether such inhibited channels can be pharmacologically rescued. Methods and Results Over-expressing Rem in adult guinea pig heart cells dramatically depresses L-type calcium current (ICa,L; ~90% inhibition) and moderately reduces maximum gating charge (Qmax; 33%), without appreciably diminishing the physical number of channels in the membrane. Rem-inhibited CaV1.2 channels were supra-modulated by BAY K 8644 (10-fold increase) compared to control channels (3-fold increase). However, Rem prevented protein kinase A (PKA)-mediated up-regulation of ICa,L, an effect achieved without disrupting the sympathetic signaling cascade since PKA modulation of IKS remained intact. In accord with its functional impact on ICa,L, Rem selectively prevented PKA-, but not BAY K 8644-induced prolongation of the cardiac APD. A GTP-binding-deficient Rem[T94N] mutant was functionally inert with respect to ICa,L inhibition. A chimeric construct, Rem265-H, featuring a swap of the Rem C-terminus tail for the analogous domain from H-Ras, inhibited ICa,L and Qmax to the same extent as wild type Rem despite lacking the capacity to autonomously localize to the sarcolemma. Conclusions Rem predominantly inhibits ICa,L in heart by arresting surface CaV1.2 channels in a low open probability (Po) gating mode, rather than by interfering with channel trafficking. Moreover, Rem-inhibited CaV1.2 channels can be selectively rescued by BAY K 8644 but not PKA-dependent phosphorylation. Contrary to findings in reconstituted

  19. A model of the L-type Ca2+ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms

    PubMed Central

    Sun, Liang; Fan, Jing-Song; Clark, John W; Palade, Philip T

    2000-01-01

    We have developed a mathematical model of the L-type Ca2+ current, which is based on data from whole-cell voltage clamp experiments on rat ventricular myocytes. Ion substitution methods were employed to investigate the ionic selectivity of the channel. Experiments were configured with Na+, Ca2+ or Ba2+ as the majority current carrier. The amplitude of current through the channel is attenuated in the presence of extracellular Ca2+ or Ba2+. Our model accounts for channel selectivity by using a modified Goldman-Hodgkin-Katz (GHK) configuration that employs voltage-dependent channel binding functions for external divalent ions. Stronger binding functions were used for Ca2+ than for Ba2+. Decay of the ionic current during maintained depolarization was characterized by means of voltage- and Ca2+-dependent inactivation pathways embedded in a five-state dynamic channel model. Particularly, Ca2+ first binds to calmodulin and the Ca2+-calmodulin complex is the mediator of Ca2+ inactivation. Ba2+-dependent inactivation was characterized using the same scheme, but with a decreased binding to calmodulin. A reduced amount of steady-state inactivation, as evidenced by a U-shaped curve at higher depolarization levels (>40 mV) in the presence of [Ca2+]o, was observed in double-pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby Ca2+ or Ba2+ also inhibits the voltage-dependent inactivation pathway. The five-state dynamic channel model was also used to simulate single channel activity. Calculations of the open probability of the channel model are generally consistent with experimental data. A sixth state can be used to simulate modal activity by way of introducing long silent intervals. Our model has been tested extensively using experimental data from a wide variety of voltage clamp protocols and bathing solution manipulations. It provides: (a) biophysically based explanations of putative mechanisms

  20. An inactivation gate in the selectivity filter of KCNQ1 potassium channels.

    PubMed

    Gibor, Gilad; Yakubovich, Daniel; Rosenhouse-Dantsker, Avia; Peretz, Asher; Schottelndreier, Hella; Seebohm, Guiscard; Dascal, Nathan; Logothetis, Diomedes E; Paas, Yoav; Attali, Bernard

    2007-12-15

    Inactivation is an inherent property of most voltage-gated K(+) channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba(2+) to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba(2+) trapping at elevated external K(+) concentrations. Hence, KCNQ1 slow inactivation considerably differs from C-type inactivation where vacation of K(+) from the filter was invoked. We suggest that trapping of K(+) at s(1) due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants.

  1. Structural analysis of ion selectivity in the NaK channel.

    PubMed

    Alam, Amer; Jiang, Youxing

    2009-01-01

    Here we present a detailed characterization of ion binding in the NaK pore using the high-resolution structures of NaK in complex with various cations. These structures reveal four ion binding sites with similar chemical environments but vastly different ion preference. The most nonselective of all is site 3, which is formed exclusively by backbone carbonyl oxygen atoms and resides deep within the selectivity filter. Additionally, four water molecules in combination with four backbone carbonyl oxygen atoms are seen to participate in K(+) and Rb(+) ion chelation, at both the external entrance and the vestibule of the NaK filter, confirming the channel's preference for an octahedral ligand configuration for K(+) and Rb(+) binding. In contrast, Na(+) binding in the NaK filter, particularly at site 4, utilizes a pyramidal ligand configuration that requires the participation of a water molecule in the cavity. Therefore, the ability of the NaK filter to bind both Na(+) and K(+) ions seemingly arises from the ions' ability to use the existing environment in unique ways, rather than from any structural rearrangements of the filter itself.

  2. Ivabradine – the first selective sinus node If channel inhibitor in the treatment of stable angina

    PubMed Central

    Sulfi, S; Timmis, AD

    2006-01-01

    Summary Heart rate, a major determinant of angina in coronary disease, is also an important predictor of cardiovascular mortality. Lowering heart rate is therefore one of the most important therapeutic approaches in the treatment of stable angina pectoris. To date, β-blockers and some calcium-channel antagonists reduce heart rate, but their use may be limited by adverse reactions or contraindications. Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node controlled by the If current. Ivabradine is the first specific heart rate-lowering agent that has completed clinical development for stable angina pectoris. It is selective for the If current, lowering heart rate at concentrations that do not affect other cardiac ionic currents. Specific heart-rate lowering with ivabradine reduces myocardial oxygen demand, simultaneously improving oxygen supply. Ivabradine has no negative inotropic or lusitropic effects, preserving ventricular contractility, and does not change any major electrophysiological parameters unrelated to heart rate. Randomised clinical studies in patients with stable angina show that ivabradine effectively reduces heart rate, improves exercise capacity and reduces the number of angina attacks. It has superior anti-anginal and anti-ischaemic activity to placebo and is non-inferior to atenolol and amlodipine. Ivabradine therefore offers a valuable approach to lowering heart rate exclusively and provides an attractive alternative to conventional treatment for a wide range of patients with confirmed stable angina. PMID:16451297

  3. Fragmentation of doubly charged HDO, H{sub 2}O, and D{sub 2}O molecules induced by proton and monocharged fluorine beam impact at 3 keV

    SciTech Connect

    Martin, S.; Chen, L.; Brédy, R.; Bernard, J.; Cassimi, A.

    2015-03-07

    Doubly charged ions HDO{sup 2+}, H{sub 2}O{sup 2+}, and D{sub 2}O{sup 2+} were prepared selectively to triplet or singlet excited states in collisions with F{sup +} or H{sup +} projectiles at 3 keV. Excitation energies of dications following two-body or three-body dissociation channels were measured and compared with recent calculations using ab initio multi-reference configuration interaction method [Gervais et al., J. Chem. Phys. 131, 024302 (2009)]. For HDO{sup 2+}, preferential cleavage of O–H rather than O–D bond has been observed and the ratio between the populations of the fragmentation channels OD{sup +}-H{sup +} and OH{sup +}-D{sup +} were measured. The kinetic energy release has been measured and compared with previous experiments.

  4. Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations

    PubMed Central

    Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir

    2012-01-01

    The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate. PMID:22412190

  5. Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.

    PubMed

    Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir; Wang, KeWei; Zheng, Jie

    2012-04-01

    The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate.

  6. Purification, sequence, and model structure of charybdotoxin, a potent selective inhibitor of calcium-activated potassium channels.

    PubMed Central

    Gimenez-Gallego, G; Navia, M A; Reuben, J P; Katz, G M; Kaczorowski, G J; Garcia, M L

    1988-01-01

    Charybdotoxin (ChTX), a protein present in the venom of the scorpion Leiurus quinquestriatus var. hebraeus, has been purified to homogeneity by a combination of ion-exchange and reversed-phase chromatography. Polyacrylamide gel electrophoresis, amino acid analysis, and complete amino acid sequence determination of the pure protein reveal that it consists of a single polypeptide chain of 4.3 kDa. Purified ChTX is a potent and selective inhibitor of the approximately 220-pS Ca2+-activated K+ channel present in GH3 anterior pituitary cells and primary bovine aortic smooth muscle cells. The toxin reversibly blocks channel activity by interacting at the external pore of the channel protein with an apparent Kd of 2.1 nM. The primary structure of ChTX is similar to a number of neurotoxins of diverse origin, which suggests that ChTX is a member of a superfamily of proteins that modify ion-channel activities. On the basis of this similarity, the three-dimensional structure of ChTX has been modeled from the known crystal structure of alpha-bungarotoxin. These studies indicate that ChTX is useful as a probe of Ca2+-activated K+-channel function and suggest that the proposed tertiary structure of ChTX may provide insight into the mechanism of channel block. Images PMID:2453055

  7. 5E- and 5Z-farnesylacetones from Sargassum siliquastrum as novel selective L-type calcium channel blockers.

    PubMed

    Shin, Woon-Seob; Oh, Sangtae; An, Sung-Wan; Park, Gab-Man; Kwon, Daeho; Ham, Jungyeob; Lee, Seokjoon; Park, Byong-Gon

    2013-04-01

    A specific blocker of L-type Ca(2+) channels may be useful in decreasing arterial tone by reducing the open-state probability of L-type Ca(2+) channels. The aim of the present study was to evaluate the farnesylacetones, which are major active constituents of Sargassum siliquastrum, regarding their vasodilatation efficacies, selectivities toward L-type Ca(2+) channels, and in vivo antihypertensive activities. The application of 5E-(farnesylacetone 311) or 5Z-farnesylacetone (farnesylacetone 312) induced concentration-dependent vasodilatation effects on the basilar artery that was pre-contracted with depolarization and showed an ignorable potential role of endothelial-derived nitric oxide. We also tested farnesylacetone 311 or 312 to determine their pharmacological profiles for the blockade of native L-type Ca(2+) channels in basilar arterial smooth muscle cells (BASMCs) and ventricular myocytes (VMCs), cloned L- (α1C/β2a/α2δ), N- (α1B/β1b/α2δ), and T-type Ca(2+) channels (α1G, α1H, and α1I). Farnesylacetone 311 or 312 showed greater selectivity toward the L-type Ca(2+) channels among the tested voltage-gated Ca(2+) channels. The ranked order of the potency for farnesylacetone 311 was cloned α1C≒L-type (BASMC)≒L-type (VMCs)>α1B>α1H>α1I>α1G and that for farnesylacetone 312 was cloned α1C≒L-type (BASMCs)≒L-type (VMCs)>α1H>α1G>α1B>α1I. The oral administration of the farnesylacetone 311 (80mg/kg) conferred potent, long-lasting antihypertensive activity in spontaneous hypertensive rats, but it did not alter the heart rate. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Maitotoxin Is a Potential Selective Activator of the Endogenous Transient Receptor Potential Canonical Type 1 Channel in Xenopus laevis Oocytes

    PubMed Central

    Flores, Pedro L.; Rodríguez, Emma; Zapata, Estrella; Carbó, Roxana; Farías, José María; Martínez, Martín

    2017-01-01

    Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels. PMID:28672825

  9. Methods for Scaling to Doubly Stochastic Form,

    DTIC Science & Technology

    1981-06-26

    BIRKHOFF, G.: Tres observaciones sobre le algebra lineal , Rev. univ. nec. Tucuman, ser A, . 147-151, [1948] BRUALDI, R.A., S.V. PARTER, and H. SCHNEIDER...scaling square, nonnegative matrices to dou- bly stochastic form are described. A generalized version of the convergence theorem in SINKI-ORN and KNOPP... matrices D and E for a given square nonnegative matrix, A, such that DAE is doubly stochastic--or determine that such :.p h" du:es 7’. -,.xist. A

  10. Potent and Selective Inhibition of the Open-Channel Conformation of AMPA Receptors by an RNA Aptamer†

    PubMed Central

    Huang, Zhen; Han, Yan; Wang, Congzhou; Niu, Li

    2010-01-01

    Inhibitors of AMPA receptors are useful as biochemical probes for structure-function studies and as drug candidates for a number of neurological disorders and diseases. Here we report the identification of an RNA inhibitor or aptamer by an in vitro evolution approach. Using a laser-pulse photolysis technique, we further characterized the mechanism of inhibition of this aptamer on the AMPA receptor channel-opening rate process in the microsecond-to-millisecond time domain. Our results show that the aptamer we isolated is a noncompetitive inhibitor that selectively inhibits the open-channel conformation of AMPA receptors with nanomolar affinity. The potency and the selectivity of this noncompetitive aptamer rival those of small molecule inhibitors. Our results therefore demonstrate the utility of this approach to develop water-soluble, highly potent and conformation-selective noncompetitive inhibitors of AMPA receptors. PMID:20518485

  11. Outage Performance of Cooperative Relay Selection with Multiple Source and Destination Antennas over Dissimilar Nakagami-m Fading Channels

    NASA Astrophysics Data System (ADS)

    Lee, Wooju; Yoon, Dongweon

    Cooperative relay selection, in which one of multiple relays is selected to retransmit the source signal to the destination, has received considerable attention in recent years, because it is a simple way to obtain cooperative diversity in wireless networks. The exact expression of outage probability for a decode-and-forward cooperative relay selection with multiple source and destination antennas over Rayleigh fading channels was recently derived in [9]. In this letter, we derive the exact expressions of outage probability and diversity-multiplexing tradeoff over independent and non-identically distributed Nakagami-m fading channels as an extension of [9]. We then analyze the effects of various parameters such as fading conditions, number of relays, and number of source and destination antennas on the outage probability.

  12. Tackling the Combined Effects of Reverberation and Masking Noise Using Ideal Channel Selection

    ERIC Educational Resources Information Center

    Hazrati, Oldooz; Loizou, Philipos C.

    2012-01-01

    Purpose: In this article, a new signal-processing algorithm is proposed and evaluated for the suppression of the combined effects of reverberation and noise. Method: The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a…

  13. Tackling the Combined Effects of Reverberation and Masking Noise Using Ideal Channel Selection

    ERIC Educational Resources Information Center

    Hazrati, Oldooz; Loizou, Philipos C.

    2012-01-01

    Purpose: In this article, a new signal-processing algorithm is proposed and evaluated for the suppression of the combined effects of reverberation and noise. Method: The proposed algorithm decomposes, on a short-term basis (every 20 ms), the reverberant stimuli into a number of channels and retains only a subset of the channels satisfying a…

  14. Structural and Functional Consequences of an Amide-to-Ester Substitution in the Selectivity Filter of a Potassium Channel

    PubMed Central

    Valiyaveetil, Francis I.; Sekedat, Matthew; MacKinnon, Roderick; Muir, W.

    2008-01-01

    The selectivity filter of K+ channels comprises four contiguous ion binding sites, S1 through S4. Structural and functional data indicate that the filter contains on average two K+ ions at any given time and that these ions reside primarily in two configurations, namely to sites S1 and S3 or to sites S2 and S4. Maximum ion flux through the channel is expected to occur when the energy difference between these two binding configurations is zero. In this study, we have used protein semisynthesis to selectively perturb site 1 within the filter of the KcsA channel through use of an amide-to-ester substitution. The modification alters K+ conduction properties. The structure of the selectivity filter is largely unperturbed by the modification, despite the loss of an ordered water molecule normally located just behind the filter. Introduction of the ester moiety was found to alter the distribution of K+, Rb+ and Cs+ within the filter, with the most dramatic change found for Rb+. The redistribution of ions is associated with the appearance of a partially hydrated ion just external to the filter, at a position where no ion is observed in the wild type channel. The appearance of this new ion-binding site creates a change in the distance between a pair of K+ ions some fraction of the time, apparently leading to a reduction in the ion conduction rate. Importantly, this finding suggests that the selectivity filter of a potassium channel is optimized both in terms of absolute ion occupancy and in terms of the separation in distance between the conducting ions. PMID:16939283

  15. T-type channels become highly permeable to sodium ions using an alternative extracellular turret region (S5-P) outside the selectivity filter.

    PubMed

    Senatore, Adriano; Guan, Wendy; Boone, Adrienne N; Spafford, J David

    2014-04-25

    T-type (Cav3) channels are categorized as calcium channels, but invertebrate ones can be highly sodium-selective channels. We illustrate that the snail LCav3 T-type channel becomes highly sodium-permeable through exon splicing of an extracellular turret and descending helix in domain II of the four-domain Cav3 channel. Highly sodium-permeable T-type channels are generated without altering the invariant ring of charged residues in the selectivity filter that governs calcium selectivity in calcium channels. The highly sodium-permeant T-type channel expresses in the brain and is the only splice isoform expressed in the snail heart. This unique splicing of turret residues offers T-type channels a capacity to serve as a pacemaking sodium current in the primitive heart and brain in lieu of Nav1-type sodium channels and to substitute for voltage-gated sodium channels lacking in many invertebrates. T-type channels would also contribute substantially to sodium leak conductances at rest in invertebrates because of their large window currents.

  16. Selectivity of a Singly Permeating Ion in Nonselective NaK Channel: Combined QM and MD Based Investigations.

    PubMed

    Sadhu, Biswajit; Sundararajan, Mahesh; Bandyopadhyay, Tusar

    2015-10-08

    Ion channels, such as potassium channels are known to discriminate ions to achieve remarkable selective transportation of K(+) over Na(+) through the membrane. The recently reported NaK ion channel, on the contrary, seems to be an exception, as it is observed to permeate most of the group IA alkali metal cations and hence is suggested to be nonselective in nature. However, does that correspond to a complete annihilation of selectivity inside the selectivity filter (SF) of the channel? What is the origin of such nonselectivity/selectivity, if any? The present computational study is an extensive multiscale modeling approach to find the probable answers to these intriguing questions. Here, we have used density functional theory (DFT) based calculations using a realistic truncated model of SF from the crystal structures of the NaK ion channel to evaluate the binding of various alkali metal ions (Na(+), K(+) and Cs(+)), free from "contamination" due to the absence any other "rivalry" cations, in its different binding sites. Among all of the possible binding sites, a vestibule is noticed to be nonselective and seen to act as a probable binding site only in the presence of multiple ions. Binding sites S3 and S4 are found to be selective for K(+) and Na(+), respectively. As an important observation, we find that calculations on oversimplified models using an isolated ion binding site may lead to an erroneous selectivity trend as it neglects the synergetics of consecutive binding sites on the final outcome. Energy decomposition analysis revealed ion-dipole electrostatics as the major contributing interaction in metal-bound binding sites. Our investigations find that although NaK is permeable to monovalent alkali metal ions, strongly "site specific" selectivity does exist at the three well-defined noncontiguous binding sites of the SF. Different important physicomechanical parameters (such as ligating environment, synergistic influence of binding sites, and topological

  17. Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

    PubMed Central

    Upadhyay, Sanjeev Kumar; Eckel-Mahan, Kristin L.; Mirbolooki, M. Reza; Tjong, Indra; Griffey, Stephen M.; Schmunk, Galina; Koehne, Amanda; Halbout, Briac; Iadonato, Shawn; Pedersen, Brian; Borrelli, Emiliana; Wang, Ping H.; Mukherjee, Jogeshwar; Sassone-Corsi, Paolo; Chandy, K. George

    2013-01-01

    Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesity-inducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased β-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance. PMID:23729813

  18. Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure—a suggested HPNS partial mechanism

    PubMed Central

    Aviner, Ben; Gradwohl, Gideon; Mor Aviner, Merav; Levy, Shiri; Grossman, Yoram

    2014-01-01

    Professional deep sea divers experience motor and cognitive impairment, known as High Pressure Neurological Syndrome (HPNS), when exposed to pressures of 100 msw (1.1 MPa) and above, considered to be the result of synaptic transmission alteration. Previous studies have indicated modulation of presynaptic Ca2+ currents at high pressure. We directly measured for the first time pressure effects on the currents of voltage dependent Ca2+ channels (VDCCs) expressed in Xenopus oocytes. Pressure selectivity augmented the current in CaV1.2 and depressed it in CaV3.2 channels. Pressure application also affected the channels' kinetics, such as ƮRise, ƮDecay. Pressure modulation of VDCCs seems to play an important role in generation of HPNS signs and symptoms. PMID:24904281

  19. An iterative detection method of MIMO over spatial correlated frequency selective channel: using list sphere decoding for simplification

    NASA Astrophysics Data System (ADS)

    Shi, Zhiping; Yan, Bing

    2010-08-01

    In multiple-input multiple-output(MIMO) wireless systems, combining good channel codes(e.g., Non-binary Repeat Accumulate codes) with adaptive turbo equalization is a good option to get better performance and lower complexity under Spatial Correlated Frequency Selective(SCFS) Channel. The key of this method is after joint antennas MMSE detection (JAD/MMSE) based on interruption cancelling using soft information, considering the detection result as an output of a Gaussian equivalent flat fading channel, and performing maximum likelihood detection(ML) to get more correct estimated result. But the using of ML brings great complexity increase, which is not allowed. In this paper, a low complexity method called list sphere decoding is introduced and applied to replace the ML in order to simplify the adaptive iterative turbo equalization system.

  20. Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

    PubMed Central

    Varga, Zoltan; Gurrola-Briones, Georgina; Papp, Ferenc; Rodríguez de la Vega, Ricardo C.; Pedraza-Alva, Gustavo; Tajhya, Rajeev B.; Gaspar, Rezso; Cardenas, Luis; Rosenstein, Yvonne; Beeton, Christine; Possani, Lourival D.

    2012-01-01

    Blockade of Kv1.3 K+ channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (α-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (Kd = 2.9 pM) and exhibits >1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca2+ signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases. PMID:22622363

  1. Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 potassium channels of human T cells.

    PubMed

    Varga, Zoltan; Gurrola-Briones, Georgina; Papp, Ferenc; Rodríguez de la Vega, Ricardo C; Pedraza-Alva, Gustavo; Tajhya, Rajeev B; Gaspar, Rezso; Cardenas, Luis; Rosenstein, Yvonne; Beeton, Christine; Possani, Lourival D; Panyi, Gyorgy

    2012-09-01

    Blockade of Kv1.3 K(+) channels in T cells is a promising therapeutic approach for the treatment of autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus. Vm24 (α-KTx 23.1) is a novel 36-residue Kv1.3-specific peptide isolated from the venom of the scorpion Vaejovis mexicanus smithi. Vm24 inhibits Kv1.3 channels of human lymphocytes with high affinity (K(d) = 2.9 pM) and exhibits >1500-fold selectivity over other ion channels assayed. It inhibits the proliferation and Ca(2+) signaling of human T cells in vitro and reduces delayed-type hypersensitivity reactions in rats in vivo. Our results indicate that Vm24 has exceptional pharmacological properties that make it an excellent candidate for treatment of certain autoimmune diseases.

  2. Double photoionization of doubly-excited lithium

    NASA Astrophysics Data System (ADS)

    Armstrong, G.; Pindzola, M. S.; Kheifets, A.; Schuricke, M.; Veeravalli, G.; Dornes, Ch.; Zhu, G.; Joachimsmeyer, K.; Treusch, R.; Dorn, A.; Colgan, J.

    2012-06-01

    We present triple differential cross sections and recoil ion momentum distributions for double photoionization of the 1s2s2p state of lithium. Double ionization of lithium may be treated as a two-active-electron process, where the ``active'' 2s and 2p electrons move in the field of the ``frozen-core'' Li^2+ 1s state.The time-dependent close-coupling (TDCC) method is used to solve the two-electron time-dependent Schr"odinger equation in full dimensionality. This work is motivated by recent FLASH experiments, which have obtained recoil-ion momentum distributions at a photon energy of 59 eV, where the 1s2s2p state is first reached via a 1s-2p photoexcitation from the initial ground state, and may then be doubly-ionized after the absorption of a second photon. The TDCC calculations in this work treat the subsequent photoionization of this doubly-excited state. The results are compared to those obtained by the convergent close-coupling method and to measurement, and provide a first comparison between theory and experiment in this fundamental few-photon few-body problem.

  3. Examining the Relationship Between Flexible Resources and Health Information Channel Selection.

    PubMed

    Manierre, Matthew

    2016-01-01

    This study examines how variations in flexible resources influence where individuals begin their search for health information. Access to flexible resources such as money, power, and knowledge can alter the accessibility of channels for health information, such as doctors, the Internet, and print media. Using the HINTS 3 sample, whether information channel utilization is predicted by the same factors in two groups with distinct levels of access to flexible resources, as approximated by high and low levels of education, is investigated. Differences in access to flexible resources are hypothesized to produce variations in channel utilization in bivariate analyses, as well as changes in coefficient strength and statistical significance in multivariate models. Multinomial logit models were used to assess how a number of variables influence the probability of using a specific information channel first in either flexible resource group. Results suggest that individuals with higher levels of education, a proxy for flexible resources, are more likely to report seeking information from the Internet first, which is consistent with research on the digital divide. It appears that diminished access to flexible resources is also associated with heightened utilization of offline channels, including doctors. A handful of differences in predictors were found between the low and high flexible resource groups when multivariate models were compared. Future research should take into account the distinctions between different offline channels while also seeking to further understand how social inequality relates to the utilization of different channels and corresponding health outcomes.

  4. Bathymetric survey of the Cayuga Inlet flood-control channel and selected tributaries in Ithaca, New York, 2016

    USGS Publications Warehouse

    Wernly, John F.; Nystrom, Elizabeth A.; Coon, William F.

    2017-09-08

    From July 14 to July 20, 2016, the U.S. Geological Survey, in cooperation with the City of Ithaca, New York, and the New York State Department of State, surveyed the bathymetry of the Cayuga Inlet flood-control channel and the mouths of selected tributaries to Cayuga Inlet and Cayuga Lake in Ithaca, N.Y. The flood-control channel, built by the U.S. Army Corps of Engineers between 1965 and 1970, was designed to convey flood flows from the Cayuga Inlet watershed through the City of Ithaca and minimize possible flood damages. Since that time, the channel has infrequently been maintained by dredging, and sediment accumulation and resultant shoaling have greatly decreased the conveyance of the channel and its navigational capability.U.S. Geological Survey personnel collected bathymetric data by using an acoustic Doppler current profiler. The survey produced a dense dataset of water depths that were converted to bottom elevations. These elevations were then used to generate a geographic information system bathymetric surface. The bathymetric data and resultant bathymetric surface show the current condition of the channel and provide the information that governmental agencies charged with maintaining the Cayuga Inlet for flood-control and navigational purposes need to make informed decisions regarding future maintenance measures.

  5. Riparian vegetation patterns in relation to fluvial landforms and channel evolution along selected rivers of Tuscany (Central Italy)

    USGS Publications Warehouse

    Hupp, C.R.; Rinaldi, M.

    2007-01-01

    Riparian vegetation distribution patterns and diversity relative to various fluvial geomorphic channel patterns, landforms, and processes are described and interpreted for selected rivers of Tuscany, Central Italy; with emphasis on channel evolution following human impacts. Field surveys were conducted along thirteen gauged reaches for species presence, fluvial landforms, and the type and amount of channel/riparian zone change. Inundation frequency of different geomorphic surfaces was determined, and vegetation data were analyzed using BDA (binary discriminate analysis) and DCA (detrended correspondence analysis) and related to hydrogeomorphology. Multivariate analyses revealed distinct quantitative vegetation patterns relative to six major fluvial geomorphic surfaces. DCA of the vegetation data also showed distinct associations of plants to processes of adjustment that are related to stage of channel evolution, and clearly separated plants along disturbance/landform/soil moisture gradients. Species richness increases from the channel bed to the terrace and on heterogeneous riparian areas, whereas species richness decreases from moderate to intense incision and from low to intense narrowing. ?? 2007 by Association of American Geographers.

  6. Reversal of Ion Charge Selectivity Renders the Pentameric Ligand-Gated Ion Channel GLIC Insensitive to Anesthetics

    PubMed Central

    Tillman, Tommy; Cheng, Mary H.; Chen, Qiang; Tang, Pei; Xu, Yan

    2014-01-01

    Pentameric ligand gated ion channels (pLGICs) are a family of structurally homologous cationic and anionic channels involved in neurotransmission. Cationic members of the pLGIC family are typically inhibited by general anesthetics, while anionic members are potentiated. GLIC is a prokaryotic cationic pLGIC and can be inhibited by clinical concentrations of general anesthetics. The introduction of three mutations, Y221A (Y–3′A), E222P (E–2′P) and N224R (N0′R), at the selectivity filter and one, A237T (A13′T), at the hydrophobic gate, converted GLIC to an anion channel. The mutated GLIC (GLIC4) became insensitive to the anesthetics propofol and etomidate as well as the channel blocker picrotoxin. Molecular dynamics (MD) simulations revealed changes in the structure and dynamics of GLIC4 in comparison to GLIC, particularly in the tilting angles of the pore-lining helix (TM2) that consequently resulted in different pore radius and hydration profiles. Propofol binding to an intra-subunit site of GLIC shifted the tilting angles of TM2 towards closure at the hydrophobic gate region, consistent with propofol inhibition of GLIC. In contrast, the pore of GLIC4 was much more resilient to perturbation from propofol binding. This study underscores the importance of pore dynamics and conformation to anesthetic effects on channel functions. PMID:22978431

  7. The selective serotonin reuptake inhibitor dapoxetine inhibits voltage-dependent K(+) channels in rabbit coronary arterial smooth muscle cells.

    PubMed

    Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Sung Eun; Jung, Won-Kyo; Ha, Kwon-Soo; Han, Eun-Taek; Hong, Seok-Ho; Firth, Amy L; Choi, Il-Whan; Park, Won Sun

    2017-04-01

    We investigated the inhibitory effect of dapoxetine, a selective serotonin reuptake inhibitor (SSRI), on voltage-dependent K(+) (Kv) channels using native smooth muscle cells from rabbit coronary arteries. Dapoxetine inhibited Kv channel currents in a concentration-dependent manner, with an IC50 value of 2.68±0.94 μmol/L and a slope value (Hill coefficient) of 0.63±0.11. Application of 10 μmol/L dapoxetine accelerated the rate of inactivation of Kv currents. Although dapoxetine did not modify current activation kinetics, it caused a significant negative shift in the inactivation curves. Application of train step (1 or 2 Hz) progressively increased the inhibitory effect of dapoxetine on Kv channels. In addition, the recovery time constant was extended in its presence, suggesting that the longer recovery time constant from inactivation underlies a use-dependent inhibition of the channel. From these results, we conclude that dapoxetine inhibits Kv channels in a dose-, time-, use-, and state (open)-dependent manner, independent of serotonin reuptake inhibition.

  8. Subunit-selective role of the M3 transmembrane domain of the nicotinic acetylcholine receptor in channel gating.

    PubMed

    De Rosa, María José; Corradi, Jeremías; Bouzat, Cecilia

    2008-02-01

    The nicotinic acetylcholine receptor (AChR) can be either hetero-pentameric, composed of alpha and non-alpha subunits, or homo-pentameric, composed of alpha7 subunits. To explore the subunit-selective contributions of transmembrane domains to channel gating we analyzed single-channel activity of chimeric muscle AChRs. We exchanged M3 between alpha1 and epsilon or alpha7 subunits. The replacement of M3 in alpha1 by epsilonM3 significantly alters activation properties. Channel activity appears as bursts of openings whose durations are 20-fold longer than those of wild-type AChRs. In contrast, 7-fold briefer openings are observed in AChRs containing the reverse epsilon chimeric subunit. The duration of the open state decreases with the increase in the number of alpha1M3 segments, indicating additive contributions of M3 of all subunits to channel closing. Each alpha1M3 segment decreases the energy barrier of the closing process by approximately 0.8 kcal/mol. Partial chimeric subunits show that small stretches of the M3 segment contribute additively to the open duration. The replacement of alpha1 sequence by alpha7 in M3 leads to 3-fold briefer openings whereas in M1 it leads to 10-fold prolonged openings, revealing that the subunit-selective role is unique to each transmembrane segment.

  9. Reduction of the pectoral spine and girdle in domesticated Channel catfish is likely caused by changes in selection pressure.

    PubMed

    Fine, Michael L; Lahiri, Shweta; Sullivan, Amanda D H; Mayo, Mark; Newton, Scott H; Sismour, Edward N

    2014-07-01

    Locked pectoral spines of the Channel Catfish Ictalurus punctatus more than double the fish's width and complicate ingestion by gape-limited predators. The spine mates with the pectoral girdle, a robust structure that anchors the spine. This study demonstrates that both spine and girdle exhibit negative allometric growth and that pectoral spines and girdles are lighter in domesticated than in wild Channel Catfish. This finding could be explained by changes in selection pressure for spine growth during domestication or by an epigenetic effect in which exposure to predators in wild fish stimulates pectoral growth. We tested the epigenetic hypothesis by exposing domesticated Channel Catfish fingerlings to Largemouth Bass Micropterus salmoides predators for 13 weeks. Spines and girdles grow isometrically in the fingerlings, and regression analysis indicates no difference in proportional pectoral growth between control and predator-exposed fish. Therefore a change in selection pressure likely accounts for smaller pectoral growth in domesticated Channel Catfish. Decreasing spine growth in older fish suggests anti-predator functions are most important in smaller fish. Additionally, growth of the appendicular and axial skeleton is controlled differentially, and mechanical properties of the spine and not just its length are an important component of this defensive adaptation.

  10. Cation-selective channels in the vacuolar membrane of Saccharomyces: Dependence on calcium, redox state, and voltage

    SciTech Connect

    Bertl, A.; Slayman, C.L. )

    1990-10-01

    The vacuolar membrane of the yeast Saccharomyces cerevisiae, which is proposed as a system for functional expression of membrane proteins, was examined by patch-clamp techniques. Its most conspicuous feature, in the absence of energizing substrates, is a cation channel /with a characteristic conductance of {approx}120 pS for symmetric 100 mM KCl solutions and with little selectivity between K{sup {plus}} and Na{sup {plus}} but strong selectivity for cations over anions. Channel gating is voltage-dependent. The time-averaged current-voltage curve shows strong rectification, with negative currents much larger than positive currents. The open probability also depends strongly on cytoplasmic Ca{sup 2{plus}} concentration but, for ordinary recording conditions, is high only at unphysiologically high Ca{sup 2{plus}}. However, reducing agents such as dithiothreitol and 2-mercaptoethanol poise the channels so that they can be activated by micromolar cytoplasmic Ca{sup 2{plus}}. The channels are blocked irreversibly by chloramine T, which is known to oxidize exposed methionine and cysteine residues specifically.

  11. Cation-selective channels in the vacuolar membrane of Saccharomyces: dependence on calcium, redox state, and voltage.

    PubMed Central

    Bertl, A; Slayman, C L

    1990-01-01

    The vacuolar membrane of the yeast Saccharomyces cerevisiae, which is proposed as a system for functional expression of membrane proteins, was examined by patch-clamp techniques. Its most conspicuous feature, in the absence of energizing substrates, is a cation channel with a characteristic conductance of approximately 120 pS for symmetric 100 mM KCl solutions and with little selectivity between K+ and Na+ (PNa+/PK+ approximately 1) but strong selectivity for cations over anions (PCl-/PK+ less than 0.1). Channel gating is voltage-dependent; open probability, Po, reaches maximum (approximately 0.7) at a transmembrane voltage of -80 mV (cytoplasmic surface negative) and declines at both more negative and more positive voltages (i.e., to 0 around +80 mV). The time-averaged current-voltage curve shows strong rectification, with negative currents (positive charges flowing from vacuolar side to cytoplasmic side) much larger than positive currents. The open probability also depends strongly on cytoplasmic Ca2+ concentration but, for ordinary recording conditions, is high only at unphysiologically high (greater than or equal to 1 mM) Ca2+. However, reducing agents such as dithiothreitol and 2-mercaptoethanol poise the channels so that they can be activated by micromolar cytoplasmic Ca2+. The channels are blocked irreversibly by chloramine T, which is known to oxidize exposed methionine and cysteine residues specifically. Images PMID:1700419

  12. Phosphoinositide 3-kinase isoforms selectively couple receptors to vascular L-type Ca(2+) channels.

    PubMed

    Macrez, N; Mironneau, C; Carricaburu, V; Quignard, J F; Babich, A; Czupalla, C; Nürnberg, B; Mironneau, J

    2001-10-12

    Heterodimeric class I phosphoinositide 3-kinase (PI3K) has been shown to be involved in the stimulation of voltage-gated Ca(2+) channels by various mediators. In this study, we bring evidences that vascular L-type Ca(2+) channels can be modulated by both tyrosine kinase-regulated class Ia and G protein-regulated class Ib PI3Ks. Purified recombinant PI3Ks increased the peak Ca(2+) channel current density when applied intracellularly. Furthermore, PI3Kalpha-, beta-, and delta-mediated stimulations of Ca(2+) channel currents were increased by preactivation by a phosphotyrosyl peptide, whereas PI3Kgamma- and beta-mediated effects were increased by Gbetagamma. In freshly isolated and cultured vascular myocytes, angiotensin II and Gbetagamma stimulated L-type Ca(2+) channel current. In contrast, platelet-derived growth factor (PDGF)-BB and the phosphotyrosyl peptide did not stimulate Ca(2+) channel current in freshly isolated cells despite the presence of endogenous PDGF receptors and PI3Kalpha and PI3Kgamma. Interestingly, when endogenous PI3Kbeta expression arose in cultured myocytes, both PDGF and phosphotyrosyl peptide stimulated Ca(2+) channels through PI3Kbeta, as revealed by the inhibitory effect of an anti-PI3Kbeta antibody. These results suggest that endogenous PI3Kbeta but not PI3Kalpha is specifically involved in PDGF receptor-induced stimulation of Ca(2+) channels and that different isoforms of PI3K regulate physiological increases of Ca(2+) influx in vascular myocytes stimulated by vasoconstrictor or growth factor.

  13. Neutron interaction with doubly-magic {sup 40}Ca

    SciTech Connect

    Smith, A.B. |

    1993-11-01

    Differential neutron elastic and inelastic-scattering cross sections of elemental calcium (96.94% doubly-magic {sup 40}Ca) are measured from {approx} 1.5 to 10 MeV with sufficient detail to determine their energy-averaged behavior in the highly fluctuating environment. These results, combined with values previously reported in the literature, are assessed in the contexts of optical-statistical, dispersive optical, and coupled-channels models, applicable to the energy domain 0 {yields} 30+ MeV, with particular emphasis on the lower energies where the interpretations are sensitive to the dispersion relationship and the effective mass. The interpretations define the energy dependencies of the potential parameters (resolving prior ambiguities), suggest that previous estimates of the prominent low-energy (n,p) and (n,a) reactions are too large, reasonably describe observables to at least 30 MeV, and provide a vehicle for extrapolation into the bound-state regime that gives a good description of hole- and particle-state binding energies. The resulting real-potential parameters (in contrast to many {sup 40}Ca parameters reported in the literature) are shown consistent with global trends.

  14. Signal of doubly charged Higgs at e+e- colliders

    NASA Astrophysics Data System (ADS)

    Hue, L. T.; Huong, D. T.; Long, H. N.; Hung, H. T.; Thao, N. H.

    2015-11-01

    The masses and signals of the production of doubly charged Higgses (DCH) in the framework of the supersymmetric reduced minimal 3-3-1 model are investigated. In the DCH sector, we prove that there always exists a region of the parameter space where the mass of the lightest DCH is of the order of O(100) GeV even when all other new particles are very heavy. The lightest DCH mainly decays to two same-sign leptons while the dominant decay channels of the heavy DCHs are those decaying to heavy particles. We analyze each production cross section for e^+e^- ⇒ H^{++} H^{-} as a function of a few kinematic variables, which are useful to discuss the creation of DCHs in e^+e^- colliders as an indicator of new physics beyond the Standard Model. A numerical study shows that the cross sections for creating the lightest DCH can reach values of a few pb. The other two DCHs are too heavy, beyond the observable range of experiments. The lightest DCH may be detected by the International Linear Collider or the Compact Linear Collider by searching for its decay to a same-sign charged lepton pair.

  15. Doubly-polarised pion photoproduction on the nucleon at MAMI

    NASA Astrophysics Data System (ADS)

    Costanza, Susanna

    2017-04-01

    The A2 Collaboration at MAMI (Mainz) carried out new measurements of the helicity dependence of the total inclusive photo-absorption cross section and of the partial cross sections for several reaction channels on the proton and on the neutron in the photon energy region 200 < Eγ < 1500 MeV. The experiments were performed at the tagged photon beam facility of the MAMI accelerator in Mainz, using circularly and linearly polarised photons on longitudinally polarised proton, deuteron and 3He targets. Hadronic reaction products were detected by the large acceptance Crystal Ball-TAPS spectrometer, complemented by plastic scintillators and vertex detectors for charged particle tracking and identification. These new, high-quality doubly-polarised pion-photoproduction data sets provide a valuable input to the study of the nucleon structure and excitation spectrum by significantly constraining the electromagnetic multipole evaluation performed by the different available partial wave analysis models. Furthermore, the helicity dependent observables provide the main ingredient for the verification of the well-known Gerasimov-Drell-Hearn (GDH) sum rule, which relates the helicity-dependent photoasborption process to the main static nucleon properties (mass, charge, spin).

  16. Selective phosphorylation modulates the PIP2 sensitivity of the CaM-SK channel complex

    PubMed Central

    Zhang, Miao; Meng, Xuan-Yu; Cui, Meng; Pascal, John M.; Logothetis, Diomedes E.; Zhang, Ji-Fang

    2015-01-01

    Phosphatidylinositol bisphosphate (PIP2) regulates the activities of many membrane proteins including ion channels through direct interactions. However, the affinity of PIP2 is so high for some channel proteins that its physiological role as a modulator has been questioned. Here we show that PIP2 is an important cofactor for activation of small conductance Ca2+-activated potassium channels (SK) by Ca2+-bound calmodulin (CaM). Removal of the endogenous PIP2 inhibits SK channels. The PIP2-binding site resides at the interface of CaM and the SK C-terminus. We further demonstrate that the affinity of PIP2 for its target proteins can be regulated by cellular signaling. Phosphorylation of CaM T79, located adjacent to the PIP2-binding site, by Casein Kinase 2 reduces the affinity of PIP2 for the CaM-SK channel complex by altering the dynamic interactions among amino acid residues surrounding the PIP2-binding site. This effect of CaM phosphorylation promotes greater channel inhibition by G-protein-mediated hydrolysis of PIP2. PMID:25108821

  17. (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels.

    PubMed

    Akbulut, Yasemin; Gaunt, Hannah J; Muraki, Katsuhiko; Ludlow, Melanie J; Amer, Mohamed S; Bruns, Alexander; Vasudev, Naveen S; Radtke, Lea; Willot, Matthieu; Hahn, Sven; Seitz, Tobias; Ziegler, Slava; Christmann, Mathias; Beech, David J; Waldmann, Herbert

    2015-03-16

    Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.

  18. Gas-phase reactions of doubly charged actinide cations with alkanes and alkenes--probing the chemical activity of 5f electrons from Th to Cm.

    PubMed

    Marçalo, Joaquim; Santos, Marta; Gibson, John K

    2011-11-07

    Small alkanes (methane, ethane, propane, n-butane) and alkenes (ethene, propene, 1-butene) were used to probe the gas-phase reactivity of doubly charged actinide cations, An(2+) (An = Th, Pa, U, Np, Pu, Am, Cm), by means of Fourier transform ion cyclotron resonance mass spectrometry. Different combinations of doubly and singly charged ions were observed as reaction products, comprising species formed via metal-ion induced eliminations of small molecules, simple adducts and ions resulting from electron, hydride or methide transfer channels. Th(2+), Pa(2+), U(2+) and Np(2+) preferentially yielded doubly charged products of hydrocarbon activation, while Pu(2+), Am(2+) and Cm(2+) reacted mainly through transfer channels. Cm(2+) was also capable of forming doubly charged products with some of the hydrocarbons whereas Pu(2+) and Am(2+) were not, these latter two ions conversely being the only for which adduct formation was observed. The product distributions and the reaction efficiencies are discussed in relation to the electronic configurations of the metal ions, the energetics of the reactions and similar studies previously performed with doubly charged lanthanide and transition metal cations. The conditions for hydrocarbon activation to occur as related to the accessibility of electronic configurations with one or two 5f and/or 6d unpaired electrons are examined and the possible chemical activity of the 5f electrons in these early actinide ions, particularly Pa(2+), is considered. This journal is © the Owner Societies 2011

  19. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels

    PubMed Central

    Hougaard, C; Eriksen, B L; Jørgensen, S; Johansen, T H; Dyhring, T; Madsen, L S; Strøbæk, D; Christophersen, P

    2007-01-01

    Background and purpose: Positive modulators of small conductance Ca2+-activated K+ channels (SK1, SK2, and SK3) exert hyperpolarizing effects that influence the activity of excitable and non-excitable cells. The prototype compound 1-EBIO or the more potent compound NS309, do not distinguish between the SK subtypes and they also activate the related intermediate conductance Ca2+-activated K+ channel (IK). This paper demonstrates, for the first time, subtype-selective positive modulation of SK channels. Experimental approach: Using patch clamp and fluorescence techniques we studied the effect of the compound cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) on recombinant hSK1-3 and hIK channels expressed in HEK293 cells. CyPPA was also tested on SK3 and IK channels endogenously expressed in TE671 and HeLa cells. Key results: CyPPA was found to be a positive modulator of hSK3 (EC50 = 5.6 ± 1.6 μM, efficacy 90 ± 1.8 %) and hSK2 (EC50 = 14 ± 4 μM, efficacy 71 ± 1.8 %) when measured in inside-out patch clamp experiments. CyPPA was inactive on both hSK1 and hIK channels. At hSK3 channels, CyPPA induced a concentration-dependent increase in the apparent Ca2+-sensitivity of channel activation, changing the EC50(Ca2+) from 429 nM to 59 nM. Conclusions and implications: As a pharmacological tool, CyPPA may be used in parallel with the IK/SK openers 1-EBIO and NS309 to distinguish SK3/SK2- from SK1/IK-mediated pharmacological responses. This is important for the SK2 and SK1 subtypes, since they have overlapping expression patterns in the neocortical and hippocampal regions, and for SK3 and IK channels, since they co-express in certain peripheral tissues. PMID:17486140

  20. On the Structural Basis for Size-selective Permeation of Organic Cations through the Voltage-gated Sodium Channel

    PubMed Central

    Sun, Ye-Ming; Favre, Isabelle; Schild, Laurent; Moczydlowski, Edward

    1997-01-01

    Recent evidence indicates that ionic selectivity in voltage-gated Na+ channels is mediated by a small number of residues in P-region segments that link transmembrane elements S5 and S6 in each of four homologous domains denoted I, II, III, and IV. Important determinants for this function appear to be a set of conserved charged residues in the first three homologous domains, Asp(I), Glu(II), and Lys(III), located in a region of the pore called the DEKA locus. In this study, we examined several Ala-substitution mutations of these residues for alterations in ionic selectivity, inhibition of macroscopic current by external Ca2+ and H+, and molecular sieving behavior using a series of organic cations ranging in size from ammonium to tetraethylammonium. Whole-cell recording of wild-type and mutant channels of the rat muscle μ1 Na+ channel stably expressed in HEK293 cells was used to compare macroscopic current–voltage behavior in the presence of various external cations and an intracellular reference solution containing Cs+ and very low Ca2+. In particular, we tested the hypothesis that the Lys residue in domain III of the DEKA locus is responsible for restricting the permeation of large organic cations. Mutation of Lys(III) to Ala largely eliminated selectivity among the group IA monovalent alkali cations (Li+, Na+, K+, Rb+, Cs+) and permitted inward current of group IIA divalent cations (Mg2+, Ca2+, Sr2+, Ba2+). This same mutation also resulted in the acquisition of permeability to many large organic cations such as methylammonium, tetramethylammonium, and tetraethylammonium, all of which are impermeant in the native channel. The results lead to the conclusion that charged residues of the DEKA locus play an important role in molecular sieving behavior of the Na+ channel pore, a function that has been previously attributed to a hypothetical region of the channel called the “selectivity filter.” A detailed examination of individual contributions of the Asp(I), Glu

  1. Monovalent Ion Selectivity Sequences of the Rat Connexin43 Gap Junction Channel

    PubMed Central

    Wang, Hong-Zhan; Veenstra, Richard D.

    1997-01-01

    The relative permeability sequences of the rat connexin 43 (rCx43) gap junction channel to seven cations and chloride were examined by double whole cell patch clamp recording of single gap junction channel currents in rCx43 transfected neuroblastoma 2A (N2A) cell pairs. The measured maximal single channel slope conductances (γj, in pS) of the junctional current-voltage relationships in 115 mM XCl were RbCl (103) ≥ CsCl (102) > KCl (97) > NaCl (79) ≥ LiCl (78) > TMACl (65) > TEACl (53) and for 115 mM KY were KBr (105) > KCl (97) > Kacetate (77) > Kglutamate (61). The single channel conductance-aqueous mobility relationships for the test cations and anions were linear. However, the predicted minimum anionic and cationic conductances of these plots did not accurately predict the rCx43 channel conductance in 115 mM KCl. Instead, the conductance of the rCx43 channel in 115 mM KCl was accurately predicted from cationic and anionic conductance-mobility plots by applying a mobility scaling factor Dx/Do, which depends upon the relative radii of the permeant ions to an estimated pore radius. Relative permeabilities were determined for all of the monovalent cations and anions tested from asymmetric salt reversal potential measurements and the Goldman-Hodgkin-Katz voltage equation. These experiments estimate the relative chloride to potassium permeability to be 0.13. The relationship between the relative cation permeability and hydrated radius was modeled using the hydrodynamic equation assuming a pore radius of 6.3 ± 0.4 Å. Our data quantitatively demonstrate that the rCx43 gap junction channel is permeable to monovalent atomic and organic cations and anions and the relative permeability sequences are consistent with an Eisenman sequence II or I, respectively. These predictions about the rCx43 channel pore provide a useful basis for future investigations into the structural determinants of the conductance and permeability properties of the connexin channel pore. PMID

  2. In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels -- mirage or pot of gold?

    PubMed

    Bon, Robin S; Beech, David J

    2013-10-01

    The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and

  3. Receptor model for the molecular basis of tissue selectivity of 1,4-dihydropyridine calcium channel drugs

    NASA Astrophysics Data System (ADS)

    Langs, David A.; Strong, Phyllis D.; Triggle, David J.

    1990-09-01

    Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the 215-1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from others reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltagesensing α-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S `reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.

  4. Evaluation of habitat quality for selected wildlife species associated with back channels.

    USGS Publications Warehouse

    Anderson, James T.; Zadnik, Andrew K.; Wood, Petra Bohall; Bledsoe, Kerry

    2013-01-01

    The islands and associated back channels on the Ohio River, USA, are believed to provide critical habitat features for several wildlife species. However, few studies have quantitatively evaluated habitat quality in these areas. Our main objective was to evaluate the habitat quality of back and main channel areas for several species using habitat suitability index (HSI) models. To test the effectiveness of these models, we attempted to relate HSI scores and the variables measured for each model with measures of relative abundance for the model species. The mean belted kingfisher (Ceryle alcyon) HSI was greater on the main than back channel. However, the model failed to predict kingfisher abundance. The mean reproduction component of the great blue heron (Ardea herodias) HSI, total common muskrat (Ondatra zibethicus) HSI, winter cover component of the snapping turtle (Chelydra serpentina) HSI, and brood-rearing component of the wood duck (Aix sponsa) HSI were all greater on the back than main channel, and were positively related with the relative abundance of each species. We found that island back channels provide characteristics not found elsewhere on the Ohio River and warrant conservation as important riparian wildlife habitat. The effectiveness of using HSI models to predict species abundance on the river was mixed. Modifications to several of the models are needed to improve their use on the Ohio River and, likely, other large rivers.

  5. Molecular design of the voltage-dependent, anion-selective channel in the mitochondrial outer membrane.

    PubMed

    Guo, X W; Smith, P R; Cognon, B; D'Arcangelis, D; Dolginova, E; Mannella, C A

    1995-01-01

    The mitochondrial outer membrane contains numerous copies of a channel protein, VDAC, that is thought to be the main permeability pathway through this membrane for polar molecules and ions. Low-dose electron microscopy has been used to obtain images of two-dimensional crystals of this channel (produced by treating outer membranes from fungal mitochondria with phospholipase A2) embedded in vitreous ice or aurothioglucose. The angular orientation of the channels in the unit cell of one type of array has been determined by rotational correlation analysis. The location of the amino-terminal segment of the protein (which, according to circular dichroism, forms an alpha-helix in nonpolar solvents and detergent solutions) has been determined by labeling arrays with Fab prepared from antibodies directed against residues 1-20. The three-dimensional structure of the channel has been obtained by applying Fourier reconstruction methods to projections of tilted crystals embedded in aurothioglucose, followed by averaging of the three non-symmetry-related channels in the unit cell. The results of this study indicate that the wall of VDAC's lumen has several irregular features (uneven height, grooves) and that the aminoterminal segment extends away from the lumen in this crystalline state.

  6. Selective potentiation of 2-APB-induced activation of TRPV1–3 channels by acid

    PubMed Central

    Gao, Luna; Yang, Pu; Qin, Peizhong; Lu, Yungang; Li, Xinxin; Tian, Quan; Li, Yang; Xie, Chang; Tian, Jin-bin; Zhang, Chengwei; Tian, Changlin; Zhu, Michael X.; Yao, Jing

    2016-01-01

    Temperature-sensitive TRP channels are important for responses to pain and inflammation, to both of which tissue acidosis is a major contributing factor. However, except for TRPV1, acid-sensing by other ThermoTRP channels remains mysterious. We show here that unique among TRPV1–3 channels, TRPV3 is directly activated by protons from cytoplasmic side. This effect is very weak and involves key cytoplasmic residues L508, D512, S518, or A520. However, mutations of these residues did not affect a strong proton induced potentiation of TRPV3 currents elicited by the TRPV1–3 common agonist, 2-aminoethoxydiphenyl borate (2-APB), no matter if the ligand was applied from extracellular or cytoplasmic side. The acid potentiation was common among TRPV1–3 and only seen with 2-APB-related ligands. Using 1H-nuclear magnetic resonance to examine the solution structures of 2-APB and its analogs, we observed striking structural differences of the boron-containing compounds at neutral/basic as compared to acidic pH, suggesting that a pH-dependent configuration switch of 2-APB-based drugs may underlie their functionality. Supporting this notion, protons also enhanced the inhibitory action of 2-APB on TRPM8. Collectively, our findings reveal novel insights into 2-APB action on TRP channels, which should facilitate the design of new drugs for these channels. PMID:26876731

  7. A benzothiadiazine derivative and methylprednisolone are novel and selective activators of transient receptor potential canonical 5 (TRPC5) channels.

    PubMed

    Beckmann, Holger; Richter, Julia; Hill, Kerstin; Urban, Nicole; Lemoine, Horst; Schaefer, Michael

    2017-09-01

    The transient receptor potential canonical channel 5 (TRPC5) is a Ca(2+)-permeable ion channel, which is predominantly expressed in the brain. TRPC5-deficient mice exhibit a reduced innate fear response and impaired motor control. In addition, outgrowth of hippocampal and cerebellar neurons is retarded by TRPC5. However, pharmacological evidence of TRPC5 function on cellular or organismic levels is sparse. Thus, there is still a need for identifying novel and efficient TRPC5 channel modulators. We, therefore, screened compound libraries and identified the glucocorticoid methylprednisolone and N-[3-(adamantan-2-yloxy)propyl]-3-(6-methyl-1,1-dioxo-2H-1λ(6),2,4-benzothiadiazin-3-yl)propanamide (BTD) as novel TRPC5 activators. Comparisons with closely related chemical structures from the same libraries indicate important substructures for compound efficacy. Methylprednisolone activates TRPC5 heterologously expressed in HEK293 cells with an EC50 of 12μM, while BTD-induced half-maximal activation is achieved with 5-fold lower concentrations, both in Ca(2+) assays (EC50=1.4μM) and in electrophysiological whole cell patch clamp recordings (EC50=1.3 μM). The activation resulting from both compounds is long lasting, reversible and sensitive to clemizole, a recently established TRPC5 inhibitor. No influence of BTD on homotetrameric members of the remaining TRPC family was observed. On the main sensory TRP channels (TRPA1, TRPV1, TRPM3, TRPM8) BTD exerts only minor activity. Furthermore, BTD can activate heteromeric channel complexes consisting of TRPC5 and its closest relatives TRPC1 or TRPC4, suggesting a high selectivity of BTD for channel complexes bearing at least one TRPC5 subunit. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. First observation of doubly charmed baryons

    SciTech Connect

    M. A. Moinester et al.

    2003-09-25

    The SELEX experiment (E781) at Fermilab has observed two statistically compelling high mass states near 3.6 GeV/c{sup 2}, decaying to {Lambda}{sub c}{sup +} K{sup -} {pi}{sup +} and {Lambda}{sub c}{sup +} K{sup -} {pi}{sup +}{pi}{sup +}. These final states are Cabibbo-allowed decay modes of doubly charmed baryons {Xi}{sub cc}{sup +} and {Xi}{sub cc}{sup ++}, respectively. The masses are in the range expected from theoretical considerations, but the spectroscopy is surprising. SELEX also has weaker preliminary evidence for a state near 3.8 GeV/c{sup 2}, a high mass state decaying to {Lambda}{sub c}{sup +} K{sup -} {pi}{sup +}{pi}{sup +}, possibly an excited {Xi}{sub cc}{sup ++} (ccu*). Data are presented and discussed.

  9. Levels in doubly odd 138Pr

    NASA Astrophysics Data System (ADS)

    Gangopadhyay, G.; Bhowal, Samit; Bhowmik, R. K.; Datta Pramanik, U.; Ghosh, P.; Goswami, A.; Petrache, C.; Mukherjee, A.; Muralithar, S.; Raut, Rajarshi; Saha Sarkar, M.; Singh, A. K.; Singh, R. P.; Bhattacharya, S.

    2005-05-01

    The band structures of the doubly odd 138Pr nucleus have been investigated using the 128Te(14N, 4n)138Pr reaction at a beam energy of 55-65 MeV. Altogether six distinct structures have been established, of which the lower part of the yrast band and two side bands were known from earlier works. The observed level properties of the members of the yrast band have been compared with theoretical calculations performed within the Particle Rotor Model (PRM) with axially symmetric core. The experimental branching ratios and B(M1)/B(E2) values when compared with the theoretical results of the PRM, suggest an oblate core.

  10. Gravitational waves in doubly coupled bigravity

    NASA Astrophysics Data System (ADS)

    Brax, Philippe; Davis, Anne-Christine; Noller, Johannes

    2017-07-01

    We consider gravitational waves from the point of view of both their production and their propagation in doubly coupled bigravity in the metric formalism. In bigravity, the two gravitons are coupled by a nondiagonal mass matrix and show birefrigence. In particular, we find that one of the two gravitons propagates with a speed which differs from one. This deviation is tightly constrained by both the gravitational Cerenkov effect and the energy loss of binary pulsars. When emitted from astrophysical sources, the Jordan frame gravitational wave, which is a linear combination of the two propagating gravitons, has a wave form displaying beats. The best prospect of detecting this phenomenon would come from nano-Hertz interferometric experiments.

  11. Drifting localized structures in doubly diffusive convection

    NASA Astrophysics Data System (ADS)

    Knobloch, Edgar; Lo Jacono, David; Bergeon, Alain

    2016-11-01

    We use numerical continuation to compute a multiplicity of spatially localized states in doubly diffusive convection in a vertical slot driven by imposed horizontal temperature and concentration differences. The calculations focus on the so-called opposing case, in which the resulting gradients are in balance. No-slip boundary conditions are used at the sides and periodic boundary conditions with large spatial period are used in the vertical direction. This system exhibits homoclinic snaking of stationary spatially localized structures with point symmetry. In this talk we demonstrate the existence, near threshold, of drifting pulses of spatially localized convection that appear when mixed concentration boundary conditions are used, and use homotopic continuation to identify similar states in the case of fixed concentration boundary conditions. We show that these states persist to large values of the Grasshof number and provide a detailed study of their properties.

  12. Effects of doubly-connected finned surfaces on heat transfer during solidification

    NASA Astrophysics Data System (ADS)

    Sheffield, J. W.

    1982-06-01

    This paper presents the results of an experimental investigation of an enhanced heat conduction concept for the solidification of phase change materials (PCM) in thermal energy storage systems. The effects of doubly-connected fins have been demonstrated for a particular storage system configuration. The geometry is a pair of coaxial cylinders with longitudinal fins dividing the annular region into segments filled with the PCM. A 99% pure n-Octadecane paraffin was selected as the PCM because of its desirable properties. Outward solidification was achieved by convective cooling of the inner cylinder. For comparison, the investigation included singly-connected and doubly-connected finned surfaces along the unfinned surfaces of the coaxial cylinders. Axial views of the PCM containers were photographically recorded during solidification to document the growth history for each configuration.

  13. Channel selection and classification of electroencephalogram signals: an artificial neural network and genetic algorithm-based approach.

    PubMed

    Yang, Jianhua; Singh, Harsimrat; Hines, Evor L; Schlaghecken, Friederike; Iliescu, Daciana D; Leeson, Mark S; Stocks, Nigel G

    2012-06-01

    An electroencephalogram-based (EEG-based) brain-computer-interface (BCI) provides a new communication channel between the human brain and a computer. Amongst the various available techniques, artificial neural networks (ANNs) are well established in BCI research and have numerous successful applications. However, one of the drawbacks of conventional ANNs is the lack of an explicit input optimization mechanism. In addition, results of ANN learning are usually not easily interpretable. In this paper, we have applied an ANN-based method, the genetic neural mathematic method (GNMM), to two EEG channel selection and classification problems, aiming to address the issues above. Pre-processing steps include: least-square (LS) approximation to determine the overall signal increase/decrease rate; locally weighted polynomial regression (Loess) and fast Fourier transform (FFT) to smooth the signals to determine the signal strength and variations. The GNMM method consists of three successive steps: (1) a genetic algorithm-based (GA-based) input selection process; (2) multi-layer perceptron-based (MLP-based) modelling; and (3) rule extraction based upon successful training. The fitness function used in the GA is the training error when an MLP is trained for a limited number of epochs. By averaging the appearance of a particular channel in the winning chromosome over several runs, we were able to minimize the error due to randomness and to obtain an energy distribution around the scalp. In the second step, a threshold was used to select a subset of channels to be fed into an MLP, which performed modelling with a large number of iterations, thus fine-tuning the input/output relationship. Upon successful training, neurons in the input layer are divided into four sub-spaces to produce if-then rules (step 3). Two datasets were used as case studies to perform three classifications. The first data were electrocorticography (ECoG) recordings that have been used in the BCI competition

  14. Structural basis for the selective permeability of channels made of communicating junction proteins

    PubMed Central

    Ek-Vitorin, Jose F.; Burt, Janis M.

    2012-01-01

    The open state(s) of gap junction channels is evident from their permeation by small ions in response to an applied intercellular (transjunctional/transchannel) voltage gradient. That an open channel allows variable amounts of current to transit from cell-to-cell in the face of a constant intercellular voltage difference indicates channel open/closing can be complete or partial. The physiological significance of such open state options is, arguably, the main concern of junctional regulation. Because gap junctions are permeable to many substances, it is sensible to inquire whether and how each open state influences the intercellular diffusion of molecules as valuable as, but less readily detected than current-carrying ions. Presumably, structural changes perceived as shifts in channel conductivity would significantly alter the transjunctional diffusion of molecules whose limiting diameter approximates the pore’s limiting diameter. Moreover, changes in junctional permeability to some molecules might occur without evident changes in conductivity, either at macroscopic or single channel level. Open gap junction channels allow the exchange of cytoplasmic permeants between contacting cells by simple diffusion. The identity of such permeants, and the functional circumstances and consequences of their junctional exchange presently constitute the most urgent (and demanding) themes of the field. Here, we consider the necessity for regulating this exchange, the possible mechanism(s) and structural elements likely involved in such regulation, and how regulatory phenomena could be perceived as changes in chemical vs. electrical coupling; an overall reflection on our collective knowledge of junctional communication is then applied to suggest new avenues of research. PMID:22342665

  15. Baseline Channel Geometry and Aquatic Habitat Data for Selected Streams in the Matanuska-Susitna Valley, Alaska

    USGS Publications Warehouse

    Curran, Janet H.; Rice, William J.

    2009-01-01

    Small streams in the rapidly developing Matanuska-Susitna Valley in south-central Alaska are known to support anadromous and resident fish but little is known about their hydrologic and riparian conditions, or their sensitivity to the rapid development of the area or climate variability. To help address this need, channel geometry and aquatic habitat data were collected in 2005 as a baseline of stream conditions for selected streams. Three streams were selected as representative of various stream types, and one drainage network, the Big Lake drainage basin, was selected for a systematic assessment. Streams in the Big Lake basin were drawn in a Geographic Information System (GIS), and 55 reaches along 16 miles of Meadow Creek and its primary tributary Little Meadow Creek were identified from orthoimagery and field observations on the basis of distinctive physical and habitat parameters, most commonly gradient, substrate, and vegetation. Data-collection methods for sites at the three representative reaches and the 55 systematically studied reaches consisted of a field survey of channel and flood-plain geometry and collection of 14 habitat attributes using published protocols or slight modifications. Width/depth and entrenchment ratios along the Meadow-Little Meadow Creek corridor were large and highly variable upstream of Parks Highway and lower and more consistent downstream of Parks Highway. Channel width was strongly correlated with distance, increasing downstream in a log-linear relation. Runs formed the most common habitat type, and instream vegetation dominated the habitat cover types, which collectively covered 53 percent of the channel. Gravel suitable for spawning covered isolated areas along Meadow Creek and about 29 percent of Little Meadow Creek. Broad wetlands were common along both streams. For a comprehensive assessment of small streams in the Mat-Su Valley, critical additional data needs include hydrologic, geologic and geomorphic, and biologic data

  16. Guide for selecting Manning's roughness coefficients for natural channels and flood plains

    USGS Publications Warehouse

    Arcement, George J.; Schneider, Verne R.

    1989-01-01

    Although much research has been done on Manning's roughness coefficient, n, for stream channels, very little has been done concerning the roughness values for densely vegetated flood plains. The n value is determined from the values of the factors that affect the roughness of channels and flood plains. In densely vegetated flood plains, the major roughness is caused by trees, vines, and brush. The n value for this type of flood plain can be determined by measuring the vegetation density of the flood plain. Photographs of flood-plain segments where n values have been verified can be used as a comparison standard to aid in assigning n values to similar flood plains.

  17. Doubly Magic Optical Trapping for Cs Atom Hyperfine Clock Transitions

    NASA Astrophysics Data System (ADS)

    Carr, A. W.; Saffman, M.

    2016-10-01

    We analyze doubly magic trapping of Cs hyperfine transitions including previously neglected contributions from the ground state hyperpolarizability and the interaction of the laser light and a static magnetic field. Extensive numerical searches do not reveal any doubly magic trapping conditions for any pair of hyperfine states. However, including the hyperpolarizability reveals light intensity insensitive traps for a wide range of wavelengths at specific intensities. We then investigate the use of bichromatic trapping light fields. Deploying a bichromatic scheme, we demonstrate doubly magic red and blue detuned traps for pairs of states separated by one or two single photon transitions.

  18. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a

    PubMed Central

    Bende, Niraj S; Dziemborowicz, Slawomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M; King, Glenn F; Bosmans, Frank

    2014-01-01

    β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1–S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, aconcept that will be valuable for the design of insect-selective insecticides. PMID:25014760

  19. A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a

    NASA Astrophysics Data System (ADS)

    Bende, Niraj S.; Dziemborowicz, Sławomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M.; King, Glenn F.; Bosmans, Frank

    2014-07-01

    β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1-S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides.

  20. Molecular origin of the cation selectivity in OmpF porin: single channel conductances vs. free energy calculation.

    PubMed

    Danelon, Christophe; Suenaga, Atsushi; Winterhalter, Mathias; Yamato, Ichiro

    2003-07-01

    Ion current through single outer membrane protein F (OmpF) trimers was recorded and compared to molecular dynamics simulation. Unidirectional insertion was revealed from the asymmetry in channel conductance. Single trimer conductance showed particularly high values at low symmetrical salt solution. The conductance values of various alkali metal ion solutions were proportional to the monovalent cation mobility values in the bulk phase, LiClSelectivity measurements at low concentration showed that OmpF channels favored permeation of alkali metal ions over chloride and suggested size preference for smaller cations. These results suggest that there are specific interactions between the permeating cation and charged residues lining the channel walls. This hypothesis was supported by computational study which predicted that monovalent cations bind to Asp113 at low concentration. Here, free energy calculations revealed that the affinity of the alkali metal ions to its binding site increased with their atomic radii, Li(+) approximately Na(+)channel increases the translocation rate of cations under applied voltage by increasing their local concentration relative to the bulk solution.

  1. Harnessing mode-selective nonlinear optics for on-chip multi-channel all-optical signal processing

    NASA Astrophysics Data System (ADS)

    Ma, Ming; Chen, Lawrence R.

    2016-11-01

    All-optical signal processing based on nonlinear optical effects allows for the realization of important functions in telecommunications including wavelength conversion, optical multiplexing/demultiplexing, Fourier transformation, and regeneration, amongst others, on ultrafast time scales to support high data rate transmission. In integrated photonic subsystems, the majority of all-optical signal processing systems demonstrated to date typically process only a single channel at a time or perform a single processing function, which imposes a serious limitation on the functionality of integrated solutions. Here, we demonstrate how nonlinear optical effects can be harnessed in a mode-selective manner to perform simultaneous multi-channel (two) and multi-functional optical signal processing (i.e., regenerative wavelength conversion) in an integrated silicon photonic device. This approach, which can be scaled to a higher number of channels, opens up a new degree of freedom for performing a broad range of multi-channel nonlinear optical signal processing functions using a single integrated photonic device.

  2. Specific binding of aluminium and iron ions to a cation-selective cell wall channel of Microthrix parvicella.

    PubMed

    Knaf, Tobias; Schade, Margit; Lemmer, Hilde; Benz, Roland

    2013-10-01

    Heavy metal salts containing aluminium or iron are used in wastewater treatment to control excessive growth of the Gram-positive bacterium Microthrix parvicella, frequently observed in wastewater plants suffering from bulking, foaming and scum. Microthrix parvicella belongs to the class Actinobacteria but not to mycolata, although its taxonomic position in this class is not identified. Investigations using the microspheres adhesion to cells method (MAC) suggested that M. parvicella is as strongly hydrophobic as the mycolic acid containing actinomycetes. The cell wall of M. parvicella was investigated for the presence of water-filled channels using the lipid bilayer assay. An ion-permeable channel called MppA with a conductance of 600 pS in 1 M KCl was identified in cell wall extracts and purified to homogeneity. The cation-selective channel showed no voltage-dependent closure at higher voltages. Interestingly, MPPA could be blocked by heavy metal ions. Binding of polyvalent cations such as iron and aluminium was studied in titration experiments and revealed stability constants for their binding to MppA up to 700 M(-1). The cell wall channel of M. parvicella contains a binding site for polyvalent cations which may play a crucial role for the effect of heavy metals salts on M. parvicella-dominated activated sludge.

  3. Differential inhibition of cardiac and neuronal Na(+) channels by the selective serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine.

    PubMed

    Stoetzer, Carsten; Papenberg, Bastian; Doll, Thorben; Völker, Marc; Heineke, Joerg; Stoetzer, Marcus; Wegner, Florian; Leffler, Andreas

    2016-07-15

    Duloxetine and venlafaxine are selective serotonin-norepinephrine-reuptake-inhibitors used as antidepressants and co-analgesics. While venlafaxine rather than duloxetine induce cardiovascular side-effects, neither of the substances are regarded cardiotoxic. Inhibition of cardiac Na(+)-channels can be associated with cardiotoxicity, and duloxetine was demonstrated to block neuronal Na(+)-channels. The aim of this study was to investigate if the non-life threatening cardiotoxicities of duloxetine and venlafaxine correlate with a weak inhibition of cardiac Na(+)-channels. Effects of duloxetine, venlafaxine and amitriptyline were examined on endogenous Na(+)-channels in neuroblastoma ND7/23 cells and on the α-subunits Nav1.5, Nav1.7 and Nav1.8 with whole-cell patch clamp recordings. Tonic block of the cardiac Na(+)-channel Nav1.5 and rat-cardiomyocytes (CM) revealed a higher potency for duloxetine (Nav 1.5 IC50 14±1µM, CM IC50 27±3µM) as compared to venlafaxine (Nav 1.5 IC50 671±26µM, CM IC50 452±34µM). Duloxetine was as potent as the cardiotoxic antidepressant amitriptyline (IC50 13±1µM). While venlafaxine almost failed to induce use-dependent block on Nav1.5 and cardiomyocytes, low concentrations of duloxetine (1, 10µM) induced prominent use-dependent block similar to amitriptyline. Duloxetine, but not venlafaxine stabilized fast and slow inactivation and delayed recovery from inactivation. Duloxetine induced an unselective inhibition of neuronal Na(+)-channels (IC50 ND7/23 23±1µM, Nav1.7 19±2µM, Nav1.8 29±2). Duloxetine, but not venlafaxine inhibits cardiac Na(+)-channels with a potency similar to amitriptyline. These data indicate that an inhibition of Na(+)-channels does not predict a clinically relevant cardiotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Divalent Cation Selectivity Is a Function of Gating in Native and Recombinant Cyclic Nucleotide–gated Ion Channels from Retinal Photoreceptors

    PubMed Central

    Hackos, David H.; Korenbrot, Juan I.

    1999-01-01

    The selectivity of Ca2+ over Na+ is ∼3.3-fold larger in cGMP-gated channels of cone photoreceptors than in those of rods when measured under saturating cGMP concentrations, where the probability of channel opening is 85–90%. Under physiological conditions, however, the probability of opening of the cGMP-gated channels ranges from its largest value in darkness of 1–5% to essentially zero under continuous, bright illumination. We investigated the ion selectivity of cGMP-gated channels as a function of cyclic nucleotide concentration in membrane patches detached from the outer segments of rod and cone photoreceptors and have found that ion selectivity is linked to gating. We determined ion selectivity relative to Na+ (PX/PNa) from the value of reversal potentials measured under ion concentration gradients. The selectivity for Ca2+ over Na+ increases continuously as the probability of channel opening rises. The dependence of PCa/PNa on cGMP concentration, in both rods and cones, is well described by the same Hill function that describes the cGMP dependence of current amplitude. At the cytoplasmic cGMP concentrations expected in dark-adapted intact photoreceptors, PCa/PNa in cone channels is ∼7.4-fold greater than that in rods. The linkage between selectivity and gating is specific for divalent cations. The selectivity of Ca2+ and Sr2+ changes with cGMP concentration, but the selectivity of inorganic monovalent cations, Cs+ and NH4+, and organic cations, methylammonium+ and dimethylammonium+, is invariant with cGMP. Cyclic nucleotide–gated channels in rod photoreceptors are heteromeric assemblies of α and β subunits. The maximal PCa/PNa of channels formed from α subunits of bovine rod channels is less than that of heteromeric channels formed from α and β subunits. In addition, Ca2+ is a more effective blocker of channels formed by α subunits than of channels formed by α and β subunits. The cGMP-dependent shift in divalent cation selectivity is a

  5. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    PubMed Central

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  6. Calcium-activated non-selective cation channel in ventricular cells isolated from adult guinea-pig hearts.

    PubMed Central

    Ehara, T; Noma, A; Ono, K

    1988-01-01

    1. A class of Ca2+-activated non-selective cation channel was identified in ventricular cells, which were dissociated from adult guinea-pig hearts using collagenase. 2. Under cell-attached conditions the patch electrode filled with a Na+-rich solution recorded no obvious single-channel current at the resting membrane potential. Subsequent superfusion of the ventricular cell with a Na+-free Tyrode solution induced an inward-going single-channel current as well as contracture of the cell. Kinetics of this channel were not affected by varying the membrane potential. 3. Single-channel currents showing a conductance similar to those observed in the cell-attached patches were recorded in isolated inside-out membrane patches when the inner side of the membrane was exposed to a free Ca2+ concentration ([Ca2+]i) higher than 0.3 microM. The slope conductance of the channel was 14.8 +/- 2.9 pS (mean +/- S.D., n = 17) at 20-25 degrees C. 4. The reversal potential examined in the inside-out patch was about 0 mV irrespective of the Na+-rich, K+-rich, Li+-rich or Cs+-rich solutions on either side of the membrane, thereby indicating that the channel was almost equally permeable to these cations. 5. The open probability of the channel was increased by raising [Ca2+]i with the maximum value of 0.93 +/- 0.17 (n = 4) at about 10 microM [Ca2+]i. The dose-response relation was fitted to the saturation kinetics with a Hill coefficient of 3.0 and a half-maximum concentration of 1.2 microM [Ca2+]i. 6. The gating kinetics were complex; both the open and closed time histograms showed at least two exponential components with time constants of 3.8 +/- 1.3 ms and 140 +/- 110 ms for open time and 1.8 +/- 1.1 ms and 14.9 +/- 5.3 ms for closed time (n = 4) at 10 microM [Ca2+]i. Reduction of [Ca2+]i resulted in both a decrease of the time constant of the slow component in the open time histogram and an increase of the two time constants of the closed time histogram. 7. Contribution of the channel

  7. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    PubMed

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  8. Verification of roughness coefficients for selected natural and constructed stream channels in Arizona

    USGS Publications Warehouse

    Phillips, Jeff V.; Ingersoll, Todd L.

    1998-01-01

    Physical and hydraulic characteristics are presented for 14 river and canal reaches in Arizona for which 37 roughness coefficients have been determined. The verified roughness coefficients which ranged from 0.017 to 0.067, were computed from discharges, channel geometry, and water-surface profiles measured at each of the sites. The information given for each stream segment includes bed and bank descriptions, data tables showing hydraulic components, a plan view, cross-section plots, and color photographs that can be used as a comparison aid in determining roughness coefficients for similarly channeled streams. Relations derived from the data presented relate Manning's roughness coefficient (n) to various hydraulic components. For gravel-bed streams, verified roughness coefficients are related to median grain size of the bed material and hydraulic radius resulting in an equation that can be used to transfer results to similar dry-land channels. The equation developed for base values of n for gravel-bed channels in Arizona is significantly different from similarly derived equations for other regions of the United States and the world.

  9. Photographic guidance for selecting flow resistance coefficients in high-gradient channels

    Treesearch

    Steven E. Yochum; Francesco Comiti; Ellen Wohl; Gabrielle C. L. David; Luca Mao

    2014-01-01

    Photographic guidance is presented to assist with the estimation of Manning’s n and Darcy-Weisbach f in high-gradient plane-bed, step-pool, and cascade channels. Reaches both with and without instream wood are included. These coefficients are necessary for the estimation of reachaverage velocity, energy loss, and...

  10. BER Analysis of Dual-Hop Amplify-and-Forward MIMO Relaying with Best Antenna Selection in Rayleigh Fading Channels

    NASA Astrophysics Data System (ADS)

    Kim, Jung-Bin; Kim, Dongwoo

    Combining relaying and multi-input multi-output (MIMO) transmission is a generic way to overcome the channel-fading impairments. Best antenna selection is a simple but efficient MIMO method that achieves the full diversity and also serves as a lower bound reference of MIMO performance. For a dual-hop MIMO system with an ideal amplify-and-forward (AF) relaying gain and best antenna selection, we provide a probability density function (PDF) of received signal-to-noise ratio (SNR) and an analytic BER equation when using M-ary PSK in Rayleigh fading channels. The analytic result is shown to exactly match with simulated one. Furthermore, the effect of link unbalance between the first hop and the second hop, due to differences in the number of antennas deployed in both hops as well as in the average power of channel coefficients, on the BER performance is numerically investigated and the results show that the links with better balance give better performance.

  11. Optimized Energy Harvesting, Cluster-Head Selection and Channel Allocation for IoTs in Smart Cities

    PubMed Central

    Aslam, Saleem; Hasan, Najam Ul; Jang, Ju Wook; Lee, Kyung-Geun

    2016-01-01

    This paper highlights three critical aspects of the internet of things (IoTs), namely (1) energy efficiency, (2) energy balancing and (3) quality of service (QoS) and presents three novel schemes for addressing these aspects. For energy efficiency, a novel radio frequency (RF) energy-harvesting scheme is presented in which each IoT device is associated with the best possible RF source in order to maximize the overall energy that the IoT devices harvest. For energy balancing, the IoT devices in close proximity are clustered together and then an IoT device with the highest residual energy is selected as a cluster head (CH) on a rotational basis. Once the CH is selected, it assigns channels to the IoT devices to report their data using a novel integer linear program (ILP)-based channel allocation scheme by satisfying their desired QoS. To evaluate the presented schemes, exhaustive simulations are carried out by varying different parameters, including the number of IoT devices, the number of harvesting sources, the distance between RF sources and IoT devices and the primary user (PU) activity of different channels. The simulation results demonstrate that our proposed schemes perform better than the existing ones. PMID:27918424

  12. Bit error rate performance of pi/4-DQPSK in a frequency-selective fast Rayleigh fading channel

    NASA Technical Reports Server (NTRS)

    Liu, Chia-Liang; Feher, Kamilo

    1991-01-01

    The bit error rate (BER) performance of pi/4-differential quadrature phase shift keying (DQPSK) modems in cellular mobile communication systems is derived and analyzed. The system is modeled as a frequency-selective fast Rayleigh fading channel corrupted by additive white Gaussian noise (AWGN) and co-channel interference (CCI). The probability density function of the phase difference between two consecutive symbols of M-ary differential phase shift keying (DPSK) signals is first derived. In M-ary DPSK systems, the information is completely contained in this phase difference. For pi/4-DQPSK, the BER is derived in a closed form and calculated directly. Numerical results show that for the 24 kBd (48 kb/s) pi/4-DQPSK operated at a carrier frequency of 850 MHz and C/I less than 20 dB, the BER will be dominated by CCI if the vehicular speed is below 100 mi/h. In this derivation, frequency-selective fading is modeled by two independent Rayleigh signal paths. Only one co-channel is assumed in this derivation. The results obtained are also shown to be valid for discriminator detection of M-ary DPSK signals.

  13. Optimized Energy Harvesting, Cluster-Head Selection and Channel Allocation for IoTs in Smart Cities.

    PubMed

    Aslam, Saleem; Hasan, Najam Ul; Jang, Ju Wook; Lee, Kyung-Geun

    2016-12-02

    This paper highlights three critical aspects of the internet of things (IoTs), namely (1) energy efficiency, (2) energy balancing and (3) quality of service (QoS) and presents three novel schemes for addressing these aspects. For energy efficiency, a novel radio frequency (RF) energy-harvesting scheme is presented in which each IoT device is associated with the best possible RF source in order to maximize the overall energy that the IoT devices harvest. For energy balancing, the IoT devices in close proximity are clustered together and then an IoT device with the highest residual energy is selected as a cluster head (CH) on a rotational basis. Once the CH is selected, it assigns channels to the IoT devices to report their data using a novel integer linear program (ILP)-based channel allocation scheme by satisfying their desired QoS. To evaluate the presented schemes, exhaustive simulations are carried out by varying different parameters, including the number of IoT devices, the number of harvesting sources, the distance between RF sources and IoT devices and the primary user (PU) activity of different channels. The simulation results demonstrate that our proposed schemes perform better than the existing ones.

  14. Analysis of channel confined selective area growth in evolutionary growth of GaN on SiO2

    NASA Astrophysics Data System (ADS)

    Leung, Benjamin; Tsai, Miao-Chan; Song, Jie; Zhang, Yu; Xiong, Kanglin; Yuan, Ge; Coltrin, Michael E.; Han, Jung

    2015-09-01

    Here, we analyze the chemical vapor deposition of semiconductor crystals by selective area growth in a non-planar geometry. Specifically, the growth process in laterally and vertically confined masks forming single-crystal GaN on SiO2 by metal-organic chemical vapor deposition is considered in detail. A textured AlN seed is used to initiate growth of oriented GaN selectively through the mask, allowing the reduction of degrees of freedom by the evolutionary grain selection process. As shown by measurements of growth rates within the mask, the sub micron length scale of the channel opening is comparable to the mean free path of precursors in the gas phase, resulting in transport characteristics that can be described by an intermediate flow regime between continuum and free-molecular. Mass transport is modeled through kinetic theory to explain the growth rate enhancements of more than a factor of two by changes in reactor pressure. The growth conditions that enable the modification of nucleation density within the channel are then discussed, and are measured by electron-back scatter diffraction of the nucleated grains on the AlN seed. Finally, the selectivity behavior using the low fill factor masks needed in these configurations has been optimized by control of precursor flow rates and the H2 enhanced etching of the polycrystalline GaN nuclei.

  15. Structural basis for ion selectivity revealed by high-resolution crystal structure of Mg2+ channel MgtE.

    PubMed

    Takeda, Hironori; Hattori, Motoyuki; Nishizawa, Tomohiro; Yamashita, Keitaro; Shah, Syed T A; Caffrey, Martin; Maturana, Andrés D; Ishitani, Ryuichiro; Nureki, Osamu

    2014-11-04

    Magnesium is the most abundant divalent cation in living cells and is crucial to several biological processes. MgtE is a Mg(2+) channel distributed in all domains of life that contributes to the maintenance of cellular Mg(2+) homeostasis. Here we report the high-resolution crystal structures of the transmembrane domain of MgtE, bound to Mg(2+), Mn(2+) and Ca(2+). The high-resolution Mg(2+)-bound crystal structure clearly visualized the hydrated Mg(2+) ion within its selectivity filter. Based on those structures and biochemical analyses, we propose a cation selectivity mechanism for MgtE in which the geometry of the hydration shell of the fully hydrated Mg(2+) ion is recognized by the side-chain carboxylate groups in the selectivity filter. This is in contrast to the K(+)-selective filter of KcsA, which recognizes a dehydrated K(+) ion. Our results further revealed a cation-binding site on the periplasmic side, which regulate channel opening and prevents conduction of near-cognate cations.

  16. Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.

    PubMed

    Kim, Han Sol; Li, Hongliang; Kim, Hye Won; Shin, Sung Eun; Choi, Il-Whan; Firth, Amy L; Bang, Hyoweon; Bae, Young Min; Park, Won Sun

    2016-12-01

    We examined the effects of the selective serotonin reuptake inhibitor (SSRI) sertraline on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells using the voltage-clamp technique. Sertraline decreased the Kv channel current in a dose-dependent manner, with an IC50 value of 0.18 mu M and a slope value (Hill coefficient) of 0.61. Although the application of 1 mu M sertraline did not affect the steady-state activation curves, sertraline caused a significant, negative shift in the inactivation curves. Pretreatment with another SSRI, paroxetine, had no significant effect on Kv currents and did not alter the inhibitory effects of sertraline on Kv currents. From these results, we concluded that sertraline dose-dependently inhibited Kv currents independently of serotonin reuptake inhibition by shifting inactivation curves to a more negative potential.

  17. An analysis of a TDMA channel using stop-and-wait, block, and select-and-repeat ARQ error control

    NASA Astrophysics Data System (ADS)

    Saeki, B. H.; Rubin, I.

    1982-05-01

    In this paper, the multiaccess broadcast communication channel operating under a TDMA control discipline and employing an ARQ scheme is examined. The generating function of the message delay distribution is derived. The effects of nonzero bit error rates on multipacket messages under several stop-and-wait and block ARQ systems are incorporated. Numerical results for the steady-state mean and variance of the message delay are presented for a stationary transmission error process model in which errors occur as independent events. Results for this channel under a select-and-repeat ARQ system are developed for single packet messages. Stability requirements are stated, useful bounds on the average message delay at steady state are derived, and numerical examples are presented.

  18. Recent characterizations of MscS and its homologs provide insight into the basis of ion selectivity in mechanosensitive channels.

    PubMed

    Maksaev, Grigory; Haswell, Elizabeth S

    2013-01-01

    The bacterial mechanosensitive channel MscS provides an excellent model system for the study of mechanosensitivity and for investigations into the cellular response to hypoosmotic shock. Numerous studies have elucidated the structure, function and gating mechanism of Escherichia coli MscS, providing a wealth of information for the comparative analysis of MscS family members in bacteria, archaea, fungi and plants. We recently reported the electrophysiological characterization of MscS-Like (MSL)10, a MscS homolog from the model flowering plant Arabidopsis thaliana. Here we summarize our results and briefly compare MSL10 to previously described members of the MscS family. Finally, we comment on how this and other recently published studies illuminate the possible mechanisms by which ion selectivity is accomplished in this fascinating family of channels.

  19. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells.

    PubMed

    Lo, Wan-Lin; Donermeyer, David L; Allen, Paul M

    2012-09-01

    The sustained entry of Ca(2+) into CD4(+)CD8(+) double-positive thymocytes is required for positive selection. Here we identified a voltage-gated Na(+) channel (VGSC) that was essential for positive selection of CD4(+) T cells. Pharmacological inhibition of VGSC activity inhibited the sustained Ca(2+) influx induced by positively selecting ligands and the in vitro positive selection of CD4(+) but not CD8(+) T cells. In vivo short hairpin RNA (shRNA)-mediated knockdown of the gene encoding a regulatory β-subunit of a VGSC specifically inhibited the positive selection of CD4(+) T cells. Ectopic expression of VGSC in peripheral AND CD4(+) T cells bestowed the ability to respond to a positively selecting ligand, which directly demonstrated that VGSC expression was responsible for the enhanced sensitivity. Thus, active VGSCs in thymocytes provide a mechanism by which a weak positive selection signal can induce the sustained Ca(2+) signals required for CD4(+) T cell development.

  20. Highly Ca2+-selective TRPM channels regulate IP3-dependent oscillatory Ca2+ signaling in the C. elegans intestine.

    PubMed

    Xing, Juan; Yan, Xiaohui; Estevez, Ana; Strange, Kevin

    2008-03-01

    Posterior body wall muscle contraction (pBoc) in the nematode Caenorhabditis elegans occurs rhythmically every 45-50 s and mediates defecation. pBoc is controlled by inositol-1,4,5-trisphosphate (IP3)-dependent Ca2+ oscillations in the intestine. The intestinal epithelium can be studied by patch clamp electrophysiology, Ca2+ imaging, genome-wide reverse genetic analysis, forward genetics, and molecular biology and thus provides a powerful model to develop an integrated systems level understanding of a nonexcitable cell oscillatory Ca2+ signaling pathway. Intestinal cells express an outwardly rectifying Ca2+ (ORCa) current with biophysical properties resembling those of TRPM channels. Two TRPM homologues, GON-2 and GTL-1, are expressed in the intestine. Using deletion and severe loss-of-function alleles of the gtl-1 and gon-2 genes, we demonstrate here that GON-2 and GTL-1 are both required for maintaining rhythmic pBoc and intestinal Ca2+ oscillations. Loss of GTL-l and GON-2 function inhibits I(ORCa) approximately 70% and approximately 90%, respectively. I(ORCa) is undetectable in gon-2;gtl-1 double mutant cells. These results demonstrate that (a) both gon-2 and gtl-1 are required for ORCa channel function, and (b) GON-2 and GTL-1 can function independently as ion channels, but that their functions in mediating I(ORCa) are interdependent. I(ORCa), I(GON-2), and I(GTL-1) have nearly identical biophysical properties. Importantly, all three channels are at least 60-fold more permeable to Ca2+ than Na+. Epistasis analysis suggests that GON-2 and GTL-1 function in the IP3 signaling pathway to regulate intestinal Ca2+ oscillations. We postulate that GON-2 and GTL-1 form heteromeric ORCa channels that mediate selective Ca2+ influx and function to regulate IP3 receptor activity and possibly to refill ER Ca2+ stores.

  1. Doubly slanted layer structures in holographic gelatin emulsions: solar concentrators

    NASA Astrophysics Data System (ADS)

    Hung, Jenny; Chan, Po Shan; Sun, Caiming; Wing Ho, Choi; Tam, Wing Yim

    2010-04-01

    We have fabricated doubly slanted layer structures in holographic gelatin emulsions using a double-exposure two-beam interference from two light sources with different wavelengths. The doubly slanted layers, with different spacings and overlapping with each other, are fabricated such that they are slanted in opposite directions making a 30° angle with the holographic plate. The doubly slanted layer structures exhibit photonic stop bands corresponding to the two layered structures. More importantly, diffracted light beams from the slanted layers travel in different directions and emerge, through internal reflections, at the opposite edges of the gelatin plate. The doubly slanted layer structures could be used as solar concentrators such that sunlight is separated into different components and steered directly to photovoltaics with the corresponding wavelength sensitivities to enhance energy conversion efficiency.

  2. Signatures of doubly-charged Higgsinos at colliders

    SciTech Connect

    Demir, D. A.; Frank, M.; Turan, I.; Huitu, K.; Rai, S. K.

    2008-11-23

    Several supersymmetric models with extended gauge structures predict light doubly-charged Higgsinos. Their distinctive signature at the large hadron collider is highlighted by studying its production and decay characteristics.

  3. Masses and axial currents of the doubly charmed baryons

    NASA Astrophysics Data System (ADS)

    Sun, Zhi-Feng; Liu, Zhan-Wei; Liu, Xiang; Zhu, Shi-Lin

    2015-05-01

    The chiral dynamics of the doubly heavy baryons is solely governed by the light quark. In this paper, we have derived the chiral corrections to the mass of the doubly heavy baryons up to N3LO . The mass splitting of Ξc c and Ωc c at the N2LO depends on one unknown low energy constant c7. By fitting the lattice masses of Ξc c(3520 ), we estimate the mass of Ωc c to be around 3.726 GeV. Moreover, we have also performed a systematical analysis of the chiral corrections to the axial currents and axial charges of the doubly heavy baryons. The chiral structure and analytical expressions will be very useful to the chiral extrapolations of the future lattice QCD simulations of the doubly heavy baryons.

  4. A Single P-loop Glutamate Point Mutation to either Lysine or Arginine Switches the Cation–Anion Selectivity of the CNGA2 Channel

    PubMed Central

    Qu, Wei; Moorhouse, Andrew J.; Chandra, Meenak; Pierce, Kerrie D.; Lewis, Trevor M.; Barry, Peter H.

    2006-01-01

    Cyclic nucleotide-gated (CNG) channels play a critical role in olfactory and visual transduction. Site-directed mutagenesis and inside-out patch-clamp recordings were used to investigate ion permeation and selectivity in two mutant homomeric rat olfactory CNGA2 channels expressed in HEK293 cells. A single point mutation of the negatively charged pore loop (P-loop) glutamate (E342) to either a positively charged lysine or arginine resulted in functional channels, which consistently responded to cGMP, although the currents were generally extremely small. The concentration–response curve of the lysine mutant channel was very similar to that of wild-type (WT) channels, suggesting no major structural alteration to the mutant channels. Reversal potential measurements, during cytoplasmic NaCl dilutions, showed that the lysine and the arginine mutations switched the selectivity of the channel from cations (PCl/PNa = 0.07 [WT]) to anions (PCl/PNa = 14 [Lys] or 10 [Arg]). Relative anion permeability sequences for the two mutant channels, measured with bi-ionic substitutions, were NO3− > I− > Br− > Cl− > F− > acetate−, the same as those obtained for anion-selective GABA and glycine channels. The mutant channels also seem to have an extremely small single-channel conductance, measured using noise analysis of about 1–2 pS, compared to a WT value of about 29 pS. The results showed that it is predominantly the charge of the E342 residue in the P-loop, rather than the pore helix dipoles, which controls the cation–anion selectivity of this channel. However, the outward rectification displayed by both mutant channels in symmetrical NaCl solutions suggests that the negative ends of the pore helix dipoles may play a role in reducing the outward movement of Cl− ions through these anion-selective channels. These results have potential implications for the determinants of anion–cation selectivity in the large family of P-loop–containing channels. PMID:16533895

  5. Origins of Proton Transport Behavior from Selectivity Domain Mutations of the Aquaporin-1 Channel

    PubMed Central

    Chen, Hanning; Wu, Yujie; Voth, Gregory A.

    2006-01-01

    The permeation free-energy profile and maximum ion conductance of proton transport along the channel of three aquaporin-1 (AQP1) mutants (H180A/R195V, H180A, and R195V) are calculated via molecular dynamics simulations and Poisson-Nernst-Planck theory. The proton dynamics was described by the multistate empirical valence bond (MS-EVB) model. The results reveal three major contributions to the overall free-energy barrier for proton transport in AQP1: 1), the bipolar field, 2), the electrostatic repulsion due to the Arg-195 residue, and 3), the dehydration penalty due to the narrow channel pore. The double mutation (H180A/R195V) drastically drops the overall free-energy barrier by roughly 20 kcal/mol via simultaneously relaxing the direct electrostatic interaction (by R195V) and dehydration effect (by H180A). PMID:16581846

  6. Doubly Fed Induction Machine Control For Wind Energy Conversion System

    DTIC Science & Technology

    2009-06-01

    Induction Generator (DFIG), Voltage Source Inverter (VSI), Space Vector Modulation (SVM), Wind Turbine, Field Programmable Gate Array ( FPGA ), Wind...basics of using a doubly-fed induction generator (DFIG) to convert the mechanical energy of the wind into useful electrical power that can be used to...thesis covers the basics of using a doubly-fed induction generator (DFIG) to convert the mechanical energy of the wind into useful electrical power

  7. Searching for doubly-charged Higgs bosons at future colliders

    SciTech Connect

    Gunion, J.F.; Loomis, C.; Pitts, K.T.

    1996-10-01

    Doubly-charged Higgs bosons ({Delta}{sup --}/{Delta}{sup ++}) appear in several extensions to the Standard Model and can be relatively light. We review the theoretical motivation for these states and present a study of the discovery reach in future runs of the Fermilab Tevatron for pair-produced doubly-charged Higgs bosons decaying to like-sign lepton pairs. We also comment on the discovery potential at other future colliders. 16 refs., 3 figs., 1 tab.

  8. On Frequency Offset Estimation Using the iNET Preamble in Frequency Selective Fading Channels

    DTIC Science & Technology

    2014-03-01

    ASM fields; (bottom) the relationship between the indexes of the received samples r(n), the signal samples s(n), the preamble samples p (n) and the short...frequency offset estimators for SOQPSK-TG equipped with the iNET preamble and operating in ISI channels. Four of the five estimators exam - ined here are...sync marker ( ASM ), and data bits (an LDPC codeword). The availability of a preamble introduces the possibility of data-aided synchro- nization in

  9. Data from Channel-Change Monitoring at Selected Sites in Maricopa County, Arizona, 1997-2002

    DTIC Science & Technology

    2004-01-01

    the gaging station but decreases in height upstream. The right bank is 5–7 ft high, slopes gently, and is vegetated with palo verde trees...channel, which constitute the flood plain, are covered with scattered tamarisk, palo verde , and other bushes and shrubs. The left bank is a man-made...County, on the left bank, 400 ft downstream from the Interstate 8 bridge, 29 mi west of Casa Grande, 28 mi east of Gila Bend, and 18 mi west of

  10. A K(+)-selective CNG channel orchestrates Ca(2+) signalling in zebrafish sperm.

    PubMed

    Fechner, Sylvia; Alvarez, Luis; Bönigk, Wolfgang; Müller, Astrid; Berger, Thomas K; Pascal, Rene; Trötschel, Christian; Poetsch, Ansgar; Stölting, Gabriel; Siegfried, Kellee R; Kremmer, Elisabeth; Seifert, Reinhard; Kaupp, U Benjamin

    2015-12-09

    Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca(2+) signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K(+) channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca(2+) influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca(2+) entry. Ca(2+) induces spinning-like swimming, different from swimming of sperm from other species. The "spinning" mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization.

  11. A K+-selective CNG channel orchestrates Ca2+ signalling in zebrafish sperm

    PubMed Central

    Fechner, Sylvia; Alvarez, Luis; Bönigk, Wolfgang; Müller, Astrid; Berger, Thomas K; Pascal, Rene; Trötschel, Christian; Poetsch, Ansgar; Stölting, Gabriel; Siegfried, Kellee R; Kremmer, Elisabeth; Seifert, Reinhard; Kaupp, U Benjamin

    2015-01-01

    Calcium in the flagellum controls sperm navigation. In sperm of marine invertebrates and mammals, Ca2+ signalling has been intensely studied, whereas for fish little is known. In sea urchin sperm, a cyclic nucleotide-gated K+ channel (CNGK) mediates a cGMP-induced hyperpolarization that evokes Ca2+ influx. Here, we identify in sperm of the freshwater fish Danio rerio a novel CNGK family member featuring non-canonical properties. It is located in the sperm head rather than the flagellum and is controlled by intracellular pH, but not cyclic nucleotides. Alkalization hyperpolarizes sperm and produces Ca2+ entry. Ca2+ induces spinning-like swimming, different from swimming of sperm from other species. The “spinning” mode probably guides sperm into the micropyle, a narrow entrance on the surface of fish eggs. A picture is emerging of sperm channel orthologues that employ different activation mechanisms and serve different functions. The channel inventories probably reflect adaptations to species-specific challenges during fertilization. DOI: http://dx.doi.org/10.7554/eLife.07624.001 PMID:26650356

  12. Effect of amiloride on the poorly selective cation channel of larval bullfrog skin.

    PubMed

    Hillyard, S D; Van Driessche, W

    1989-01-01

    A small, inward-directed, short-circuit current (SCC) was measured across the isolated skin of larval bullfrogs (Rana catesbeiana) when either NaCl or KCl Ringer solution bathed the mucosal surface. The addition of amiloride, in concentrations of 1-100 microM, produced a stepwise increase in SCC. As SCC values became maximally elevated by amiloride, the plateau value (So) of the Lorentzian component in the power-density spectrum increased, whereas the corner frequency (fc) decreased. This agonist effect of amiloride can be explained by an increase in the open probability and possibly the single-channel current of the larval channel. When the amiloride concentration was increased above 100 microM, the SCC values declined progressively but usually remained above pretreatment values. This suggests an antagonist effect of amiloride that is concurrent with the agonist effect. The removal of Ca2+ from the mucosal Ringers increased SCC in conjunction with an increase in So and a decrease in fc. Under these conditions, the maximal agonist effect of amiloride was observed at concentrations of 10-20 microM. Ca2+ thus exerts an inhibitory effect on the larval cation channel that interferes with the agonist effect of amiloride. The addition of Ba2+ to Ca2+-free preparations lowered SCC and reduced the agonist effect of amiloride.

  13. Data selection criteria in star-based monitoring of GOES imager visible-channel responsivities

    NASA Astrophysics Data System (ADS)

    Chang, I.-Lok; Crosby, David; Dean, Charles; Weinreb, Michael; Baltimore, Perry; Baucom, Jeanette; Han, Dejiang

    2004-10-01

    Monitoring the responsivities of the visible channels of the operational Geostationary Operational Environmental Satellites (GOES) is an on-going effort at NOAA. Various techniques are being used. In this paper we describe the technique based on the analysis of star signals that are used in the GOES Orbit and Attitude Tracking System (OATS) for satellite attitude and orbit determination. Time series of OATS star observations give information on the degradation of the detectors of a visible channel. Investigations of star data from the past three years have led to several modifications of the method we initially used to calculate the exponential degradation coefficient of a star-signal time series. First we observed that different patterns of detector output versus time result when star images drift across the detector array along different trajectories. We found that certain trajectories should be rejected in the data analysis. We found also that some detector-dependent weighting coefficients used in the OATS analysis tend to scatter the star signals measured by different detectors. We present a set of modifications to our star monitoring algorithms for resolving such problems. Other simple enhancements on the algorithms will also be described. With these modifications, the time series of the star signals show less scatter. This allows for more confidence in the estimated degradation rates and a more realistic statistical analysis on the extent of uncertainty in those rates. The resulting time series and estimated degradation rates for the visible channels of GOES-8 and GOES-10 Imagers will be presented.

  14. Developing a comparative docking protocol for the prediction of peptide selectivity profiles: investigation of potassium channel toxins.

    PubMed

    Chen, Po-Chia; Kuyucak, Serdar

    2012-02-01

    During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to "predict" the various selectivity profiles of several major αKTX scorpion toxin families versus K(v)1.1, K(v)1.2 and K(v)1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and K(v)1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness.

  15. Developing a Comparative Docking Protocol for the Prediction of Peptide Selectivity Profiles: Investigation of Potassium Channel Toxins

    PubMed Central

    Chen, Po-Chia; Kuyucak, Serdar

    2012-01-01

    During the development of selective peptides against highly homologous targets, a reliable tool is sought that can predict information on both mechanisms of binding and relative affinities. These tools must first be tested on known profiles before application on novel therapeutic candidates. We therefore present a comparative docking protocol in HADDOCK using critical motifs, and use it to “predict” the various selectivity profiles of several major αKTX scorpion toxin families versus Kv1.1, Kv1.2 and Kv1.3. By correlating results across toxins of similar profiles, a comprehensive set of functional residues can be identified. Reasonable models of channel-toxin interactions can be then drawn that are consistent with known affinity and mutagenesis. Without biological information on the interaction, HADDOCK reproduces mechanisms underlying the universal binding of αKTX-2 toxins, and Kv1.3 selectivity of αKTX-3 toxins. The addition of constraints encouraging the critical lysine insertion confirms these findings, and gives analogous explanations for other families, including models of partial pore-block in αKTX-6. While qualitatively informative, the HADDOCK scoring function is not yet sufficient for accurate affinity-ranking. False minima in low-affinity complexes often resemble true binding in high-affinity complexes, despite steric/conformational penalties apparent from visual inspection. This contamination significantly complicates energetic analysis, although it is usually possible to obtain correct ranking via careful interpretation of binding-well characteristics and elimination of false positives. Aside from adaptations to the broader potassium channel family, we suggest that this strategy of comparative docking can be extended to other channels of interest with known structure, especially in cases where a critical motif exists to improve docking effectiveness. PMID:22474570

  16. Gas-Phase Reactions of Doubly Charged Lanthanide Cations with Alkanes and Alkenes. Trends in Metal(2+) Reactivity

    SciTech Connect

    Gibson, John K.; Marcalo, Joaquim; Santos, Marta; Pires de Matos, Antonio; Haire, Richard G.

    2008-12-08

    The gas-phase reactivity of doubly-charged lanthanide cations, Ln2+ (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), with alkanes (methane, ethane, propane, n-butane) and alkenes (ethene, propene, 1-butene) was studied by Fourier transform ion cyclotron resonance mass spectrometry. The reaction products consisted of different combinations of doubly-charged organometallic ions?adducts or species formed via metal-ion-induced hydrogen, dihydrogen, alkyl, or alkane eliminations from the hydrocarbons?and singly-charged ions that resulted from electron, hydride, or methide transfers from the hydrocarbons to the metal ions. The only lanthanide cations capable of activating the hydrocarbons to form doubly-charged organometallic ions were La2+, Ce2+, Gd2+, and Tb2+, which have ground-state or low-lying d1 electronic configurations. Lu2+, with an accessible d1 electronic configuration but a rather high electron affinity, reacted only through transfer channels. The remaining Ln2+ reacted via transfer channels or adduct formation. The different accessibilities of d1 electronic configurations and the range of electron affinities of the Ln2+ cations allowed for a detailed analysis of the trends for metal(2+) reactivity and the conditions for occurrence of bond activation, adduct formation, and electron, hydride, and methide transfers.

  17. Mechanical Properties of Doubly Stabilized Microtubule Filaments

    PubMed Central

    Hawkins, Taviare L.; Sept, David; Mogessie, Binyam; Straube, Anne; Ross, Jennifer L.

    2013-01-01

    Microtubules are cytoskeletal filaments responsible for cell morphology and intracellular organization. Their dynamical and mechanical properties are regulated through the nucleotide state of the tubulin dimers and the binding of drugs and/or microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics or whether one effect dominates another is not clear. This is especially important for the chemotherapeutic drug Taxol, an important anticancer agent and the only known stabilizer that reduces the rigidity of microtubules. First, we ask whether Taxol will combine additively with another stabilizer or whether one stabilizer will dominate another. We call microtubules in the presence of Taxol and another stabilizer, doubly stabilized. Second, since Taxol is often added to a number of cell types for therapeutic purposes, it is important from a biomedical perspective to understand how Taxol added to these systems affects the mechanical properties in treated cells. To address these questions, we use the method of freely fluctuating filaments with our recently developed analysis technique of bootstrapping to determine the distribution of persistence lengths of a large population of microtubules treated with different stabilizers, including Taxol, guanosine-5′ [(α, β)-methyleno] triphosphate, guanosine-5′-O-(3-thiotriphosphate), tau, and MAP4. We find that combinations of these stabilizers have novel effects on the mechanical properties of microtubules. PMID:23561528

  18. Learning doubly sparse transforms for images.

    PubMed

    Ravishankar, Saiprasad; Bresler, Yoram

    2013-12-01

    The sparsity of images in a transform domain or dictionary has been exploited in many applications in image processing. For example, analytical sparsifying transforms, such as wavelets and discrete cosine transform (DCT), have been extensively used in compression standards. Recently, synthesis sparsifying dictionaries that are directly adapted to the data have become popular especially in applications such as image denoising. Following up on our recent research, where we introduced the idea of learning square sparsifying transforms, we propose here novel problem formulations for learning doubly sparse transforms for signals or image patches. These transforms are a product of a fixed, fast analytic transform such as the DCT, and an adaptive matrix constrained to be sparse. Such transforms can be learnt, stored, and implemented efficiently. We show the superior promise of our learnt transforms as compared with analytical sparsifying transforms such as the DCT for image representation. We also show promising performance in image denoising that compares favorably with approaches involving learnt synthesis dictionaries such as the K-SVD algorithm. The proposed approach is also much faster than K-SVD denoising.

  19. Aromaticity of the doubly charged [8]circulenes.

    PubMed

    Baryshnikov, Gleb V; Valiev, Rashid R; Karaush, Nataliya N; Sundholm, Dage; Minaev, Boris F

    2016-04-07

    Magnetically induced current densities and current pathways have been calculated for a series of fully annelated dicationic and dianionic tetraphenylenes, which are also named [8]circulenes. The gauge including magnetically induced current (GIMIC) method has been employed for calculating the current density susceptibilities. The aromatic character and current pathways are deduced from the calculated current density susceptibilities showing that the neutral [8]circulenes have two concentric pathways with aromatic and antiaromatic character, respectively. The inner octatetraene core (the hub) is found to sustain a paratropic (antiaromatic) ring current, whereas the ring current along the outer part of the macrocycle (the rim) is diatropic (aromatic). The neutral [8]circulenes can be considered nonaromatic, because the sum of the ring-current strengths of the hub and the rim almost vanishes. The aromatic character of the doubly charged [8]circulenes is completely different: the dianionic [8]circulenes and the OC-, CH-, CH2-, SiH-, GeH-, SiH2-, and GeH2-containing dicationic species sustain net diatropic ring currents i.e., they are aromatic, whereas the O-, S-, Se-, NH-, PH- and AsH-containing dicationic [8]circulenes are strongly antiaromatic. The present study also shows that GIMIC calculations on the [8]circulenes provide more accurate information about the aromatic character than that obtained using local indices such as nuclear-independent chemical shifts (NICSs) and (1)H NMR chemical shifts.

  20. Mechanical properties of doubly stabilized microtubule filaments.

    PubMed

    Hawkins, Taviare L; Sept, David; Mogessie, Binyam; Straube, Anne; Ross, Jennifer L

    2013-04-02

    Microtubules are cytoskeletal filaments responsible for cell morphology and intracellular organization. Their dynamical and mechanical properties are regulated through the nucleotide state of the tubulin dimers and the binding of drugs and/or microtubule-associated proteins. Interestingly, microtubule-stabilizing factors have differential effects on microtubule mechanics, but whether stabilizers have cumulative effects on mechanics or whether one effect dominates another is not clear. This is especially important for the chemotherapeutic drug Taxol, an important anticancer agent and the only known stabilizer that reduces the rigidity of microtubules. First, we ask whether Taxol will combine additively with another stabilizer or whether one stabilizer will dominate another. We call microtubules in the presence of Taxol and another stabilizer, doubly stabilized. Second, since Taxol is often added to a number of cell types for therapeutic purposes, it is important from a biomedical perspective to understand how Taxol added to these systems affects the mechanical properties in treated cells. To address these questions, we use the method of freely fluctuating filaments with our recently developed analysis technique of bootstrapping to determine the distribution of persistence lengths of a large population of microtubules treated with different stabilizers, including Taxol, guanosine-5' [(α, β)-methyleno] triphosphate, guanosine-5'-O-(3-thiotriphosphate), tau, and MAP4. We find that combinations of these stabilizers have novel effects on the mechanical properties of microtubules.

  1. Affinity purification of the voltage-sensitive sodium channel from electroplax with resins selective for sialic acid

    SciTech Connect

    James, W.M.; Emerick, M.C.; Agnew, W.S. )

    1989-07-11

    The voltage-sensitive sodium channel present in the eel (Electrophorus electricus) has an unusually high content of sialic acid, including {alpha}-(2{yields}8)-linked polysialic acid, not found in other electroplax membrane glycopeptides. Lectins from Limax flavus (LFA) and wheat germ (WGA) proved the most effective of 11 lectin resins tried. The most selective resin was prepared from IgM antibodies against Neisseria meningitidis {alpha}-(2{yields}8)-polysialic acid which were affinity purified and coupled to Sepharose 4B. The sodium channel was found to bind to WGA, LFA, and IgM resins and was readily eluted with the appropriate soluble carbohydrates. Experiments with LFA and IgM resins demonstrated binding and unbinding rates and displacement kinetics, which suggest highly specific binding at multiple sites on the sodium channel protein. In preparative-scale purification of protein previously fractionated by anion-exchange chromatography, without stabilizing TTX, high yields were reproducibly obtained. Further, when detergent extracts were prepared from electroplax membranes fractionated by low-speed sedimentation, a single step over the IgM resin provided a 70-fold purification, yielding specific activities of 3,200 pmol of ({sup 3}H)TTX-binding sites/mg of protein and a single polypeptide of {approximately}285,000 Da on SDS-acrylamide gels. No small peptides were observed after this 5-h isolation. The authors describe a cation-dependent stabilization with millimolar levels of monovalent and micromolar levels of divalent species.

  2. Affinity purification of the voltage-sensitive sodium channel from electroplax with resins selective for sialic acid.

    PubMed

    James, W M; Emerick, M C; Agnew, W S

    1989-07-11

    The voltage-sensitive sodium channel present in the eel (Electrophorus electricus) has an unusually high content of sialic acid, including alpha-(2----8)-linked polysialic acid, not found in other electroplax membrane glycopeptides. Lectins from Limax flavus (LFA) and wheat germ (WGA) proved the most effective of 11 lectin resins tried. The most selective resin was prepared from IgM antibodies against Neisseria meningitidis alpha-(2----8)-polysialic acid which were affinity purified and coupled to Sepharose 4B. The sodium channel was found to bind to WGA, LFA, and IgM resins and was readily eluted with the appropriate soluble carbohydrates. Experiments with LFA and IgM resins demonstrated binding and unbinding rates and displacement kinetics, which suggest highly specific binding at multiple sites on the sodium channel protein. In preparative-scale purification of protein previously fractionated by anion-exchange chromatography, without stabilizing TTX, high yields were reproducibly obtained. Further, when detergent extracts were prepared from electroplax membranes fractionated by low-speed sedimentation, a single step over the IgM resin provided a 70-fold purification, yielding specific activities of 3200 pmol of [3H]TTX-binding sites/mg of protein and a single polypeptide of approximately 285,000 Da on SDS-acrylamide gels. No small peptides were observed after this 5-h isolation. We further describe a cation-dependent stabilization with millimolar levels of monovalent and micromolar levels of divalent species.

  3. MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity.

    PubMed

    Santamaria-Herrera, Mireille Aline; Ríos-Pérez, Erick Benjamín; de la Rosa, Juan Antonio Manuel; García-Castañeda, Maricela; Osornio-Garduño, Diana Stephanie; Ramos-Mondragón, Roberto; Mancilla-Percino, Teresa; Avila, Guillermo

    2016-06-15

    In cardiac muscle cells both T-and L-type Ca(2+) channels (TTCCs and LTCCs, respectively) are expressed, and the latter are relevant to a process known as excitation-contraction coupling (ECC). Evidence obtained from docking studies suggests that isoindolines derived from α-amino acids bind to the LTCC CaV1.2. In the present study, we investigated whether methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP), which is derived from L-leucine, modulates both Ca(2+) channels and ECC. To this end, mechanical properties, as well as Ca(2+) transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on CaV1.2 (transiently expressed in 293T/17 cells) were also studied. In this system, evidence was found for an inhibitory action that develops and recovers in min, with an IC50 of 450µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca(2+) transients, contractions, and window currents of LTCCs were all reduced more strongly in atrial cells. Interestingly, while the modulation of LTCCs was state-independent in these cells, it was state-dependent, and dual, on the ventricular ones. Furthermore, practically all of the ventricular LTCCs were closed at resting membrane potentials. This could explain their resistance to MDIMP, as they were affected in only open or inactivated states. All these features in turn explain the preferential down-regulation of the atrial ECC. Thus, our results support the view that isoindolines bind to Ca(2+) channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Alpha-helical hydrophobic polypeptides form proton-selective channels in lipid bilayers

    NASA Technical Reports Server (NTRS)

    Oliver, A. E.; Deamer, D. W.

    1994-01-01

    Proton translocation is important in membrane-mediated processes such as ATP-dependent proton pumps, ATP synthesis, bacteriorhodopsin, and cytochrome oxidase function. The fundamental mechanism, however, is poorly understood. To test the theoretical possibility that bundles of hydrophobic alpha-helices could provide a low energy pathway for ion translocation through the lipid bilayer, polyamino acids were incorporated into extruded liposomes and planar lipid membranes, and proton translocation was measured. Liposomes with incorporated long-chain poly-L-alanine or poly-L-leucine were found to have proton permeability coefficients 5 to 7 times greater than control liposomes, whereas short-chain polyamino acids had relatively little effect. Potassium permeability was not increased markedly by any of the polyamino acids tested. Analytical thin layer chromatography measurements of lipid content and a fluorescamine assay for amino acids showed that there were approximately 135 polyleucine or 65 polyalanine molecules associated with each liposome. Fourier transform infrared spectroscopy indicated that a major fraction of the long-chain hydrophobic peptides existed in an alpha-helical conformation. Single-channel recording in both 0.1 N HCl and 0.1 M KCl was also used to determine whether proton-conducting channels formed in planar lipid membranes (phosphatidylcholine/phosphatidylethanolamine, 1:1). Poly-L-leucine and poly-L-alanine in HCl caused a 10- to 30-fold increase in frequency of conductive events compared to that seen in KCl or by the other polyamino acids in either solution. This finding correlates well with the liposome observations in which these two polyamino acids caused the largest increase in membrane proton permeability but had little effect on potassium permeability. Poly-L-leucine was considerably more conductive than poly-L-alanine due primarily to larger event amplitudes and, to a lesser extent, a higher event frequency. Poly-L-leucine caused two

  5. Alpha-helical hydrophobic polypeptides form proton-selective channels in lipid bilayers

    NASA Technical Reports Server (NTRS)

    Oliver, A. E.; Deamer, D. W.

    1994-01-01

    Proton translocation is important in membrane-mediated processes such as ATP-dependent proton pumps, ATP synthesis, bacteriorhodopsin, and cytochrome oxidase function. The fundamental mechanism, however, is poorly understood. To test the theoretical possibility that bundles of hydrophobic alpha-helices could provide a low energy pathway for ion translocation through the lipid bilayer, polyamino acids were incorporated into extruded liposomes and planar lipid membranes, and proton translocation was measured. Liposomes with incorporated long-chain poly-L-alanine or poly-L-leucine were found to have proton permeability coefficients 5 to 7 times greater than control liposomes, whereas short-chain polyamino acids had relatively little effect. Potassium permeability was not increased markedly by any of the polyamino acids tested. Analytical thin layer chromatography measurements of lipid content and a fluorescamine assay for amino acids showed that there were approximately 135 polyleucine or 65 polyalanine molecules associated with each liposome. Fourier transform infrared spectroscopy indicated that a major fraction of the long-chain hydrophobic peptides existed in an alpha-helical conformation. Single-channel recording in both 0.1 N HCl and 0.1 M KCl was also used to determine whether proton-conducting channels formed in planar lipid membranes (phosphatidylcholine/phosphatidylethanolamine, 1:1). Poly-L-leucine and poly-L-alanine in HCl caused a 10- to 30-fold increase in frequency of conductive events compared to that seen in KCl or by the other polyamino acids in either solution. This finding correlates well with the liposome observations in which these two polyamino acids caused the largest increase in membrane proton permeability but had little effect on potassium permeability. Poly-L-leucine was considerably more conductive than poly-L-alanine due primarily to larger event amplitudes and, to a lesser extent, a higher event frequency. Poly-L-leucine caused two

  6. Discovery and evaluation of selective N-type calcium channel blockers: 6-unsubstituted-1,4-dihydropyridine-5-carboxylic acid derivatives.

    PubMed

    Yamamoto, Takashi; Niwa, Seiji; Tokumasu, Munetaka; Onishi, Tomoyuki; Ohno, Seiji; Hagihara, Masako; Koganei, Hajime; Fujita, Shin-ichi; Takeda, Tomoko; Saitou, Yuki; Iwayama, Satoshi; Takahara, Akira; Iwata, Seinosuke; Shoji, Masataka

    2012-06-01

    A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.

  7. Enhancing Performance of a Hybrid EEG-fNIRS System Using Channel Selection and Early Temporal Features

    PubMed Central

    Li, Rihui; Potter, Thomas; Huang, Weitian; Zhang, Yingchun

    2017-01-01

    Brain-Computer Interface (BCI) techniques hold a great promise for neuroprosthetic applications. A desirable BCI system should be portable, minimally invasive, and feature high classification accuracy and efficiency. As two commonly used non-invasive brain imaging modalities, Electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) BCI system have often been incorporated in the development of hybrid BCI systems, largely due to their complimentary properties. In this study, we aimed to investigate whether the early temporal information extracted from singular EEG and fNIRS channels on each hemisphere can be used to enhance the accuracy and efficiency of a hybrid EEG-fNIRS BCI system. Eleven healthy volunteers were recruited and underwent simultaneous EEG-fNIRS recording during a motor execution task that included left and right hand movements. Singular EEG and fNIRS channels corresponding to the motor cortices of each hemisphere were selected using a general linear model. Early temporal information was extracted from the EEG channel (0–1 s) along with initial hemodynamic dip information from fNIRS (0–2 s) for classification using a support vector machine (SVM). Results demonstrated a lofty classification accuracy using a minimal number of channels and features derived from early temporal information. In conclusion, a hybrid EEG-fNIRS BCI system can achieve higher classification accuracy (91.02 ± 4.08%) and efficiency by integrating their complimentary properties, compared to using EEG (85.64 ± 7.4%) or fNIRS alone (85.55 ± 10.72%). Such a hybrid system can also achieve minimal response lag in application by focusing on rapidly-evolving brain dynamics. PMID:28966581

  8. A plasma membrane-targeted cytosolic domain of STIM1 selectively activates ARC channels, an arachidonate-regulated store-independent Orai channel.

    PubMed

    Thompson, Jill L; Shuttleworth, Trevor J

    2012-01-01

    The Orai family of calcium channels includes the store-operated CRAC channels and store-independent, arachidonic acid (AA)-regulated ARC channels. Both depend on STIM1 for their activation but, whereas CRAC channel activation involves sensing the depletion of intracellular calcium stores via a luminal N terminal EF-hand of STIM1 in the endoplasmic reticulum (ER) membrane, ARC channels are exclusively activated by the pool of STIM1 that constitutively resides in the plasma membrane (PM). Here, the EF-hand is extracellular and unlikely to ever lose its bound calcium, suggesting that STIM1-dependent activation of ARC channels is very different from that of CRAC channels. We now show that attachment of the cytosolic portion of STIM1 to the inner face of the PM via an N terminal Lck-domain sequence is sufficient to enable normal AA-dependent activation of ARC channels, while failing to allow activation of store-operated CRAC channels. Introduction of a point mutation within the Lck-domain resulted in the loss of both PM localization and ARC channel activation. Reversing the orientation of the PM-anchored STIM1 C terminus via a C-terminal CAAX-box fails to support either CRAC or ARC channel activation. Finally, the Lck-anchored STIM1 C-terminal domain also enabled the exclusive activation of the ARC channels following physiological agonist addition. These data demonstrate that simple tethering of the cytosolic C-terminal domain of STIM1 to the inner face of the PM is sufficient to allow the full, normal and exclusive activation of ARC channels, and that the N-terminal regions of STIM1 (including the EF-hand domain) play no significant role in this activation.

  9. Nonlinear Electroosmosis and Biomolecule Electrokinetic Trapping Induced by Ion Selective Nanofluidic Channels

    NASA Astrophysics Data System (ADS)

    Wang, Ying-Chih; Han, Jongyoon

    2006-03-01

    This paper describes a nanofluidic device that can concentrate dilute biomolecule by electrokinetic trapping mechanism. This device has nanofluidic channels with a depth down to 40 nm, therefore, having significant Debye layer overlap. Depending on the strength of the applied potential across the nanochannel, one can observe phenomena such as concentration polarization; charge depletion and nonlinear electrokinetic flow in the adjacent microfluidic channel using fluorescent microscopy. By manipulating the electric field, the device can generate an extended space charge region, maintained for several hours, within a microchannel as a mean to collect and trap biomolecules. Our studies demonstrate such device can achieve up to 10 million fold sample preconcentration within 30 minutes. Besides, if applied a higher potential, a much faster chaotic flow can be seen in the microchannel adjacent to nanochannels. This kind of nonlinear electrokinetic flow is often called the electroosmosis of the second kind or induced-charge electroosmosis in electrode and ion exchange membrane studies. The presented device can be used as either a preconcentrator or an injector to other separation and detection systems preferred its performance and integrabilty. Also, it is an ideal experimental platform for studying such nonlinear electrokinetic effects, by directly tracking molecules in situ.

  10. Ultrastructure, pharmacologic inhibition, and transport selectivity of aquaporin channel-forming integral protein in proteoliposomes.

    PubMed

    Zeidel, M L; Nielsen, S; Smith, B L; Ambudkar, S V; Maunsbach, A B; Agre, P

    1994-02-15

    Reconstitution of highly purified aquaporin CHIP (channel-forming integral protein) into proteoliposomes was previously shown to confer high osmotic water permeability (Pf) to the membranes [Zeidel et al. (1992) Biochemistry 31, 7436-7440]. Here we report detailed ultrastructural, pharmacologic, and transport studies of human red cell CHIP in proteoliposomes. Freeze-fracture and transmission electron microscopy revealed a uniform distribution of CHIP which was incorporated into the membranes in both native and inverse orientations. Morphometric analysis of membranes reconstituted at three different concentrations of CHIP revealed that the intramembrane particles correspond to tetramers or possible higher order oligomers, and the Pf increased in direct proportion to the CHIP density. Proteolytic removal of the 4-kDa C-terminal cytoplasmic domain of CHIP did not alter the Pf or oligomerization in red cell membranes. CHIP exhibited a similar conductance for water when reconstituted into membranes of varied lipid compositions. The sensitivities of CHIP-mediated Pf to specific sulfhydryl reagents were identical to known sensitivities of red cell Pf, including a delayed response to p-(chloromercuri)benzenesulfonate. CHIP did not increase the permeability of the proteoliposome membranes to H+/OH- or NH3. These studies demonstrate that CHIP proteoliposomes exhibit all known characteristics of water channels in native red cells and therefore provide a defined system for biophysical analysis of transmembrane water movements.

  11. Selective expression of ligand-gated ion channels in L5 pyramidal cell axons

    PubMed Central

    Christie, Jason M.; Jahr, Craig E.

    2009-01-01

    NMDA receptor (NMDAR)-dependent strengthening of neurotransmitter release has been widely observed, including in layer 5 (L5) pyramidal cells of the visual cortex, and is attributed to the axonal expression of NMDARs. However, we failed to detect NMDAR-mediated depolarizations or Ca2+ entry in L5 pyramidal cell axons when focally stimulated with NMDAR agonists. This suggests that NMDARs are excluded from the axon. In contrast, local GABAAR activation alters axonal excitability indicating that exclusion of ligand-gated ion channels from the axon is not absolute. Because NMDARs are restricted to the dendrite, NMDARs must signal to the axon by an indirect mechanism to alter release. Although subthreshold somatic depolarizations were found to spread electrotonically hundreds of micrometers through the axon, the resulting axonal potential was insufficient to open voltage-sensitive Ca2+ channels (VSCCs). Therefore, if NMDAR-mediated facilitation of release is cell-autonomous, it may depend on voltage signaling but apparently is independent of changes in basal Ca2+. Alternatively, this facilitation may be even less direct, requiring a cascade of events that are merely triggered by NMDAR activation. PMID:19759293

  12. Arabidopsis thaliana cyclic nucleotide gated channel 3 forms a non-selective ion transporter involved in germination and cation transport.

    PubMed

    Gobert, Anthony; Park, Graeme; Amtmann, Anna; Sanders, Dale; Maathuis, Frans J M

    2006-01-01

    The Arabidopsis thaliana genome contains 20 cyclic nucleotide gated channel (CNGC) genes encoding putative non-selective ion channels. Classical and reverse genetic approaches have revealed that two members of this family (CNGC2 and CNGC4) play a role in plant defence responses whereas CNGC1 and CNGC10 may participate in heavy metal and cation transport. Yet, it remains to be resolved how the ion transport attributes of CNGCs are integrated into their physiological function. In this study, CNGC3 is characterized through heterologous expression, GUS- and GFP-reporter gene fusions, and by adopting a reverse genetics approach. A CNGC3-GFP fusion protein shows that it is mainly targeted to the plasma membrane. Promoter GUS studies demonstrate CNGC3 expression predominantly in the cortical and epidermal root cells, but also a ubiquitous presence in shoot tissues. Expression of CNGC3 in yeast indicates it can function as a Na(+) uptake and a K(+) uptake mechanism. cngc3 null mutations decreased seed germination in the presence of NaCl but not KCl. Relative to the wild type, mutant seedling growth is more resistant to the presence of toxic concentrations of NaCl and KCl. The ionic composition and ion uptake characteristics of wild-type and mutant seedlings suggests that the growth advantage in these conditions may be due to restricted ion influx in mutant plants, and that CNGC3 functions in the non-selective uptake of monovalent cations in Arabidopsis root tissue.

  13. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

    PubMed

    Camilleri, Michael; Bharucha, Adil E; Ueno, Ryuji; Burton, Duane; Thomforde, George M; Baxter, Kari; McKinzie, Sanna; Zinsmeister, Alan R

    2006-05-01

    Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

  14. The selectivity of different external binding sites for quaternary ammonium ions in cloned potassium channels.

    PubMed

    Jarolimek, W; Soman, K V; Brown, A M; Alam, M

    1995-09-01

    Tetraethylammonium (TEA) is thought to be the most effective quaternary ammonium (QA) ion blocker at the external site of K+ channels, and small changes to the TEA ion reduce its potency. To examine the properties of the external QA receptor, we applied a variety of QA ions to excised patches from human embryonic kidney cells or Xenopus oocytes transfected with the delayed rectifying K+ channels Kv 2.1 and Kv 3.1. In outside-out patches of Kv 3.1, the relative potencies were TEA > tetrapropylammonium (TPA) > tetrabutylammonium (TBA). In contrast to Kv 3.1, the relative potencies in Kv 2.1 were TBA > TEA > TPA. In Kv 3.1 and Kv 2.1, external tetrapentylammonium (TPeA) blocked K+ currents in a fast, reversible and, in contrast to TEA, time-dependent manner. The external binding of TPeA appeared to be voltage independent, unlike the effects of TPeA applied to inside-out patches. External n-alkyl-triethylammonium compounds (C8, C10 chain length) had a lower affinity than TEA in Kv 3.1, but a higher affinity than TEA in Kv 2.1. In Kv 3.1, the decrease in QA affinity was large when one or two methyl groups were substituted for ethyl groups in TEA, but minor when propyl groups replaced ethyl groups. Changes in the free energy of binding could be correlated to changes in the free energy of hydration of TEA derivatives calculated by continuum methodology. These results reveal a substantial hydrophobic component of external QA ion binding to Kv 2.1, and to a lesser degree to Kv 3.1, in addition to the generally accepted electrostatic interactions. The chain length of hydrophobic TEA derivatives affects the affinity for the hydrophobic binding site, whereas the hydropathy of QA ions determines the electrostatic interaction energy.

  15. TRP Channels

    PubMed Central

    Venkatachalam, Kartik; Montell, Craig

    2011-01-01

    The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease. PMID:17579562

  16. Gain of Imaging Fidelity by Employing a Higher Number of Independent Transmit Channels Together with Slice-Selective Radio-Frequency (RF) Shimming at 7T

    PubMed Central

    Darji, Niravkumar; Patel, Gopesh; Speck, Oliver

    2014-01-01

    Dielectric resonance effects and radio-frequency (RF) power deposition have become challenging issues for magnetic resonance imaging at ultrahigh-field (UHF) strengths. The use of transmit (Tx) coil arrays with independently-driven RF sources using a parallel transmission system is a promising method for alleviating the resulting RF inhomogeneities. In this study, the effect on homogeneity and RF-power when employing a higher number of transmit channels with multi-slice acquisition in vivo at high field strength (7T) is scrutinized. An 8-channel head coil array was driven to emulate circular polarized (CP) and 2-, 4-, and 8-channel independent transmit configurations at 7T. Static RF shimming was employed on human subjects in order to homogenize the B1+ field in the excited volume. Slice-selective and global RF shimming methods were applied with CP and 2-, 4-, and 8-channel transmit channel configurations. RF shimming was performed from CP to 2-, 4-, and 8-channel Tx configurations globally and slice-selectively. Systematic improvement in B1+ homogeneity and/or reduction in RF-power were observed. RF shimming in the human brain with 8-channel transmit and slice-selective shimming yields an increase in B1+ homogeneity of 43% and/or reduces RF-power by 68% when compared with CP global RF shimming at 7T. PMID:28788438

  17. Outage Performance Analysis of Relay Selection Schemes in Wireless Energy Harvesting Cooperative Networks over Non-Identical Rayleigh Fading Channels.

    PubMed

    Do, Nhu Tri; Bao, Vo Nguyen Quoc; An, Beongku

    2016-02-26

    In this paper, we study relay selection in decode-and-forward wireless energy harvesting cooperative networks. In contrast to conventional cooperative networks, the relays harvest energy from the source's radio-frequency radiation and then use that energy to forward the source information. Considering power splitting receiver architecture used at relays to harvest energy, we are concerned with the performance of two popular relay selection schemes, namely, partial relay selection (PRS) scheme and optimal relay selection (ORS) scheme. In particular, we analyze the system performance in terms of outage probability (OP) over independent and non-identical (i.n.i.d.) Rayleigh fading channels. We derive the closed-form approximations for the system outage probabilities of both schemes and validate the analysis by the Monte-Carlo simulation. The numerical results provide comprehensive performance comparison between the PRS and ORS schemes and reveal the effect of wireless energy harvesting on the outage performances of both schemes. Additionally, we also show the advantages and drawbacks of the wireless energy harvesting cooperative networks and compare to the conventional cooperative networks.

  18. The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases.

    PubMed

    Ye, Fang; Hu, Youtian; Yu, Weiwei; Xie, Zili; Hu, Jun; Cao, Zhijian; Li, Wenxin; Wu, Yingliang

    2016-04-19

    The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K⁺ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the "evolutionary" Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel-specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies.

  19. Selective regulation of spontaneous activity of neurons of the deep cerebellar nuclei by N-type calcium channels in juvenile rats.

    PubMed

    Alviña, Karina; Khodakhah, Kamran

    2008-05-15

    The cerebellum coordinates movement and maintains body posture. The main output of the cerebellum is formed by three deep nuclei, which receive direct inhibitory inputs from cerebellar Purkinje cells, and excitatory collaterals from mossy and climbing fibres. Neurons of deep cerebellar nuclei (DCN) are spontaneously active, and disrupting their activity results in severe cerebellar ataxia. It is suggested that voltage-gated calcium channels make a significant contribution to the spontaneous activity of DCN neurons, although the exact identity of these channels is not known. We sought to delineate the functional role and identity of calcium channels that contribute to pacemaking in DCN neurons of juvenile rats. We found that in the majority of cells blockade of calcium currents results in avid high-frequency bursting, consistent with the notion that the net calcium-dependent current in DCN neurons is outward. We showed that the bursting seen in these neurons after block of calcium channels is the consequence of reduced activation of small-conductance calcium-activated (SK) potassium channels. With the use of selective pharmacological blockers we showed that L-, P/Q-, R- and T-type calcium channels do not contribute to the spontaneous activity of DCN neurons. In contrast, blockade of high-threshold N-type calcium channels increased the firing rate and caused the cells to burst. Our results thus suggest a selective coupling of N-type voltage-gated calcium channels with calcium-activated potassium channels in DCN neurons. In addition, we demonstrate the presence of a cadmium-sensitive calcium conductance coupled with SK channels, that is pharmacologically distinct from L-, N-, P/Q-, R- and T-type calcium channels.

  20. Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification*

    PubMed Central

    Ma, Liqun; Zhang, Xuexin; Zhou, Min; Chen, Haijun

    2012-01-01

    Two-pore domain K+ channels (K2P) mediate background K+ conductance and play a key role in a variety of cellular functions. Among the 15 mammalian K2P isoforms, TWIK-1, TASK-1, and TASK-3 K+ channels are sensitive to extracellular acidification. Lowered or acidic extracellular pH (pHo) strongly inhibits outward currents through these K2P channels. However, the mechanism of how low pHo affects these acid-sensitive K2P channels is not well understood. Here we show that in Na+-based bath solutions with physiological K+ gradients, lowered pHo largely shifts the reversal potential of TWIK-1, TASK-1, and TASK-3 K+ channels, which are heterologously expressed in Chinese hamster ovary cells, into the depolarizing direction and significantly increases their Na+ to K+ relative permeability. Low pHo-induced inhibitions in these acid-sensitive K2P channels are more profound in Na+-based bath solutions than in channel-impermeable N-methyl-d-glucamine-based bath solutions, consistent with increases in the Na+ to K+ relative permeability and decreases in electrochemical driving forces of outward K+ currents of the channels. These findings indicate that TWIK-1, TASK-1, and TASK-3 K+ channels change ion selectivity in response to lowered pHo, provide insights on the understanding of how extracellular acidification modulates acid-sensitive K2P channels, and imply that these acid-sensitive K2P channels may regulate cellular function with dynamic changes in their ion selectivity. PMID:22948150

  1. Performance optimization for doubly fed wind power generation systems

    SciTech Connect

    Bhowmik, S.; Spee, R.; Enslin, J.H.R.

    1999-08-01

    Significant variation of the resource kinetic energy, in the form of wind speed, results in substantially reduced energy capture in a fixed-speed wind turbine. In order to increase the wind energy capture in the turbine, variable-speed generation (VSG) strategies have been proposed and implemented. However, that requires an expensive ac/ac power converter, which increases the capital investment significantly. Consequently, doubly fed systems have been proposed to reduce the size of the power converter and, thereby, the associated cost. Additionally, in doubly fed systems, as a fixed operating point (power and speed), power flow can be regulated between the two winding systems on the machine. This feature can by utilized to essentially minimize losses in the machine associated with the given operating point or achieve other desired performance enhancements. In this paper, a brushless doubly fed machine (BDFM) is utilized to develop a VSG wind power generator. The VSG controller employs a wind-speed-estimation-based maximum power point tracker and a heuristic-model-based maximum efficiency point tracker to optimize the power output of the system. The controller has been verified for efficacy on a 1.5-kW laboratory VSG wind generator. The strategy is applicable to all doubly fed configurations, including conventional wound-rotor induction machines, Scherbius cascades, BDFM's and doubly fed reluctance machines.

  2. Enhancement of Hippocampal Pyramidal Cell Excitability by the Novel Selective Slow-Afterhyperpolarization Channel Blocker 3-(Triphenylmethylaminomethyl)pyridine (UCL2077)

    PubMed Central

    Shah, Mala M.; Javadzadeh-Tabatabaie, Mazyar; Benton, David C. H.; Ganellin, C. Robin; Haylett, Dennis G.

    2008-01-01

    The slow afterhyperpolarization (sAHP) in hippocampal neurons has been implicated in learning and memory. However, its precise role in cell excitability and central nervous system function has not been explicitly tested for 2 reasons: 1) there are, at present, no selective inhibitors that effectively reduce the underlying current in vivo or in intact in vitro tissue preparations, and 2) although it is known that a small conductance K+ channel that activates after a rise in [Ca2+]i underlies the sAHP, the exact molecular identity remains unknown. We show that 3-(triphenylmethylaminomethyl)pyridine (UCL2077), a novel compound, suppressed the sAHP present in hippocampal neurons in culture (IC50 = 0.5 μM) and in the slice preparation (IC50 ≈ 10 μM). UCL2077 was selective, having minimal effects on Ca2+ channels, action potentials, input resistance and the medium afterhyperpolarization. UCL2077 also had little effect on heterologously expressed small conductance Ca2+-activated K+ (SK) channels. Moreover, UCL2077 and apamin, a selective SK channel blocker, affected spike firing in hippocampal neurons in different ways. These results provide further evidence that SK channels are unlikely to underlie the sAHP. This study also demonstrates that UCL2077, the most potent, selective sAHP blocker described so far, is a useful pharmacological tool for exploring the role of sAHP channels in the regulation of cell excitability in intact tissue preparations and, potentially, in vivo. PMID:16877678

  3. K-shell Auger lifetime variation in doubly ionized Ne and first row hydrides

    SciTech Connect

    Kolorenc, Premysl; Averbukh, Vitali

    2011-10-07

    We consider 1s Auger decay in doubly (core-core and core-valence) ionized Ne and in the isoelectronic first row element hydrides. We show theoretically that the presence of the spectator inner valence vacancy leads to Auger lifetime variation of up to about a factor of 2, relative to the Auger lifetimes in the singly ionized species. The origin of this effect is traced to spin selection rules. Implications on the modelling of the radiation damage in strong x-ray fields are discussed.

  4. Conformational changes in the selectivity filter of the open-state KcsA channel: an energy minimization study.

    PubMed

    Miloshevsky, Gennady V; Jordan, Peter C

    2008-10-01

    Potassium channels switch between closed and open conformations and selectively conduct K(+) ions. There are at least two gates. The TM2 bundle at the intracellular site is the primary gate of KcsA, and rearrangements at the selectivity filter (SF) act as the second gate. The SF blocks ion flow via an inactivation process similar to C-type inactivation of voltage-gated K(+) channels. We recently generated the open-state conformation of the KcsA channel. We found no major, possibly inactivating, structural changes in the SF associated with this massive inner-pore rearrangement, which suggests that the gates might act independently. Here we energy-minimize the open state of wild-type and mutant KcsA, validating in silico structures of energy-minimized SFs by comparison with crystallographic structures, and use these data to gain insight into how mutation, ion depletion, and K(+) to Na(+) substitution influence SF conformation. Both E71 or D80 protonations/mutations and the presence/absence of protein-buried water molecule(s) modify the H-bonding network stabilizing the P-loops, spawning numerous SF conformations. We find that the inactivated state corresponds to conformations with a partially unoccupied or an entirely empty SF. These structures, involving modifications in all four P-loops, are stabilized by H-bonds between amide H and carbonyl O atoms from adjacent P-loops, which block ion passage. The inner portions of the P-loops are more rigid than the outer parts. Changes are localized to the outer binding sites, with innermost site S4 persisting in the inactivated state. Strong binding by Na(+) locally contracts the SF around Na(+), releasing ligands that do not participate in Na(+) coordination, and occluding the permeation pathway. K(+) selectivity primarily appears to arise from the inability of the SF to completely dehydrate Na(+) ions due to basic structural differences between liquid water and the "quasi-liquid" SF matrix.

  5. Nerve compression activates selective nociceptive pathways and upregulates peripheral sodium channel expression in Schwann cells.

    PubMed

    Frieboes, Laura Rummler; Palispis, Winnie Anne; Gupta, Ranjan

    2010-06-01

    Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, are common musculoskeletal conditions that affect patients with debilitating loss of sensory function and pain. Although early detection and treatment are important, our understanding of pain-related molecular mechanisms remains largely unclear. Here we investigate these mechanisms using an animal model for CNC injury. To confirm that CNC injury induces pain, we assessed expression of c-fos, a gene that is rapidly expressed in spinal sensory afferents in response to painful peripheral stimuli, and TNF-alpha and IL-6, two proinflammatory cytokines that are crucial to development of inflammatory-mediated pain. Results show c-fos upregulation 1-2 weeks postinjury in the absence of TNF-alpha or IL-6 expression, indicating increased neural sensitivity without an inflammatory response. This is consistent with previous studies that showed no morphologic evidence of inflammation in the CNC model. Surprisingly, we also found de novo expression of Na(V)1.8, a sodium channel linked to the development of neuropathic pain, in endoneurial Schwann cells following injury. Until now, Na(V)1.8 expression was thought to be restricted to sensory neurons. CNC injury appears to be a unique model of noninflammatory neuropathic pain. Further investigation of the underlying molecular basis could yield promising targets for early diagnosis and treatment.

  6. Neurons and β-Cells of the Pancreas Express Connexin36, Forming Gap Junction Channels that Exhibit Strong Cationic Selectivity

    PubMed Central

    2013-01-01

    We examined the permeability of connexin36 (Cx36) homotypic gap junction (GJ) channels, expressed in neurons and β-cells of the pancreas, to dyes differing in molecular mass and net charge. Experiments were performed in HeLa cells stably expressing Cx36 tagged with EGFP by combining a dual whole-cell voltage clamp and fluorescence imaging. To assess the permeability of the single GJ channel (Pγ), we used a dual-mode excitation of fluorescent dyes that allowed us to measure cell-to-cell dye transfer at levels not resolvable using whole-field excitation solely. We demonstrate that Pγ of Cx36 for cationic dyes (EAM-1+ and EAM-2+) is ∼10-fold higher than that for an anionic dye of the same net charge and similar molecular mass, Alexa fluor-350 (AFl-350−). In addition, Pγ for Lucifer yellow (LY2−) is approximately fourfold smaller than that for AFl-350−, which suggests that the higher negativity of LY2− significantly reduces permeability. The Pγ of Cx36 for AFl-350 is approximately 358, 138, 23 and four times smaller than the Pγs of Cx43, Cx40, Cx45, and Cx57, respectively. In contrast, it is 6.5-fold higher than the Pγ of mCx30.2, which exhibits a smaller single-channel conductance. Thus, Cx36 GJs are highly cation-selective and should exhibit relatively low permeability to numerous vital negatively charged metabolites and high permeability to K+, a major charge carrier in cell– cell communication. PMID:22752717

  7. The Sodium Channel β4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons

    PubMed Central

    Ji, Xincai; Saha, Sucharita; Gao, Guangping; Lasek, Amy W.; Homanics, Gregg E.; Guildford, Melissa; Tapper, Andrew R.; Martin, Gilles E.

    2017-01-01

    Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1–4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens – NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered the properties of APs in core accumbens medium spiny neurons (MSNs). These alterations are associated with a reduction of the probability of MSNs to evoke spike-timing-dependent long-term depression (tLTD) and a reduced ability of backpropagating APs to evoke dendritic calcium transients. In contrast, long-term potentiation (tLTP) remained unaffected. Interestingly, we also showed that amphetamine-induced locomotor activity was significantly reduced in male Scn4b KO mice compared to wild-type controls. Taken together, these data indicate that the Scn4b subunit selectively controls tLTD by modulating dendritic calcium transients evoked by backpropagating APs. PMID:28243192

  8. Norharmane: old yet highly selective dual channel ratiometric fluoride and hydrogen sulfate ion sensor.

    PubMed

    Mallick, Arabinda; Katayama, Tetsuro; Ishibasi, Yukihide; Yasuda, Masakazu; Miyasaka, Hiroshi

    2011-01-21

    Norharmane provides a simple unexplored class of anion receptor, that allows for the ratiometric selective detection of F(-) and HSO(4)(-) ions. The presence of a strong base can easily form hydrogen bonds with the acidic hydrogen bond donor moiety and the relatively strong acid can easily protonate the basic hydrogen bond acceptor moiety, which can modulate the optical response and can detect the anions efficiently with high selectivity. In view of that, it is promising to conceive the use of these systems in various sensing applications as well as in other situations, such as anion transport and purification, where the availability of cheap and easy-to-make anion receptors, would be advantageous.

  9. Composition of diets selected by Sitka black-tailed deer on Channel Island, central southeast Alaska

    Treesearch

    Thomas A. Hanley; Michael P. Gillingham; Katherine L. Parker

    2014-01-01

    Composition of diets selected by tame but free-ranging deer in a natural forest environment was studied throughout a 24-month period and summarized by mean monthly percentage composition on the basis of dry-matter intake. A modifi cation of the standard bite-count method of diet determination was used. All forages were identifi ed by species and plant part (leaf, twig...

  10. Overlapping photo-ionized doubly excited resonance series for Li+ ion

    NASA Astrophysics Data System (ADS)

    Fang, T. K.; Gao, X.; Chang, T. N.

    2017-06-01

    Based on two different approaches, the B-spline-based K-matrix method and the eigenchannel R-matrix method, we present a detailed theoretical study on the photoionization from the ground and bound excited 1s2s{}1S and 1s2p{}1P states of an Li+ ion to continua between the N = 2 and N = 3 thresholds, dominated by overlapping doubly excited resonance series embedded in multiple singly ionized channels. The nearly identical theoretical spectra from these two different calculations, together with the excellent agreement between the length and velocity results, suggests that our study has successfully led to a reliable estimate of the Li+ photoionization spectra. In addition to identifying all overlapping doubly excited autoionization series, our calculated spectrum is in good agreement with the only observed data for two broad resonances. Our study has also shown that the strong interaction between neighboring resonances from different resonance series, which is responsible for the level crossing for in the He atom, is substantially smaller due to a stronger nuclear attraction to atomic electrons for the two-electron ions.

  11. Inverse probability weighted Cox regression for doubly truncated data.

    PubMed

    Mandel, Micha; de Uña-Álvarez, Jacobo; Simon, David K; Betensky, Rebecca A

    2017-09-08

    Doubly truncated data arise when event times are observed only if they fall within subject-specific, possibly random, intervals. While non-parametric methods for survivor function estimation using doubly truncated data have been intensively studied, only a few methods for fitting regression models have been suggested, and only for a limited number of covariates. In this article, we present a method to fit the Cox regression model to doubly truncated data with multiple discrete and continuous covariates, and describe how to implement it using existing software. The approach is used to study the association between candidate single nucleotide polymorphisms and age of onset of Parkinson's disease. © 2017, The International Biometric Society.

  12. Photonic crystal fiber-based surface plasmon resonance sensor with selective analyte channels and graphene-silver deposited core.

    PubMed

    Rifat, Ahmmed A; Mahdiraji, G Amouzad; Chow, Desmond M; Shee, Yu Gang; Ahmed, Rajib; Adikan, Faisal Rafiq Mahamd

    2015-05-19

    We propose a surface plasmon resonance (SPR) sensor based on photonic crystal fiber (PCF) with selectively filled analyte channels. Silver is used as the plasmonic material to accurately detect the analytes and is coated with a thin graphene layer to prevent oxidation. The liquid-filled cores are placed near to the metallic channel for easy excitation of free electrons to produce surface plasmon waves (SPWs). Surface plasmons along the metal surface are excited with a leaky Gaussian-like core guided mode. Numerical investigations of the fiber's properties and sensing performance are performed using the finite element method (FEM). The proposed sensor shows maximum amplitude sensitivity of 418 Refractive Index Units (RIU-1) with resolution as high as 2.4 × 10(-5) RIU. Using the wavelength interrogation method, a maximum refractive index (RI) sensitivity of 3000 nm/RIU in the sensing range of 1.46-1.49 is achieved. The proposed sensor is suitable for detecting various high RI chemicals, biochemical and organic chemical analytes. Additionally, the effects of fiber structural parameters on the properties of plasmonic excitation are investigated and optimized for sensing performance as well as reducing the sensor's footprint.

  13. ZD7288, a selective hyperpolarization-activated cyclic nucleotide-gated channel blocker, inhibits hippocampal synaptic plasticity

    PubMed Central

    Zhang, Xiao-xue; Min, Xiao-chun; Xu, Xu-lin; Zheng, Min; Guo, Lian-jun

    2016-01-01

    The selective hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride (ZD7288) blocks the induction of long-term potentiation in the perforant path–CA3 region in rat hippocampus in vivo. To explore the mechanisms underlying the action of ZD7288, we recorded excitatory postsynaptic potentials in perforant path–CA3 synapses in male Sprague-Dawley rats. We measured glutamate content in the hippocampus and in cultured hippocampal neurons using high performance liquid chromatography, and determined intracellular Ca2+ concentration [Ca2+]i) using Fura-2. ZD7288 inhibited the induction and maintenance of long-term potentiation, and these effects were mirrored by the nonspecific HCN channel blocker cesium. ZD7288 also decreased glutamate release in hippocampal tissue and in cultured hippocampal neurons. Furthermore, ZD7288 attenuated glutamate-induced rises in [Ca2+]i in a concentration-dependent manner and reversed 8-Br-cAMP-mediated facilitation of these glutamate-induced [Ca2+]i rises. Our results suggest that ZD7288 inhibits hippocampal synaptic plasticity both glutamate release and resultant [Ca2+]i increases in rat hippocampal neurons. PMID:27335562

  14. Photonic Crystal Fiber-Based Surface Plasmon Resonance Sensor with Selective Analyte Channels and Graphene-Silver Deposited Core

    PubMed Central

    Rifat, Ahmmed A.; Mahdiraji, G. Amouzad; Chow, Desmond M.; Shee, Yu Gang; Ahmed, Rajib; Adikan, Faisal Rafiq Mahamd

    2015-01-01

    We propose a surface plasmon resonance (SPR) sensor based on photonic crystal fiber (PCF) with selectively filled analyte channels. Silver is used as the plasmonic material to accurately detect the analytes and is coated with a thin graphene layer to prevent oxidation. The liquid-filled cores are placed near to the metallic channel for easy excitation of free electrons to produce surface plasmon waves (SPWs). Surface plasmons along the metal surface are excited with a leaky Gaussian-like core guided mode. Numerical investigations of the fiber’s properties and sensing performance are performed using the finite element method (FEM). The proposed sensor shows maximum amplitude sensitivity of 418 Refractive Index Units (RIU−1) with resolution as high as 2.4 × 10−5 RIU. Using the wavelength interrogation method, a maximum refractive index (RI) sensitivity of 3000 nm/RIU in the sensing range of 1.46–1.49 is achieved. The proposed sensor is suitable for detecting various high RI chemicals, biochemical and organic chemical analytes. Additionally, the effects of fiber structural parameters on the properties of plasmonic excitation are investigated and optimized for sensing performance as well as reducing the sensor’s footprint. PMID:25996510

  15. Charged Residues between the Selectivity Filter and S6 Segments Contribute to the Permeation Phenotype of the Sodium Channel

    PubMed Central

    Li, Ronald A.; Vélez, Patricio; Chiamvimonvat, Nipavan; Tomaselli, Gordon F.; Marbán, Eduardo

    2000-01-01

    The deep regions of the Na+ channel pore around the selectivity filter have been studied extensively; however, little is known about the adjacent linkers between the P loops and S6. The presence of conserved charged residues, including five in a row in domain III (D-III), hints that these linkers may play a role in permeation. To characterize the structural topology and function of these linkers, we neutralized the charged residues (from position 411 in D-I and its homologues in D-II, -III, and -IV to the putative start sites of S6) individually by cysteine substitution. Several cysteine mutants displayed enhanced sensitivities to Cd2+ block relative to wild-type and/or were modifiable by external sulfhydryl-specific methanethiosulfonate reagents when expressed in TSA-201 cells, indicating that these amino acids reside in the permeation pathway. While neutralization of positive charges did not alter single-channel conductance, negative charge neutralizations generally reduced conductance, suggesting that such charges facilitate ion permeation. The electrical distances for Cd2+ binding to these residues reveal a secondary “dip” into the membrane field of the linkers in domains II and IV. Our findings demonstrate significant functional roles and surprising structural features of these previously unexplored external charged residues. PMID:10613920

  16. Dark energy and doubly coupled bigravity

    NASA Astrophysics Data System (ADS)

    Brax, Philippe; Davis, Anne-Christine; Noller, Johannes

    2017-05-01

    We analyse the late time cosmology and the gravitational properties of doubly coupled bigravity in the constrained vielbein formalism (equivalent to the metric formalism) when the mass of the massive graviton is of the order of the present Hubble rate. We focus on one of the two branches of background cosmology where the ratio between the scale factors of the two metrics is algebraically determined. We find that the late time physics depends on the mass of the graviton, which dictates the future asymptotic cosmological constant. The Universe evolves from a matter dominated epoch to a dark energy dominated era where the equation of state of dark energy can always be made close to  -1 now by appropriately tuning the graviton mass. We also analyse the perturbative spectrum of the theory in the quasi-static approximation, well below the strong coupling scale where no instability is present, and we show that there are five scalar degrees of freedom, two vectors and two gravitons. In Minkowski space, where the four Newtonian potentials vanish, the theory manifestly reduces to one massive and one massless graviton. In a cosmological FRW background for both metrics, four of the five scalars are Newtonian potentials which lead to a modification of gravity on large scales. The fifth one gives rise to a ghost which decouples from pressure-less matter in the quasi-static approximation. In this scalar sector, gravity is modified with effects on both the growth of structure and the lensing potential. In particular, we find that the Σ parameter governing the Poisson equation of the weak lensing potential can differ from one in the recent past of the Universe. Overall, the nature of the modification of gravity at low energy, which reveals itself in the growth of structure and the lensing potential, is intrinsically dependent on the couplings to matter and the potential term of the vielbeins. We also find that the time variation of Newton’s constant in the Jordan frame can

  17. An easy prepared dual-channel chemosensor for selective and instant detection of fluoride based on double Schiff-base

    NASA Astrophysics Data System (ADS)

    Leng, Yan-Li; Zhang, Jian-Hui; Li, Qiao; Zhang, You-Ming; Lin, Qi; Yao, Hong; Wei, Tai-Bao

    2016-10-01

    A colorimetric and fluorescent dual-channel fluoride chemosensor N,N‧-bis (4-diethylaminosalicylidene) hydrazine (sensor S) bearing two imine groups has been designed and synthesized. This structurally simple probe displays rapid response and high selectivity for fluoride over other common anions (Cl-, Br-, I-, AcO-, H2PO4-, HSO4-, ClO4-, CN- and SCN-) in a highly polar aqueous DMSO solution. Mechanism studies suggested that the sensor firstly combined with F- through hydrogen bonds and then experienced the deprotonation process at higher concentrations of F- anion to the two Ar-OH groups. The detection limit was 5.78 × 10- 7 M of F-, which points to the high detection sensitivity. Test strips based on sensor S were fabricated, which could act as a convenient and efficient F- test kit to detect F- for "in-the-field" measurement.

  18. An easy prepared dual-channel chemosensor for selective and instant detection of fluoride based on double Schiff-base.

    PubMed

    Leng, Yan-Li; Zhang, Jian-Hui; Li, Qiao; Zhang, You-Ming; Lin, Qi; Yao, Hong; Wei, Tai-Bao

    2016-10-05

    A colorimetric and fluorescent dual-channel fluoride chemosensor N,N'-bis (4-diethylaminosalicylidene) hydrazine (sensor S) bearing two imine groups has been designed and synthesized. This structurally simple probe displays rapid response and high selectivity for fluoride over other common anions (Cl(-), Br(-), I(-), AcO(-), H2PO4(-), HSO4(-), ClO4(-), CN(-) and SCN(-)) in a highly polar aqueous DMSO solution. Mechanism studies suggested that the sensor firstly combined with F(-) through hydrogen bonds and then experienced the deprotonation process at higher concentrations of F(-) anion to the two Ar-OH groups. The detection limit was 5.78×10(-7)M of F(-), which points to the high detection sensitivity. Test strips based on sensor S were fabricated, which could act as a convenient and efficient F(-) test kit to detect F(-) for "in-the-field" measurement.

  19. The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases

    PubMed Central

    Ye, Fang; Hu, Youtian; Yu, Weiwei; Xie, Zili; Hu, Jun; Cao, Zhijian; Li, Wenxin; Wu, Yingliang

    2016-01-01

    The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K+ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the “evolutionary” Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel–specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies. PMID:27104568

  20. Use-dependent block of the voltage-gated Na(+) channel by tetrodotoxin and saxitoxin: effect of pore mutations that change ionic selectivity.

    PubMed

    Huang, Chien-Jung; Schild, Laurent; Moczydlowski, Edward G

    2012-10-01

    Voltage-gated Na(+) channels (NaV channels) are specifically blocked by guanidinium toxins such as tetrodotoxin (TTX) and saxitoxin (STX) with nanomolar to micromolar affinity depending on key amino acid substitutions in the outer vestibule of the channel that vary with NaV gene isoforms. All NaV channels that have been studied exhibit a use-dependent enhancement of TTX/STX affinity when the channel is stimulated with brief repetitive voltage depolarizations from a hyperpolarized starting voltage. Two models have been proposed to explain the mechanism of TTX/STX use dependence: a conformational mechanism and a trapped ion mechanism. In this study, we used selectivity filter mutations (K1237R, K1237A, and K1237H) of the rat muscle NaV1.4 channel that are known to alter ionic selectivity and Ca(2+) permeability to test the trapped ion mechanism, which attributes use-dependent enhancement of toxin affinity to electrostatic repulsion between the bound toxin and Ca(2+) or Na(+) ions trapped inside the channel vestibule in the closed state. Our results indicate that TTX/STX use dependence is not relieved by mutations that enhance Ca(2+) permeability, suggesting that ion-toxin repulsion is not the primary factor that determines use dependence. Evidence now favors the idea that TTX/STX use dependence arises from conformational coupling of the voltage sensor domain or domains with residues in the toxin-binding site that are also involved in slow inactivation.

  1. Non-pore lining amino acid side chains influence anion selectivity of the human CFTR Cl− channel expressed in mammalian cell lines

    PubMed Central

    Linsdell, Paul; Zheng, Shu-Xian; Hanrahan, John W

    1998-01-01

    The effects of individually mutating two adjacent threonine residues in the sixth membrane-spanning region (TM6) of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel on permeation properties were examined using patch clamp recording from mammalian cell lines stably expressing human CFTR.A number of mutations of T338 significantly affected the permeation properties of the channel. Increases and decreases in single channel conductance were observed for different mutants. Anion selectivity was strongly affected, with no two channel variants sharing the same selectivity sequence. Several mutations led to strong inward rectification of the macroscopic current-voltage relationship. The effects of these mutations on permeation properties were correlated with the size