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Sample records for ion channel density

  1. Step density model of laser sustained ion channel and Coulomb explosion

    SciTech Connect

    Rajouria, Satish Kumar; Malik, H. K.; Tripathi, V. K.; Kumar, Pawan

    2015-02-15

    An analytical model of laser sustained ion channel in plasma is developed, assuming electron density to be zero in the inner region and constant outside. The radius of the channel is such that the ponderomotive force on electrons at the channel boundary is balanced by the channel space charge force. The laser is TM eigen mode of the system with Bessel function profile in the interior and modified Bessel function outside. The channel radius increases with laser intensity and the ratio of laser frequency to plasma frequency. Ion Coulomb explosion of the channel, on longer time scale, produces ion energy distribution, an increasing function of energy with a sharp cutoff equal to electron ponderomotive energy at the channel boundary. At peak laser intensity ≈2×10{sup 19}W/cm{sup 2} at 1 μm wavelength and spot size of 8 μm, the cutoff ion energy in a plasma of density ∼10{sup 19}cm{sup −3} is ∼0.73 MeV.

  2. Bubble gating in biological ion channels: A density functional theory study

    NASA Astrophysics Data System (ADS)

    Gußmann, Florian; Roth, Roland

    2017-06-01

    We study the behavior of a waterlike liquid inside the gate of a biological ion channel following the basic geometry of the well studied potassium channel KcsA. We calculate the three-dimensional density distribution ρ (r ) of the liquid within the framework of classical density functional theory and observe the formation of a low density region (bubble) when the gate is narrow. This observation corresponds to a finite-size form of capillary evaporation and supports the so-called bubble-gate theory. From the density profile we also compute the energy landscape of the gate and the energy required to change the gate from a closed (narrow) to an open (wide) state and vice versa.

  3. Density-functional theory study of gramicidin A ion channel geometry and electronic properties.

    PubMed

    Todorović, Milica; Bowler, David R; Gillan, Michael J; Miyazaki, Tsuyoshi

    2013-12-06

    Understanding the mechanisms underlying ion channel function from the atomic-scale requires accurate ab initio modelling as well as careful experiments. Here, we present a density functional theory (DFT) study of the ion channel gramicidin A (gA), whose inner pore conducts only monovalent cations and whose conductance has been shown to depend on the side chains of the amino acids in the channel. We investigate the ground state geometry and electronic properties of the channel in vacuum, focusing on their dependence on the side chains of the amino acids. We find that the side chains affect the ground state geometry, while the electrostatic potential of the pore is independent of the side chains. This study is also in preparation for a full, linear scaling DFT study of gA in a lipid bilayer with surrounding water. We demonstrate that linear scaling DFT methods can accurately model the system with reasonable computational cost. Linear scaling DFT allows ab initio calculations with 10,000-100,000 atoms and beyond, and will be an important new tool for biomolecular simulations.

  4. Accounting for Finite Size of Ions in Nanofluidic Channels Using Density Functional Theory

    NASA Astrophysics Data System (ADS)

    McCallum, Christopher; Gillespie, Dirk; Pennathur, Sumita

    2016-11-01

    The physics of nanofluidic devices are dominated by ion-wall interactions within the electric double layer (EDL). A full understanding of the EDL allows for better exploitation of micro and nanofluidic devices for applications such as biologic separations, desalination, and energy conversion, Although continuum theory is generally used to study the fluidics within these channels, in very confined geometries, high surface charge channels, or significant solute concentration systems, continuum theories such as Poisson-Boltzmann cease to be valid because the finite size of ions is not considered. Density functional theory (DFT) provides an accurate and efficient method for predicting the concentration of ions and the electrostatic potential near a charged wall because it accounts for more complex electrostatic and hard-sphere correlations. This subsequently allows for a better model for ion flux, fluid flow, and current in electrokinetic systems at high surface charge, confined geometries, and concentrated systems. In this work, we present a theoretical approach utilizing DFT to predict unique flow phenomena in nanofluidic, electrokinetic systems. CBET-1402736 from the National Science Foundation.

  5. Cardiac ion channels

    PubMed Central

    Priest, Birgit T; McDermott, Jeff S

    2015-01-01

    Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype. PMID:26556552

  6. Mechanically Activated Ion Channels.

    PubMed

    Ranade, Sanjeev S; Syeda, Ruhma; Patapoutian, Ardem

    2015-09-23

    Mechanotransduction, the conversion of physical forces into biochemical signals, is essential for various physiological processes such as the conscious sensations of touch and hearing, and the unconscious sensation of blood flow. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels.

  7. Mechanically Activated Ion Channels

    PubMed Central

    Ranade, Sanjeev S.; Syeda, Ruhma; Patapoutian, Ardem

    2015-01-01

    Mechanotransduction, the conversion of physical forces into biochemical signals, is an essential component of numerous physiological processes including not only conscious senses of touch and hearing, but also unconscious senses such as blood pressure regulation. Mechanically activated (MA) ion channels have been proposed as sensors of physical force, but the identity of these channels and an understanding of how mechanical force is transduced has remained elusive. A number of recent studies on previously known ion channels along with the identification of novel MA ion channels have greatly transformed our understanding of touch and hearing in both vertebrates and invertebrates. Here, we present an updated review of eukaryotic ion channel families that have been implicated in mechanotransduction processes and evaluate the qualifications of the candidate genes according to specified criteria. We then discuss the proposed gating models for MA ion channels and highlight recent structural studies of mechanosensitive potassium channels. PMID:26402601

  8. Cholesterol and Ion Channels

    PubMed Central

    Levitan, Irena; Fang, Yun; Rosenhouse-Dantsker, Avia; Romanenko, Victor

    2010-01-01

    A variety of ion channels, including members of all major ion channel families, have been shown to be regulated by changes in the level of membrane cholesterol and partition into cholesterol-rich membrane domains. In general, several types of cholesterol effects have been described. The most common effect is suppression of channel activity by an increase in membrane cholesterol, an effect that was described for several types of inwardly-rectifying K+ channels, voltage-gated K+ channels, Ca+2 sensitive K+ channels, voltage-gated Na+ channels, N-type voltage-gated Ca+2 channels and volume-regulated anion channels. In contrast, several types of ion channels, such as epithelial amiloride-sensitive Na+ channels and Transient Receptor Potential channels, as well as some of the types of inwardly-rectifying and voltage-gated K+ channels were shown to be inhibited by cholesterol depletion. Cholesterol was also shown to alter the kinetic properties and current-voltage dependence of several voltage-gated channels. Finally, maintaining membrane cholesterol level is required for coupling ion channels to signalling cascades. In terms of the mechanisms, three general mechanisms have been proposed: (i) specific interactions between cholesterol and the channel protein, (ii) changes in the physical properties of the membrane bilayer and (iii) maintaining the scaffolds for protein-protein interactions. The goal of this review is to describe systematically the role of cholesterol in regulation of the major types of ion channels and to discuss these effects in the context of the models proposed. PMID:20213557

  9. Ion channels in microbes

    PubMed Central

    Martinac, Boris; Saimi, Yoshiro; Kung, Ching

    2008-01-01

    Summary Studies of ion channels have for long been dominated by the animalcentric, if not anthropocentric view of physiology. The structures and activities of ion channels had, however, evolved long before the appearance of complex multicellular organisms on Earth. The diversity of ion channels existing in cellular membranes of prokaryotes is a good example. Though at first it may appear as a paradox that most of what we know about the structure of eukaryotic ion channels is based on the structure of bacterial channels, this should not be surprising given the evolutionary relatedness of all living organisms and suitability of microbial cells for structural studies of biological macromolecules in a laboratory environment. Genome sequences of the human as well as various microbial, plant and animal organisms unambiguously established the evolutionary links, whereas crystallographic studies of the structures of major types of ion channels published over the last decade clearly demonstrated the advantage of using microbes as experimental organisms. The purpose of this review is not only to provide an account of acquired knowledge on microbial ion channels but also to show that the study of microbes and their ion channels may also hold a key to solving unresolved molecular mysteries in the future. PMID:18923187

  10. Ion channels in microbes.

    PubMed

    Martinac, Boris; Saimi, Yoshiro; Kung, Ching

    2008-10-01

    Studies of ion channels have for long been dominated by the animalcentric, if not anthropocentric, view of physiology. The structures and activities of ion channels had, however, evolved long before the appearance of complex multicellular organisms on earth. The diversity of ion channels existing in cellular membranes of prokaryotes is a good example. Although at first it may appear as a paradox that most of what we know about the structure of eukaryotic ion channels is based on the structure of bacterial channels, this should not be surprising given the evolutionary relatedness of all living organisms and suitability of microbial cells for structural studies of biological macromolecules in a laboratory environment. Genome sequences of the human as well as various microbial, plant, and animal organisms unambiguously established the evolutionary links, whereas crystallographic studies of the structures of major types of ion channels published over the last decade clearly demonstrated the advantage of using microbes as experimental organisms. The purpose of this review is not only to provide an account of acquired knowledge on microbial ion channels but also to show that the study of microbes and their ion channels may also hold a key to solving unresolved molecular mysteries in the future.

  11. Ion channels in plants

    PubMed Central

    Baluška, František; Mancuso, Stefano

    2013-01-01

    In his recent opus magnum review paper published in the October issue of Physiology Reviews, Rainer Hedrich summarized the field of plant ion channels.1 He started from the earliest electric recordings initiated by Charles Darwin of carnivorous Dionaea muscipula,1,2 known as Venus flytrap, and covered the topic extensively up to the most recent discoveries on Shaker-type potassium channels, anion channels of SLAC/SLAH families, and ligand-activated channels of glutamate receptor-like type (GLR) and cyclic nucleotide-gated channels (CNGC).1 PMID:23221742

  12. Ion channels in inflammation.

    PubMed

    Eisenhut, Michael; Wallace, Helen

    2011-04-01

    Most physical illness in vertebrates involves inflammation. Inflammation causes disease by fluid shifts across cell membranes and cell layers, changes in muscle function and generation of pain. These disease processes can be explained by changes in numbers or function of ion channels. Changes in ion channels have been detected in diarrhoeal illnesses, pyelonephritis, allergy, acute lung injury and systemic inflammatory response syndromes involving septic shock. The key role played by changes in ion transport is directly evident in inflammation-induced pain. Expression or function of all major categories of ion channels like sodium, chloride, calcium, potassium, transient receptor potential, purinergic receptor and acid-sensing ion channels can be influenced by cyto- and chemokines, prostaglandins, leukotrienes, histamine, ATP, reactive oxygen species and protons released in inflammation. Key pathways in this interaction are cyclic nucleotide, phosphoinositide and mitogen-activated protein kinase-mediated signalling, direct modification by reactive oxygen species like nitric oxide, ATP or protons and disruption of the cytoskeleton. Therapeutic interventions to modulate the adverse and overlapping effects of the numerous different inflammatory mediators on each ion transport system need to target adversely affected ion transport systems directly and locally.

  13. Mitochondrial Ion Channels

    PubMed Central

    O’Rourke, Brian

    2009-01-01

    In work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This process requires a membrane with relatively low permeability to ions to minimize energy dissipation. However, a wealth of evidence now indicates that both selective and nonselective ion channels are present in the mitochondrial inner membrane, along with several known channels on the outer membrane. Some of these channels are active under physiological conditions, and others may be activated under pathophysiological conditions to act as the major determinants of cell life and death. This review summarizes research on mitochondrial ion channels and efforts to identify their molecular correlates. Except in a few cases, our understanding of the structure of mitochondrial ion channels is limited, indicating the need for focused discovery in this area. PMID:17059356

  14. Negative Ion Density Fronts

    SciTech Connect

    Igor Kaganovich

    2000-12-18

    Negative ions tend to stratify in electronegative plasmas with hot electrons (electron temperature Te much larger than ion temperature Ti, Te > Ti ). The boundary separating a plasma containing negative ions, and a plasma, without negative ions, is usually thin, so that the negative ion density falls rapidly to zero-forming a negative ion density front. We review theoretical, experimental and numerical results giving the spatio-temporal evolution of negative ion density fronts during plasma ignition, the steady state, and extinction (afterglow). During plasma ignition, negative ion fronts are the result of the break of smooth plasma density profiles during nonlinear convection. In a steady-state plasma, the fronts are boundary layers with steepening of ion density profiles due to nonlinear convection also. But during plasma extinction, the ion fronts are of a completely different nature. Negative ions diffuse freely in the plasma core (no convection), whereas the negative ion front propagates towards the chamber walls with a nearly constant velocity. The concept of fronts turns out to be very effective in analysis of plasma density profile evolution in strongly non-isothermal plasmas.

  15. Ion channeling revisited

    SciTech Connect

    Doyle, Barney Lee; Corona, Aldo; Nguyen, Anh

    2014-09-01

    A MS Excel program has been written that calculates accidental, or unintentional, ion channeling in cubic bcc, fcc and diamond lattice crystals or polycrystalline materials. This becomes an important issue when simulating the creation by energetic neutrons of point displacement damage and extended defects using beams of ions. All of the tables and graphs in the three Ion Beam Analysis Handbooks that previously had to be manually looked up and read from were programed into Excel in handy lookup tables, or parameterized, for the case of the graphs, using rather simple exponential functions with different powers of the argument. The program then offers an extremely convenient way to calculate axial and planar half-angles and minimum yield or dechanneling probabilities, effects on half-angles of amorphous overlayers, accidental channeling probabilities for randomly oriented crystals or crystallites, and finally a way to automatically generate stereographic projections of axial and planar channeling half-angles. The program can generate these projections and calculate these probabilities for axes and [hkl] planes up to (555).

  16. Ion channels in the RPE.

    PubMed

    Wimmers, Sönke; Karl, Mike O; Strauss, Olaf

    2007-05-01

    In close interaction with photoreceptors, the retinal pigment epithelium (RPE) plays an essential role for visual function. The analysis of RPE functions, specifically ion channel functions, provides a basis to understand many degenerative diseases of the retina. The invention of the patch-clamp technique significantly improved the knowledge of ion channel structure and function, which enabled a new understanding of cell physiology and patho-physiology of many diseases. In this review, ion channels identified in the RPE will be described in terms of their specific functional role in RPE physiology. The RPE expresses voltage- and ligand-gated K(+), Cl(-), and Ca(2+)-conducting channels. K(+) and Cl(-) channels are involved in transepithelial ion transport and volume regulation. Voltage-dependent Ca(2+) channels act as regulators of secretory activity, and ligand-gated cation channels contribute to RPE function by providing driving forces for ion transport or by influencing intracellular Ca(2+) homoeostasis. Collectively, activity of these ion channels determines the physiology of the RPE and its interaction with photoreceptors. Furthermore, changes in ion channel function, such as mutations in ion channel genes or a changed regulation of ion channel activity, have been shown to lead to degenerative diseases of the retina. Increasing knowledge about the properties of RPE ion channels has not only provided a new understanding of RPE function but has also provided greater understanding of RPE function in health and disease.

  17. Ion Channels in Epithelial Cells

    NASA Astrophysics Data System (ADS)

    Palmer, Lawrence G.

    Ion channels in epithelial cells serve to move ions, and in some cases fluid, between compartments of the body. This function of the transfer of material is fundamentally different from that of the transfer of information, which is the main job of most channels in excitable cells. Nevertheless the basic construction of the channels is similar in many respects in the two tissue types. This chapter reviews the nature of channels in epithelia and discusses how their functions have evolved to accomplish the basic tasks for which they are responsible. I will focus on three channel types: epithelial Na+ channels, inward-rectifier K+ channels, and CFTR Cl- channels.

  18. Ion channel therapeutics for pain

    PubMed Central

    Skerratt, Sarah E; West, Christopher W

    2015-01-01

    Pain is a complex disease which can progress into a debilitating condition. The effective treatment of pain remains a challenge as current therapies often lack the desired level of efficacy or tolerability. One therapeutic avenue, the modulation of ion channel signaling by small molecules, has shown the ability to treat pain. However, of the 215 ion channels that exist in the human genome, with 85 ion channels having a strong literature link to pain, only a small number of these channels have been successfully drugged for pain. The focus of future research will be to fully explore the possibilities surrounding these unexplored ion channels. Toward this end, a greater understanding of ion channel modulation will be the greatest tool we have in developing the next generation of drugs for the treatment of pain. PMID:26218246

  19. Agonist-activated ion channels

    PubMed Central

    Colquhoun, David

    2006-01-01

    This paper looks at ion channels as an example of the pharmacologist's stock in trade, the action of an agonist on a receptor to produce a response. Looked at in this way, ion channels have been helpful because they are still the only system which is simple enough for quantitative investigation of transduction mechanisms. A short history is given of attempts to elucidate what happens between the time when agonist first binds, and the time when the channel opens. PMID:16402101

  20. Ultrasound modulates ion channel currents

    PubMed Central

    Kubanek, Jan; Shi, Jingyi; Marsh, Jon; Chen, Di; Deng, Cheri; Cui, Jianmin

    2016-01-01

    Transcranial focused ultrasound (US) has been demonstrated to stimulate neurons in animals and humans, but the mechanism of this effect is unknown. It has been hypothesized that US, a mechanical stimulus, may mediate cellular discharge by activating mechanosensitive ion channels embedded within cellular membranes. To test this hypothesis, we expressed potassium and sodium mechanosensitive ion channels (channels of the two-pore-domain potassium family (K2P) including TREK-1, TREK-2, TRAAK; NaV1.5) in the Xenopus oocyte system. Focused US (10 MHz, 0.3–4.9 W/cm2) modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. The effects were reversible upon repeated stimulation and were abolished when a channel blocker (ranolazine to block NaV1.5, BaCl2 to block K2P channels) was applied to the solution. These data reveal at the single cell level that focused US modulates the activity of specific ion channels to mediate transmembrane currents. These findings open doors to investigations of the effects of  US on ion channels expressed in neurons, retinal cells, or cardiac cells, which may lead to important medical applications. The findings may also pave the way to the development of sonogenetics: a non-invasive, US-based analogue of optogenetics. PMID:27112990

  1. Simulating complex ion channel kinetics with IonChannelLab

    PubMed Central

    Covarrubias, Manuel; Sánchez-Rodríguez, Jorge E; Perez-Cornejo, Patricia; Arreola, Jorge

    2010-01-01

    In-silico simulation based on Markov chains is a powerful way to describe and predict the activity of many transport proteins including ion channels. However, modeling and simulation using realistic models of voltage- or ligand-gated ion channels exposed to a wide range of experimental conditions require building complex kinetic schemes and solving complicated differential equations. To circumvent these problems, we developed IonChannelLab a software tool that includes a user-friendly Graphical User Interface and a simulation library. This program supports channels with Ohmic or Goldman-Hodgkin-Katz behavior and can simulate the time-course of ionic and gating currents, single channel behavior and steady-state conditions. The program allows the simulation of experiments where voltage, ligand and ionic concentration are varied independently or simultaneously. PMID:20935453

  2. Classical density functional theory of fluids as a multi-scale modeling tool for charged fluids: Electrical double layers, biological ion channels, dielectric interfaces

    NASA Astrophysics Data System (ADS)

    Gillespie, Dirk

    2010-03-01

    Classical density functional theory (DFT) of fluids (not quantum mechanical DFT of electron orbitals) has the potential to be a powerful modeling technique in many areas of science including ionic liquids, colloids, polymers, and proteins. DFT of fluids is a thermodynamic (statistical) theory in the grand canonical ensemble; given the particle interactions, equations are solved directly for the ensemble-averaged quantities. Because DFT is a thermodynamic theory where the ensemble-averaged quantities are computed directly, it computes results quickly (minutes for 1D problems, ˜1 hour for 3D) and in arbitrarily low concentrations and it produces steady-state results. The DFT method is generally applicable to fluids in confining geometries or at interfaces. In this presentation the focus is on new results of DFT applications to electrolytes at charged interfaces and ion current through biological ion channels. A new technical advance of a DFT for dielectric interfaces will also be presented.

  3. Marine Toxins Targeting Ion Channels

    PubMed Central

    Arias, Hugo R.

    2006-01-01

    This introductory minireview points out the importance of ion channels for cell communication. The basic concepts on the structure and function of ion channels triggered by membrane voltage changes, the so-called voltage-gated ion channels (VGICs), as well as those activated by neurotransmitters, the so-called ligand-gated ion channel (LGICs), are introduced. Among the most important VGIC superfamiles, we can name the voltage-gated Na+ (NaV), Ca2+ (CaV), and K+ (KV) channels. Among the most important LGIC super families, we can include the Cys-loop or nicotinicoid, the glutamate-activated (GluR), and the ATP-activated (P2XnR) receptor superfamilies. Ion channels are transmembrane proteins that allow the passage of different ions in a specific or unspecific manner. For instance, the activation of NaV, CaV, or KV channels opens a pore that is specific for Na+, Ca2+, or K+, respectively. On the other hand, the activation of certain LGICs such as nicotinic acetylcholine receptors, GluRs, and P2XnRs allows the passage of cations (e.g., Na+, K+, and/or Ca2+), whereas the activation of other LGICs such as type A γ-butyric acid and glycine receptors allows the passage of anions (e.g., Cl− and/or HCO3−). In this regard, the activation of NaV and CaV as well as ligand-gated cation channels produce membrane depolarization, which finally leads to stimulatory effects in the cell, whereas the activation of KV as well as ligand-gated anion channels induce membrane hyperpolarization that finally leads to inhibitory effects in the cell. The importance of these ion channel superfamilies is emphasized by considering their physiological functions throughout the body as well as their pathophysiological implicance in several neuronal diseases. In this regard, natural molecules, and especially marine toxins, can be potentially used as modulators (e.g., inhibitors or prolongers) of ion channel functions to treat or to alleviate a specific ion channel-linked disease (e

  4. The ion-channel laser

    SciTech Connect

    Whittum, D.H.; Sessler, A.M. ); Dawson, J.M. . Dept. of Physics)

    1990-01-01

    A relativistic electron beam propagating through a plasma in the ion-focused regime exhibits an electromagnetic instability at a resonant frequency {omega} {approximately} 2{gamma}{sup 2} {omega}{sub {beta}}. Growth is enhanced by optical guiding in the ion channel, which acts as dielectric waveguide, with fiber parameter V {approximately} 2 (I/I{sub A}){sup 1/2}. A 1-D theory for such an ion-channel laser'' is formulated, scaling laws are derived and numerical examples are given. Possible experimental evidence is noted. 23 refs., 1 fig., 1 tab.

  5. Ion Channels in Brain Metastasis

    PubMed Central

    Klumpp, Lukas; Sezgin, Efe C.; Eckert, Franziska; Huber, Stephan M.

    2016-01-01

    Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

  6. Demystifying Mechanosensitive Piezo Ion Channels.

    PubMed

    Xu, X Z Shawn

    2016-06-01

    Mechanosensitive channels mediate touch, hearing, proprioception, and blood pressure regulation. Piezo proteins, including Piezo1 and Piezo2, represent a new class of mechanosensitive channels that have been reported to play key roles in most, if not all, of these modalities. The structural architecture and molecular mechanisms by which Piezos act as mechanosensitive channels, however, remain mysterious. Two new studies have now provided critical insights into the atomic structure and molecular basis of the ion permeation and mechano-gating properties of the Piezo1 channel.

  7. Sensing pressure with ion channels.

    PubMed

    Nilius, Bernd; Honoré, Eric

    2012-08-01

    Opening of stretch-activated ion channels (SACs) is the earliest event occurring in mechanosensory transduction. The molecular identity of mammalian SACs has long remained a mystery. Only very recently, Piezo1 and Piezo2 have been shown to be essential components of distinct SACs and moreover, purified Piezo1 forms cationic channels when reconstituted into artificial bilayers. In line with these findings, dPiezo was demonstrated to act in the Drosophila mechanical nociception pathway. Finally, the 3D structure of the two-pore domain potassium channel (K(2P)), TRAAK [weakly inward rectifying K⁺ channel (TWIK)-related arachidonic acid stimulated K⁺ channel], has recently been solved, providing valuable information about pharmacology, selectivity and gating mechanisms of stretch-activated K⁺ channels (SAKs). These recent findings allow a better understanding of the molecular basis of molecular and cellular mechanotransduction. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Ion channels in development and cancer.

    PubMed

    Bates, Emily

    2015-01-01

    Ion channels have emerged as regulators of developmental processes. In model organisms and in people with mutations in ion channels, disruption of ion channel function can affect cell proliferation, cell migration, and craniofacial and limb patterning. Alterations of ion channel function affect morphogenesis in fish, frogs, mammals, and flies, demonstrating that ion channels have conserved roles in developmental processes. One model suggests that ion channels affect proliferation and migration through changes in cell volume. However, ion channels have not explicitly been placed in canonical developmental signaling cascades until recently. This review gives examples of ion channels that influence developmental processes, offers a potential underlying molecular mechanism involving bone morphogenetic protein (BMP) signaling, and finally explores exciting possibilities for manipulating ion channels to influence cell fate for regenerative medicine and to impact disease.

  9. Hydrophobic Gating in Ion Channels

    PubMed Central

    Aryal, Prafulla; Sansom, Mark S.P.; Tucker, Stephen J.

    2016-01-01

    Biological ion channels are nanoscale transmembrane pores. When water and ions are enclosed within the narrow confines of a sub-nanometer hydrophobic pore, they exhibit behavior not evident from macroscopic descriptions. At this nanoscopic level, the unfavorable interaction between the lining of a hydrophobic pore and water may lead to liquid-vapor oscillations. The resultant transient vapor state is ‘dewetted’ i.e. effectively devoid of water molecules within all, or part of the pore, thus leading to an energetic barrier to ion conduction. This process, termed ‘hydrophobic gating’, was first observed in molecular dynamics simulations of model nanopores, where the principles underlying hydrophobic gating (i.e. changes in diameter, polarity, or transmembrane voltage) have now been extensively validated. Computational, structural and functional studies now indicate that biological ion channels may also exploit hydrophobic gating to regulate ion flow within their pores. Here we review the evidence for this process, and propose that this unusual behavior of water represents an increasingly important element in understanding the relationship between ion channel structure and function. PMID:25106689

  10. Microbial Senses and Ion Channels

    NASA Astrophysics Data System (ADS)

    Kung, Ching; Zhou, Xin-Liang; Su, Zhen-Wei; Haynes, W. John; Loukin, Sephan H.; Saimi, Yoshiro

    The complexity of animals and plants is due largely to cellular arrangement. The structures and activities of macromolecules had, however, evolved in early microbes long before the appearance of this complexity. Among such molecules are those that sense light, heat, force, water, and ligands. Though historically and didactically associated with the nervous system, ion channels also have deep evolutionary roots. For example, force sensing with channels, which likely began as water sensing through membrane stretch generated by osmotic pressure, must be ancient and is universal in extant species. Extant microbial species, such as the model bacterium Escherichia coli and yeast Saccharomyces cerevisiae, are equipped with stretch-activated channels. The ion channel proteins MscL and MscS show clearly that these bacterial channels receive stretch forces from the lipid bilayer. TRPY1, the mechanosensitive channel in yeast, is being developed towards a similar basic understanding of channels of the TRP (transientreceptor- potential) superfamily. TRPY1 resides in the vacuolar membrane and releases Ca2+ from the vacuole to the cytoplasm upon hyperosmotic shock. Unlike in most TRP preparations from animals, the mechanosensitivity of TRPY1 can be examined directly under patch clamp in either whole-vacuole mode or excised patch mode. The combination of direct biophysical examination in vitro with powerful microbial genetics in vivo should complement the study of mechanosensations of complex animals and plants.

  11. Ferritin Protein Nanocage Ion Channels

    PubMed Central

    Tosha, Takehiko; Behera, Rabindra K.; Ng, Ho-Leung; Bhattasali, Onita; Alber, Tom; Theil, Elizabeth C.

    2012-01-01

    Ferritin protein nanocages, self-assembled from four-α-helix bundle subunits, use Fe2+ and oxygen to synthesize encapsulated, ferric oxide minerals. Ferritin minerals are iron concentrates stored for cell growth. Ferritins are also antioxidants, scavenging Fenton chemistry reactants. Channels for iron entry and exit consist of helical hairpin segments surrounding the 3-fold symmetry axes of the ferritin nanocages. We now report structural differences caused by amino acid substitutions in the Fe2+ ion entry and exit channels and at the cytoplasmic pores, from high resolution (1.3–1.8 Å) protein crystal structures of the eukaryotic model ferritin, frog M. Mutations that eliminate conserved ionic or hydrophobic interactions between Arg-72 and Asp-122 and between Leu-110 and Leu-134 increase flexibility in the ion channels, cytoplasmic pores, and/or the N-terminal extensions of the helix bundles. Decreased ion binding in the channels and changes in ordered water are also observed. Protein structural changes coincide with increased Fe2+ exit from dissolved, ferric minerals inside ferritin protein cages; Fe2+ exit from ferritin cages depends on a complex, surface-limited process to reduce and dissolve the ferric mineral. High concentrations of bovine serum albumin or lysozyme (protein crowders) to mimic the cytoplasm restored Fe2+ exit in the variants to wild type. The data suggest that fluctuations in pore structure control gating. The newly identified role of the ferritin subunit N-terminal extensions in gating Fe2+ exit from the cytoplasmic pores strengthens the structural and functional analogies between ferritin ion channels in the water-soluble protein assembly and membrane protein ion channels gated by cytoplasmic N-terminal peptides. PMID:22362775

  12. Improvement in fusion reactor performance due to ion channeling

    SciTech Connect

    Emmert, G.A.; El-Guebaly, L.A.; Kulcinski, G.L.; Santarius, J.F.; Sviatoslavsky, I.N.; Meade, D.M.

    1994-11-01

    Ion channeling is a recent idea for improving the performance of fusion reactors by increasing the fraction of the fusion power deposited in the ions. In this paper the authors assess the effect of ion channeling on D-T and D-{sup 3}He reactors. The figures of merit used are the fusion power density and the cost of electricity. It is seen that significant ion channeling can lead to about a 50-65% increase in the fusion power density. For the Apollo D-{sup 3}He reactor concept the reduction in the cost of electricity can be as large as 30%.

  13. Improved Ion-Channel Biosensors

    NASA Technical Reports Server (NTRS)

    Nadeau, Jay; White, Victor; Dougherty, Dennis; Maurer, Joshua

    2004-01-01

    An effort is underway to develop improved biosensors of a type based on ion channels in biomimetic membranes. These sensors are microfabricated from silicon and other materials compatible with silicon. As described, these sensors offer a number of advantages over prior sensors of this type.

  14. A Latin American Perspective on Ion Channels.

    PubMed

    Elgoyhen, Ana Belén; Barajas-López, Carlos

    2016-09-01

    Ion channels, both ligand- and voltage-gated, play fundamental roles in many physiologic processes. Alteration in ion channel function underlies numerous pathologies, including hypertension, diabetes, chronic pain, epilepsy, certain cancers, and neuromuscular diseases. In addition, an increasing number of inherited and de novo ion channel mutations have been shown to contribute to disease states. Ion channels are thus a major class of pharmacotherapeutic targets.

  15. Ion channels in analgesia research.

    PubMed

    Rosenbaum, Tamara; Simon, Sidney A; Islas, Leon D

    2010-01-01

    Several recent techniques have allowed us to pinpoint the receptors responsible for the detection of nociceptive stimuli. Among these receptors, ion channels play a fundamental role in the recognition and transduction of stimuli that can cause pain. During the last decade, compelling evidence has been gathered on the role of the TRPV1 channel in inflammatory and neuropathic states. Activation of TRPV1 in nociceptive neurons results in the release of neuropeptides and transmitters, leading to the generation of action potentials that will be sent to higher CNS areas, where they will often be perceived as pain. Its activation will also evoke the peripheral release of pro-inflammatory compounds that may sensitize other neurons to physical, thermal, or chemical stimuli. For these reasons, and because its continuous activation causes analgesia, TRPV1 is now considered a viable drug target for clinical use in the management of pain. Using the TRPV1 channel as an example, here we describe some basic biophysical approaches used to study the properties of ion channels involved in pain and in analgesia.

  16. Functional ion channels in stem cells

    PubMed Central

    Li, Gui-Rong; Deng, Xiu-Ling

    2011-01-01

    Bioelectrical signals generated by ion channels play crucial roles in excitation genesis and impulse conduction in excitable cells as well as in cell proliferation, migration and apoptosis in proliferative cells. Recent studies have demonstrated that multiple ion channels are heterogeneously present in different stem cells; however, patterns and phenotypes of ion channels are species- and/or origin-dependent. This editorial review focuses on the recent findings related to the expression of functional ion channels and the roles of these channels in regulation of cell proliferation in stem cells. Additional effort is required in the future to clarify the ion channel expression in different types of stem cells; special attention should be paid to the relationship between ion channels and stem cell proliferation, migration and differentiation. PMID:21607133

  17. High throughput screening technologies for ion channels

    PubMed Central

    Yu, Hai-bo; Li, Min; Wang, Wei-ping; Wang, Xiao-liang

    2016-01-01

    Ion channels are involved in a variety of fundamental physiological processes, and their malfunction causes numerous human diseases. Therefore, ion channels represent a class of attractive drug targets and a class of important off-targets for in vitro pharmacological profiling. In the past decades, the rapid progress in developing functional assays and instrumentation has enabled high throughput screening (HTS) campaigns on an expanding list of channel types. Chronologically, HTS methods for ion channels include the ligand binding assay, flux-based assay, fluorescence-based assay, and automated electrophysiological assay. In this review we summarize the current HTS technologies for different ion channel classes and their applications. PMID:26657056

  18. ICEPO: the ion channel electrophysiology ontology.

    PubMed

    Hinard, V; Britan, A; Rougier, J S; Bairoch, A; Abriel, H; Gaudet, P

    2016-01-01

    Ion channels are transmembrane proteins that selectively allow ions to flow across the plasma membrane and play key roles in diverse biological processes. A multitude of diseases, called channelopathies, such as epilepsies, muscle paralysis, pain syndromes, cardiac arrhythmias or hypoglycemia are due to ion channel mutations. A wide corpus of literature is available on ion channels, covering both their functions and their roles in disease. The research community needs to access this data in a user-friendly, yet systematic manner. However, extraction and integration of this increasing amount of data have been proven to be difficult because of the lack of a standardized vocabulary that describes the properties of ion channels at the molecular level. To address this, we have developed Ion Channel ElectroPhysiology Ontology (ICEPO), an ontology that allows one to annotate the electrophysiological parameters of the voltage-gated class of ion channels. This ontology is based on a three-state model of ion channel gating describing the three conformations/states that an ion channel can adopt: closed, open and inactivated. This ontology supports the capture of voltage-gated ion channel electrophysiological data from the literature in a structured manner and thus enables other applications such as querying and reasoning tools. Here, we present ICEPO (ICEPO ftp site:ftp://ftp.nextprot.org/pub/current_release/controlled_vocabularies/), as well as examples of its use. © The Author(s) 2016. Published by Oxford University Press.

  19. Atomic absorption spectroscopy in ion channel screening.

    PubMed

    Stankovich, Larisa; Wicks, David; Despotovski, Sasko; Liang, Dong

    2004-10-01

    This article examines the utility of atomic absorption spectroscopy, in conjunction with cold flux assays, to ion channel screening. The multiplicity of ion channels that can be interrogated using cold flux assays and atomic absorption spectroscopy is summarized. The importance of atomic absorption spectroscopy as a screening tool is further elaborated upon by providing examples of the relevance of ion channels to various physiological processes and targeted diseases.

  20. Computing rates of Markov models of voltage-gated ion channels by inverting partial differential equations governing the probability density functions of the conducting and non-conducting states.

    PubMed

    Tveito, Aslak; Lines, Glenn T; Edwards, Andrew G; McCulloch, Andrew

    2016-07-01

    Markov models are ubiquitously used to represent the function of single ion channels. However, solving the inverse problem to construct a Markov model of single channel dynamics from bilayer or patch-clamp recordings remains challenging, particularly for channels involving complex gating processes. Methods for solving the inverse problem are generally based on data from voltage clamp measurements. Here, we describe an alternative approach to this problem based on measurements of voltage traces. The voltage traces define probability density functions of the functional states of an ion channel. These probability density functions can also be computed by solving a deterministic system of partial differential equations. The inversion is based on tuning the rates of the Markov models used in the deterministic system of partial differential equations such that the solution mimics the properties of the probability density function gathered from (pseudo) experimental data as well as possible. The optimization is done by defining a cost function to measure the difference between the deterministic solution and the solution based on experimental data. By evoking the properties of this function, it is possible to infer whether the rates of the Markov model are identifiable by our method. We present applications to Markov model well-known from the literature.

  1. Ion Channels in Innate and Adaptive Immunity

    PubMed Central

    Feske, Stefan; Wulff, Heike; Skolnik, Edward Y.

    2016-01-01

    Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy. PMID:25861976

  2. Tracing the roots of ion channels.

    PubMed

    Jan, L Y; Jan, Y N

    1992-05-29

    Two sets of recent findings draw our attention to questions concerning the origin of ion channels. First, there is sequence similarity among five classes of channels: voltage-gated channels, a putative Ca(2+)-activated K+ channel, cyclic nucleotide-gated cation channels, a putative Ca2+ channel for phosphoinositide-mediated Ca2+ entry, and a plant K+ channel/transporter. Like voltage-gated K+ channels, the most recently identified members of the superfamily share the basic design of one set of six potential membrane-spanning segments plus the H5 sequence; as such, they may resemble more closely the ancestral channel, which is likely to predate the separation of the animal and plant kingdoms. Second, several members of the ABC superfamily function as ion channels, even though they were previously known as transporters or enzymes. Did some ancestral enzymes subsequently acquire channel/transporter function? Or could it be the other way around? Aside from evolutionary considerations, enzymes and ion channels can no longer be treated as separate and nonoverlapping groups of proteins. When one molecule exhibits both functions, there are interesting mechanistic questions: How might the enzyme activity such as ATP hydrolysis be coupled to activation/regulation of the intrinsic channel activity? How might interactions between the permeant ions and the channel pore in turn regulate the enzymatic function of the same molecule? It seems possible that the latter is an extension of the observed coupling between permeant ions and the gating machinery of an ion channel (Swenson and Armstrong, 1981). Finally, the potential cross-regulation between channel activity and enzyme activity within the same molecule offers many intriguing possibilities for the integration of different cellular functions.

  3. Ion channels as targets for cancer therapy

    PubMed Central

    Li, Minghua; Xiong, Zhi-Gang

    2011-01-01

    Cancer is a leading cause of death in the world. Conventional treatments have severe side effects and low survival rate. It is important to discover new targets and therapeutic strategies to improve the clinical outcomes of cancer patients. Ion channels are specialized membrane proteins that play important roles in various physiological processes. Recent studies have shown that abnormal expression and/or activity of a number of ion channels e.g. voltage-gated K+, Na+, Ca2+ channels, TRP channels, and epithelial Na+/degenerin family of ion channels, are involved in the growth/proliferation, migration and/or invasion of cancer cells. In this review, we summarize the present knowledge about the roles of different ion channels in the development of cancer. PMID:21760973

  4. Modeling ion channels: Past, present, and future

    PubMed Central

    2014-01-01

    Ion channels are membrane-bound enzymes whose catalytic sites are ion-conducting pores that open and close (gate) in response to specific environmental stimuli. Ion channels are important contributors to cell signaling and homeostasis. Our current understanding of gating is the product of 60 plus years of voltage-clamp recording augmented by intervention in the form of environmental, chemical, and mutational perturbations. The need for good phenomenological models of gating has evolved in parallel with the sophistication of experimental technique. The goal of modeling is to develop realistic schemes that not only describe data, but also accurately reflect mechanisms of action. This review covers three areas that have contributed to the understanding of ion channels: traditional Eyring kinetic theory, molecular dynamics analysis, and statistical thermodynamics. Although the primary emphasis is on voltage-dependent channels, the methods discussed here are easily generalized to other stimuli and could be applied to any ion channel and indeed any macromolecule. PMID:24935742

  5. Arachidonic acid and ion channels: an update

    PubMed Central

    Meves, H

    2008-01-01

    Arachidonic acid (AA), a polyunsaturated fatty acid with four double bonds, has multiple actions on living cells. Many of these effects are mediated by an action of AA or its metabolites on ion channels. During the last 10 years, new types of ion channels, transient receptor potential (TRP) channels, store-operated calcium entry (SOCE) channels and non-SOCE channels have been studied. This review summarizes our current knowledge about the effects of AA on TRP and non-SOCE channels as well as classical ion channels. It aims to distinguish between effects of AA itself and effects of AA metabolites. Lipid mediators are of clinical interest because some of them (for example, leukotrienes) play a role in various diseases, others (such as prostaglandins) are targets for pharmacological therapeutic intervention. PMID:18552881

  6. Dendritic Ion Channel Trafficking and Plasticity

    PubMed Central

    Shah, Mala M.; Hammond, Rebecca S.; Hoffman, Dax

    2010-01-01

    Dendrites, the elaborate processes emerging from neuronal cell bodies, receive most excitatory synaptic inputs. Voltage- and calcium-gated ion channels are abundant in dendrites and modify the shape, propagation and integration of synaptic signals. These ion channels also determine intrinsic dendritic excitability and are therfore important for the induction and manifestation of Hebbian and non-Hebbian plasticity. Revealingly, dendritic channels have distinct expression patterns and biophysical properties from those present in other neuronal compartments. Recent evidence suggests that dendritic ion channels are locally regulated, perhaps contributing to different forms of plasticity. In this review, we will discuss the implications of regulating dendritic ion channel function and trafficking in the context of plasticity and information processing. PMID:20363038

  7. Discovery of functional antibodies targeting ion channels.

    PubMed

    Wilkinson, Trevor C I; Gardener, Matthew J; Williams, Wendy A

    2015-04-01

    Ion channels play critical roles in physiology and disease by modulation of cellular functions such as electrical excitability, secretion, cell migration, and gene transcription. Ion channels represent an important target class for drug discovery that has been largely addressed, to date, using small-molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative formats of biologics. Antibodies display high specificity and affinity for their target antigen, and they have the potential to target ion channels very selectively. Nevertheless, isolating antibodies to this target class is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery in addition to the complexity of screening for function. In this article, we will review the current state of ion channel biologics discovery and the progress that has been made. We will also highlight the challenges in isolating functional antibodies to these targets and how these challenges may be addressed. Finally, we also illustrate successful approaches to isolating functional monoclonal antibodies targeting ion channels by way of a number of case studies drawn from recent publications. © 2014 Society for Laboratory Automation and Screening.

  8. Pair creation in heavy ion channeling

    NASA Astrophysics Data System (ADS)

    Belov, N. A.; Harman, Z.

    2016-04-01

    Heavy ions channeled through crystals with multi-GeV kinetic energies can create electron-positron pairs. In the framework of the ion, the energy of virtual photons arising from the periodic crystal potential may exceed the threshold 2mec2. The repeated periodic collisions with the crystal ions yield high pair production rates. When the virtual photon frequency matches a nuclear transition in the ion, the production rate can be resonantly increased. In this two-step excitation-pair conversion scheme, the excitation rates are coherently enhanced, and scale approximately quadratically with the number of crystal sites along the channel.

  9. Pressure effects on stopping power of solids for channeled ions

    NASA Astrophysics Data System (ADS)

    Pathak, A. P.; Cruz, S. A.; Soullard, J.

    2005-01-01

    Pressure effects on the energy loss of swift channeled ions through silicon are considered. This is accomplished by estimating the changes in orbital charge densities and the corresponding mean ionization potentials, induced by increasing pressure. The bulk density for the compressed material is obtained from available experimental information on the corresponding equation of state for pressures up to 11.3 GPa, beyond which a structural phase transformation occurs. The high pressure is simulated by first caging the individual Si atom in a small spherical volume V and estimated as P=-partial derivative E/partial derivative V, where E is the total electronic energy for a particular confinement volume. The energy is selfconsistently calculated through a recently developed shell-wise version of the Thomas-Fermi-Dirac-Weizsacker density functional, which compares favorably with ab initio calculations on the basis of a cluster model where the Si atom is surrounded by neon (helium) atoms (in a molecular scheme). The resulting individual electronic shell charge densities are then averaged along planar channels to find the effective charge densities needed in the channeling energy loss calculations for channeled ions. The position dependence of the energy loss in the channels for the free and high-pressure case is calculated for 5 Me V protons and alpha particles along the (110) planar channels.

  10. Ion channels and the hallmarks of cancer.

    PubMed

    Prevarskaya, Natalia; Skryma, Roman; Shuba, Yaroslav

    2010-03-01

    Plasma membrane (PM) ion channels contribute to virtually all basic cellular processes and are also involved in the malignant phenotype of cancer cells. Here, we review the role of ion channels in cancer in the context of their involvement in the defined hallmarks of cancer: 1) self-sufficiency in growth signals, 2) insensitivity to antigrowth signals, 3) evasion of programmed cell death (apoptosis), 4) limitless replicative potential, 5) sustained angiogenesis and 6) tissue invasion and metastasis. Recent studies have indicated that the contribution of specific ion channels to these hallmarks varies for different types of cancer. Therefore, to determine the importance of ion channels as targets for cancer diagnosis and treatment their expression, function and regulation must be assessed for each cancer.

  11. Natural Products and Ion Channel Pharmacology

    PubMed Central

    Teichert, Russell W.; Olivera, Baldomero M.

    2014-01-01

    An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of their prey, predators or competitors, which appears to require a large set of ion-channel targeted compounds acting in concert. Some of these compounds (e.g. Ziconotide (Prialt)) have already found important biomedical applications. The elucidation of molecular mechanisms mediating biotic interactions should yield a rich stream of potent and selective natural products for the drug pipeline. PMID:21426200

  12. Alcohol intoxication: Ion channels and genetics

    SciTech Connect

    Harris, A.R.; Allan, A.M. )

    1989-04-01

    Acute in vitro exposure to ethanol and other intoxicant-anesthetics activates {gamma}-aminobutyric acid (GABA)-stimulated chloride channels and inhibits voltage-dependent calcium and sodium channels of isolated brain membranes. The question of whether these neurochemical actions are responsible for intoxication in vivo has been addressed using animal populations displaying genetic differences in sensitivity to alcohol and benzodiazepine intoxication. These genetic approaches include inbred strains, selected lines, recombinant inbred strains, and heterogeneous stocks. Genetic differences in ion channel function provide strong evidence for a role of the GABA-stimulated chloride channel in ethanol and benzodiazepine intoxication; the role of calcium and sodium channels is less clear.

  13. Flufenamic acid as an ion channel modulator

    PubMed Central

    Guinamard, Romain; Simard, Christophe; Negro, Christopher Del

    2014-01-01

    Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10-6 M in TRPM4 channel inhibition to 10-3 M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and systems levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential. PMID:23356979

  14. Reconstruction of Cell Surface Densities of Ion Pumps, Exchangers, and Channels from mRNA Expression, Conductance Kinetics, Whole-Cell Calcium, and Current-Clamp Voltage Recordings, with an Application to Human Uterine Smooth Muscle Cells

    PubMed Central

    Atia, Jolene; McCloskey, Conor; Shmygol, Anatoly S.; Rand, David A.; van den Berg, Hugo A.; Blanks, Andrew M.

    2016-01-01

    Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the ‘conductance repertoire’ being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset. Each entity within the conductance repertoire was modeled independently and its gating parameter values were fixed using the available biophysical data. The only remaining free parameters were the surface densities for each entity. We characterise the space of combinations of surface densities (density vectors) consistent with experimentally observed membrane potential and calcium waveforms. This yields insights on the functional redundancy of the system as well as its behavioral versatility. Our approach couples high-throughput transcriptomic data with physiological behaviors in health and disease, and provides a formal method to link genotype to phenotype in excitable systems. We accurately predict current densities and chart functional redundancy. For example, we find that to evoke the observed voltage waveform, the BK channel is functionally redundant whereas hERG is essential. Furthermore, our analysis suggests that activation of calcium-activated chloride conductances by intracellular calcium release is the key factor underlying spontaneous depolarisations. PMID:27105427

  15. Clustered Ion Channels and Action Potentials

    NASA Astrophysics Data System (ADS)

    Zeng, Shangyou; Shuai, Jianwei; Jung, Peter

    2002-03-01

    It is known that even in unmyelinated neurons the ion channels relevant for action potential generation are in many cases spatially clustered. We study the consequences of spatial clustering of the ion channels for the generation and propagation of action potentials. In particular we report on the frequency and temporal coherence of spontaneous spikes generated by clusters of various sizes and on cluster-cluster synchronization along an axon. For the channel dynamics, we are using a stochastic Hodgkin-Huxley model supplemented by synaptic noise. The axon is modeled by an one dimensional cable equation.

  16. Ion channels regulating mast cell biology.

    PubMed

    Ashmole, I; Bradding, P

    2013-05-01

    Mast cells play a central role in the pathophysiology of asthma and related allergic conditions. Mast cell activation leads to the degranulation of preformed mediators such as histamine and the secretion of newly synthesised proinflammatory mediators such as leukotrienes and cytokines. Excess release of these mediators contributes to allergic disease states. An influx of extracellular Ca2+ is essential for mast cell mediator release. From the Ca2+ channels that mediate this influx, to the K+ , Cl- and transient receptor potential channels that set the cell membrane potential and regulate Ca2+ influx, ion channels play a critical role in mast cell biology. In this review we provide an overview of our current knowledge of ion channel expression and function in mast cells with an emphasis on how channels interact to regulate Ca2+ signalling.

  17. Superposition properties of interacting ion channels.

    PubMed Central

    Keleshian, A M; Yeo, G F; Edeson, R O; Madsen, B W

    1994-01-01

    Quantitative analysis of patch clamp data is widely based on stochastic models of single-channel kinetics. Membrane patches often contain more than one active channel of a given type, and it is usually assumed that these behave independently in order to interpret the record and infer individual channel properties. However, recent studies suggest there are significant channel interactions in some systems. We examine a model of dependence in a system of two identical channels, each modeled by a continuous-time Markov chain in which specified transition rates are dependent on the conductance state of the other channel, changing instantaneously when the other channel opens or closes. Each channel then has, e.g., a closed time density that is conditional on the other channel being open or closed, these being identical under independence. We relate the two densities by a convolution function that embodies information about, and serves to quantify, dependence in the closed class. Distributions of observable (superposition) sojourn times are given in terms of these conditional densities. The behavior of two channel systems based on two- and three-state Markov models is examined by simulation. Optimized fitting of simulated data using reasonable parameters values and sample size indicates that both positive and negative cooperativity can be distinguished from independence. PMID:7524711

  18. Optimum ion channel properties in the squid giant axon

    NASA Astrophysics Data System (ADS)

    Adair, Robert K.

    2004-04-01

    Evolutionary pressures are presumed to act so as to maximize the efficiency of biological systems. However, the utility of that premise is marred by the difficulties in defining and evaluating both the efficiency of systems and the character of the available variation space. Following Hodgkin and Adrian, we examine the character of voltage gated ion channels in the nonmyelinated giant axons of the squid and find that both the channel densities and channel transition rates have values that nearly optimize signal sensitivity as well as signal velocity.

  19. Vacuolar ion channels in the liverwort Marchantia polymorpha: influence of ion channel inhibitors.

    PubMed

    Koselski, Mateusz; Trebacz, Kazimierz; Dziubinska, Halina

    2017-05-01

    Potassium-permeable slow activating vacuolar channels (SV) and chloride-permeable channels in the vacuole of the liverwort Marchantia polymorpha were characterized in respect to calcium dependence, selectivity, and pharmacology. The patch-clamp method was used in the study of ion channel activity in the vacuoles from the liverwort Marchantia polymorpha. The whole-vacuole recordings allowed simultaneous observation of two types of currents-predominant slow activated currents recorded at positive voltages and fast activated currents recorded at negative voltages. Single-channel recordings carried out in the gradient of KCl indicated that slow activated currents were carried by potassium-permeable slowly activating vacuolar channels (SV) and fast activated currents-by chloride-permeable channels. Both types of the channels were dependent in an opposite way on calcium, since elimination of this ion from the cytoplasmic side caused inhibition of SV channels, but the open probability of chloride-permeable channels even increased. The dependence of the activity of both channels on different types of ion channel inhibitors was studied. SV channels exhibited different sensitivity to potassium channel inhibitors. These channels were insensitive to 3 mM Ba(2+), but were blocked by 3 mM tetraethyl ammonium (TEA). Moreover, the activity of the channels was modified in a different way by calcium channel inhibitors. 200 µM Gd(3+) was an effective blocker, but 50 µM ruthenium red evoked bursts of the channel activity resulting in an increase in the open probability. Different effectiveness of anion channel inhibitors was observed in chloride-permeable channels. After the application of 100 µM Zn(2+), a decrease in the open probability was recorded but the channels were still active. 50 µM DIDS was more effective, as it completely blocked the channels.

  20. The Origins of Transmembrane Ion Channels

    NASA Technical Reports Server (NTRS)

    Pohorille, Andrew; Wilson, Michael A.

    2012-01-01

    Even though membrane proteins that mediate transport of ions and small molecules across cell walls are among the largest and least understood biopolymers in contemporary cells, it is still possible to shed light on their origins and early evolution. The central observation is that transmembrane portions of most ion channels are simply bundles of -helices. By combining results of experimental and computer simulation studies on synthetic models and natural channels, mostly of non-genomic origin, we show that the emergence of -helical channels was protobiologically plausible, and did not require highly specific amino acid sequences. Despite their simple structure, such channels could possess properties that, at the first sight, appear to require markedly larger complexity. Specifically, we explain how the antiamoebin channels, which are made of identical helices, 16 amino acids in length, achieve efficiency comparable to that of highly evolved channels. We further show that antiamoebin channels are extremely flexible, compared to modern, genetically coded channels. On the basis of our results, we propose that channels evolved further towards high structural complexity because they needed to acquire stable rigid structures and mechanisms for precise regulation rather than improve efficiency. In general, even though architectures of membrane proteins are not nearly as diverse as those of water-soluble proteins, they are sufficiently flexible to adapt readily to the functional demands arising during evolution.

  1. Ion channels and transporters in metastasis.

    PubMed

    Stock, Christian; Schwab, Albrecht

    2015-10-01

    An elaborate interplay between ion channels and transporters, components of the cytoskeleton, adhesion molecules, and signaling cascades provides the basis for each major step of the metastatic cascade. Ion channels and transporters contribute to cell motility by letting through or transporting ions essential for local Ca2+, pH and--in cooperation with water permeable aquaporins--volume homeostasis. Moreover, in addition to the actual ion transport they, or their auxiliary subunits, can display non-conducting activities. They can exert kinase activity in order to phosphorylate cytoskeletal constituents or their associates. They can become part of signaling processes by permeating Ca2+, by generating local pH-nanodomains or by being final downstream effectors. A number of channels and transporters are found at focal adhesions, interacting directly or indirectly with proteins of the extracellular matrix, with integrins or with components of the cytoskeleton. We also include the role of aquaporins in cell motility. They drive the outgrowth of lamellipodia/invadopodia or control the number of β1 integrins in the plasma membrane. The multitude of interacting ion channels and transporters (called transportome) including the associated signaling events holds great potential as therapeutic target(s) for anticancer agents that are aimed at preventing metastasis. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

  2. Probability density functions in turbulent channel flow

    NASA Technical Reports Server (NTRS)

    Dinavahi, Surya P. G.

    1992-01-01

    The probability density functions (pdf's) of the fluctuating velocity components, as well as their first and second derivatives, are calculated using data from the direct numerical simulations (DNS) of fully developed turbulent channel flow. It is observed that, beyond the buffer region, the pdf of each of these quantities is independent of the distance from the channel wall. It is further observed that, beyond the buffer region, the pdf's for all the first derivatives collapse onto a single universal curve and those of the second derivatives also collapse onto another universal curve, irrespective of the distance from the wall. The kinetic-energy dissipation rate exhibits log normal behavior.

  3. Studying mechanosensitive ion channels using liposomes.

    PubMed

    Martinac, Boris; Rohde, Paul R; Battle, Andrew R; Petrov, Evgeny; Pal, Prithwish; Foo, Alexander Fook; Vásquez, Valeria; Huynh, Thuan; Kloda, Anna

    2010-01-01

    Mechanosensitive (MS) ion channels are the primary molecular transducers of mechanical force into electrical and/or chemical intracellular signals in living cells. They have been implicated in innumerable mechanosensory physiological processes including touch and pain sensation, hearing, blood pressure control, micturition, cell volume regulation, tissue growth, or cellular turgor control. Much of what we know about the basic physical principles underlying the conversion of mechanical force acting upon membranes of living cells into conformational changes of MS channels comes from studies of MS channels reconstituted into artificial liposomes. Using bacterial MS channels as a model, we have shown by reconstituting these channels into liposomes that there is a close relationship between the physico-chemical properties of the lipid bilayer and structural dynamics bringing about the function of these channels.

  4. Mechanosensitive Ion Channels in Cardiovascular Physiology.

    PubMed

    Teng, Jinfeng; Loukin, Steve; Kung, Ching

    EC coupling is subjected to a mechanical feedback, which originates from physical force-sensing ion channels in the pericardium and elsewhere. Reviewed here are the most recent developments that greatly advanced our understanding of these mechanosensitive (MS) channels, including TRPs and K2p's. Patch clamp has continued to demonstrate the direct channel activation by membrane stretch. Crystallography and cryo-electron microscopy have revealed the structures of several MS channels at atomic resolution. Some have been purified to homogeneity, reconstituted into lipid bilayer, and still retain their ability to respond to stretch force. A force-from-lipid (FFL) theory has been advanced that emphasizes the strong binding between channel proteins and lipids. Through these bonds, the sharp lateral tension (akin to surface tension) of the bilayer can transmit added force to the channel protein. Like temperature sensitivity, sensitivity to mechanical force is far more pervasive than we previously realize, and is especially important to the beating heart.

  5. Tuning Photochromic Ion Channel Blockers

    PubMed Central

    2011-01-01

    Photochromic channel blockers provide a conceptually simple and convenient way to modulate neuronal activity with light. We have recently described a family of azobenzenes that function as tonic blockers of Kv channels but require UV-A light to unblock and need to be actively switched by toggling between two different wavelengths. We now introduce red-shifted compounds that fully operate in the visible region of the spectrum and quickly turn themselves off in the dark. Furthermore, we have developed a version that does not block effectively in the dark-adapted state, can be switched to a blocking state with blue light, and reverts to the inactive state automatically. Photochromic blockers of this type could be useful for the photopharmacological control of neuronal activity under mild conditions. PMID:22860175

  6. Acid-Sensing Ion Channels and Pain.

    PubMed

    Gu, Qihai; Lee, Lu-Yuan

    2010-05-11

    Pathophysiological conditions such as inflammation, ischemia, infection and tissue injury can all evoke pain, and each is accompanied by local acidosis. Acid sensing ion channels (ASICs) are proton-gated cation channels expressed in both central and peripheral nervous systems. Increasing evidence suggests that ASICs represent essential sensors for tissue acidosis-related pain. This review provides an update on the role of ASICs in pain sensation and discusses their therapeutic potential for pain management.

  7. The Earliest Ion Channels in Protocellular Membranes

    NASA Technical Reports Server (NTRS)

    Mijajlovic, Milan; Pohorille, Andrew; Wilson, Michael; Wei, Chenyu

    2010-01-01

    Cellular membranes with their hydrophobic interior are virtually impermeable to ions. Bulk of ion transport through them is enabled through ion channels. Ion channels of contemporary cells are complex protein molecules which span the membrane creating a cylindrical pore filled with water. Protocells, which are widely regarded as precursors to modern cells, had similarly impermeable membranes, but the set of proteins in their disposal was much simpler and more limited. We have been, therefore, exploring an idea that the first ion channels in protocellular membranes were formed by much smaller peptide molecules that could spontaneously selfassemble into short-lived cylindrical bundles in a membrane. Earlier studies have shown that a group of peptides known as peptaibols is capable of forming ion channels in lipid bilayers when they are exposed to an electric field. Peptaibols are small, non-genetically encoded peptides produced by some fungi as a part of their system of defense against bacteria. They are usually only 14-20 residues long, which is just enough to span the membrane. Their sequence is characterized by the presence of non-standard amino acids which, interestingly, are also expected to have existed on the early earth. In particular, the presence of 2-aminoisobutyric acid (AIB) gives peptaibols strong helix forming propensities. Association of the helices inside membranes leads to the formation of cylindrical bundles, typically containing 4 to 10 monomers. Although peptaibols are excellent candidates for models of the earliest ion channels their structures, which are stabilized only by van der Waals forces and occasional hydrogen bonds between neighboring helices, are not very stable. Although it might properly reflect protobiological reality, it is also a major obstacle in studying channel behavior. For this reason we focused on two members of the peptaibol family, trichotoxin and antiamoebin, which are characterized by a single conductance level. This

  8. The earliest ion channels in protocellular membranes

    NASA Astrophysics Data System (ADS)

    Mijajlovic, Milan; Pohorille, Andrew; Wilson, Michael; Wei, Chenyu

    Cellular membranes with their hydrophobic interior are virtually impermeable to ions. Bulk of ion transport through them is enabled through ion channels. Ion channels of contemporary cells are complex protein molecules which span the membrane creating a cylindrical pore filled with water. Protocells, which are widely regarded as precursors to modern cells, had similarly impermeable membranes, but the set of proteins in their disposal was much simpler and more limited. We have been, therefore, exploring an idea that the first ion channels in protocellular membranes were formed by much smaller peptide molecules that could spontaneously self-assemble into short-lived cylindrical bundles in a membrane. Earlier studies have shown that a group of peptides known as peptaibols is capable of forming ion channels in lipid bilayers when they are exposed to an electric field. Peptaibols are small, non-genetically encoded peptides produced by some fungi as a part of their system of defense against bacteria. They are usually only 14-20 residues long, which is just enough to span the membrane. Their sequence is characterized by the presence of non-standard amino acids which, interestingly, are also expected to have existed on the early earth. In particular, the presence of 2-aminoisobutyric acid (AIB) gives peptaibols strong helix forming propensities. Association of the helices inside membranes leads to the formation of cylindrical bundles, typically containing 4 to 10 monomers. Although peptaibols are excellent candidates for models of the earliest ion channels their struc-tures, which are stabilized only by van der Waals forces and occasional hydrogen bonds between neighboring helices, are not very stable. Although it might properly reflect protobiological real-ity, it is also a major obstacle in studying channel behavior. For this reason we focused on two members of the peptaibol family, trichotoxin and antiamoebin, which are characterized by a single conductance level. This

  9. Channeling technique to make nanoscale ion beams

    NASA Astrophysics Data System (ADS)

    Biryukov, V. M.; Bellucci, S.; Guidi, V.

    2005-04-01

    Particle channeling in a bent crystal lattice has led to an efficient instrument for beam steering at accelerators [Biryukov et al., Crystal Channeling and its Application at High Energy Accelerators, Springer, Berlin, 1997], demonstrated from MeV to TeV energies. In particular, crystal focusing of high-energy protons to micron size has been demonstrated at IHEP with the results well in match with Lindhard (critical angle) prediction. Channeling in crystal microstructures has been proposed as a unique source of a microbeam of high-energy particles [Bellucci et al., Phys. Rev. ST Accel. Beams 6 (2003) 033502]. Channeling in nanostructures (single-wall and multi-wall nanotubes) offers the opportunities to produce ion beams on nanoscale. Particles channeled in a nanotube (with typical diameter of about 1 nm) are trapped in two dimensions and can be steered (deflected, focused) with the efficiency similar to that of crystal channeling or better. This technique has been a subject of computer simulations, with experimental efforts under way in several high-energy labs, including IHEP. We present the theoretical outlook for making channeling-based nanoscale ion beams and report the experience with crystal-focused microscale proton beams.

  10. Amending the uniformity of ion beam current density profile

    NASA Astrophysics Data System (ADS)

    Zhou, Xiaowei; Xu, Dequan; Liu, Ying; Xu, Xiangdong; Fu, Shaojun

    2008-03-01

    The uniformity of ion beam current density profile has been amended by changing the flow of the gas and making a new beam channel. The platform scanned in the horizontal orientation in this experiment, so the horizontal ion beam current distribution had hardly any effect on the etching uniformity and amending the ion beam current density profile in the vertical orientation was sufficient for the purpose of plat etching profile. The ratio of the ion source's working gas inputs has some effect for the uniformity and a ratio of 6.50sccm: 8.00sccm: 9.60sccm of the three gas inputs flow1: flow2: flow3 will lead to a more uniform profile. According to the horizontal distribution and the original vertical ion beam current density distribution measured by Faraday Cup, a new beam channel was made. The uniformity of ion beam current density profile is enhanced from +/-4.31%to +/-1.96% in this experiment.

  11. Amplification of electromagnetic signals by ion channels.

    PubMed Central

    Galvanovskis, J; Sandblom, J

    1997-01-01

    Cells may respond to the exposure of low-frequency electromagnetic fields with changes in cell division, ion influx, chemical reaction rates, etc. The chain of events leading to such responses is difficult to study, mainly because of extremely small energies associated with low-frequency fields, usually much smaller than the thermal noise level. However, the presence of stochastic systems (for instance, ion channels) provides a basis for signal amplification, and could therefore, despite the low signal-to-noise ratio of the primary response, lead to the transmission of weak signals along the signaling pathways of cells. We have explored this possibility for an ion channel model, and we present a theory, based on the formalism of stochastically driven processes, that relates the time averages of the ion channel currents to the amplitude and frequency of the applied signal. It is concluded from this theory that the signal-to-noise ratio increases with the number of channels, the magnitude of the rate constants, and the frequency response of the intracellular sensing system (for instance, a calcium oscillator). The amplification properties of the stochastic system are further deduced from numerical simulations carried out on the model, which consists of multiple identical two-state channels, and the behavior for different parameters is examined. Numerical estimates of the parameters show that under optimum conditions, even very weak low-frequency electromagnetic signals (<100 Hz and down to 100 microT) may be detected in a cellular system with a large number of ion channels. PMID:9414219

  12. Inherited ion channel diseases: a brief review.

    PubMed

    Lieve, Krystien V V; Wilde, Arthur A M

    2015-10-01

    Ion channelopathies are diseases caused by dysfunctional ion channels that may lead to sudden death. These diseases can be either acquired or inherited. The main phenotypes observed in patients carrying these heritable arrhythmia syndromes are congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. In the recent years, tremendous progress has been made in the recognition, mechanisms, and treatment of these diseases. The goal of this review is to provide an overview of the main phenotypes, genetic underpinnings, risk stratification, and treatment options for these so-called cardiac ion channelopathies.

  13. 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

  14. Examination of Ion Channel Protein Orientation in Supported Lipid Bilayers

    NASA Astrophysics Data System (ADS)

    Shinozaki, Youichi; Sumitomo, Koji; Tanaka, Aya; Kasai, Nahoko; Torimitsu, Keiichi

    2011-10-01

    We investigated techniques for regulating the orientation of ion channel-type membrane proteins reconstituted in lipid bilayers. Free ion channel proteins aligned their long axis parallel to the substrate. In contrast, immunochemical and atomic force microscopy images revealed that ion channels reconstituted in supported lipid bilayers oriented upward, with their long axis perpendicular to the substrate. Our data demonstrates that the reconstitution of ion channels into planar lipid bilayers by rupturing small unilamellar proteoliposomes is a promising way of aligning ion channels upward in a membrane and of obtaining ion channels with controlled functions.

  15. Conductance of Ion Channels - Theory vs. Experiment

    NASA Technical Reports Server (NTRS)

    Pohorille, Andrew; Wilson, Michael; Mijajlovic, Milan

    2013-01-01

    Transmembrane ion channels mediate a number of essential physiological processes in a cell ranging from regulating osmotic pressure to transmission of neural signals. Kinetics and selectivity of ion transport is of critical importance to a cell and, not surprisingly, it is a subject of numerous experimental and theoretical studies. In this presentation we will analyze in detail computer simulations of two simple channels from fungi - antiamoebin and trichotoxin. Each of these channels is made of an alpha-helical bundle of small, nongenomically synthesized peptides containing a number of rare amino acids and exhibits strong antimicrobial activity. We will focus on calculating ionic conductance defined as the ratio of ionic current through the channel to applied voltage. From molecular dynamics simulations, conductance can be calculated in at least two ways, each involving different approximations. Specifically, the current, given as the number of charges transferred through the channel per unit of time, can be obtained from the number of events in which ions cross the channel during the simulation. This method works well for large currents (high conductance values and/or applied voltages). If the number of crossing events is small, reliable estimates of current are difficult to achieve. Alternatively, conductance can be estimated assuming that ion transport can be well approximated as diffusion in the external potential given by the free energy profile. Then, the current can be calculated by solving the one-dimensional diffusion equation in this external potential and applied voltage (the generalized Nernst-Planck equation). To do so three ingredients are needed: the free energy profile, the position-dependent diffusion coefficient and the diffusive flux of ions into the channel. All these quantities can be obtained from molecular dynamics simulations. An important advantage of this method is that it can be used equally well to estimating large and small currents

  16. Targeting ion channels in cystic fibrosis.

    PubMed

    Mall, Marcus A; Galietta, Luis J V

    2015-09-01

    Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause a characteristic defect in epithelial ion transport that plays a central role in the pathogenesis of cystic fibrosis (CF). Hence, pharmacological correction of this ion transport defect by targeting of mutant CFTR, or alternative ion channels that may compensate for CFTR dysfunction, has long been considered as an attractive approach to a causal therapy of this life-limiting disease. The recent introduction of the CFTR potentiator ivacaftor into the therapy of a subgroup of patients with specific CFTR mutations was a major milestone and enormous stimulus for seeking effective ion transport modulators for all patients with CF. In this review, we discuss recent breakthroughs and setbacks with CFTR modulators designed to rescue mutant CFTR including the common mutation F508del. Further, we examine the alternative chloride channels TMEM16A and SLC26A9, as well as the epithelial sodium channel ENaC as alternative targets in CF lung disease, which remains the major cause of morbidity and mortality in patients with CF. Finally, we will focus on the hurdles that still need to be overcome to make effective ion transport modulation therapies available for all patients with CF irrespective of their CFTR genotype.

  17. Calcium homeostasis modulator (CALHM) ion channels

    PubMed Central

    Tanis, Jessica E.; Taruno, Akiyuki

    2017-01-01

    Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca2+ concentration ([Ca2+]o). In the presence of physiological [Ca2+]o (~1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong de-polarizations. Reducing [Ca2+]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca2+o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four trans-membrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ~14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca2+ and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca2+]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neuro-transmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca2+o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology. PMID:26603282

  18. Calcium homeostasis modulator (CALHM) ion channels.

    PubMed

    Ma, Zhongming; Tanis, Jessica E; Taruno, Akiyuki; Foskett, J Kevin

    2016-03-01

    Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ∼14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology.

  19. Plasma Channel Transport for Heavy Ion Fusion: Investigation of Beam Transport, Channel Initiation and Stability

    NASA Astrophysics Data System (ADS)

    Tauschwitz, Andreas; Niemann, Christoph; Penache, Dan; Birkner, Richard; Hoffmann, Dieter H. H.; Kobloch, Renate; Neff, Stefan; Presura, Radu; Ponce, Dave; Rosmej, Frank; Yu, Simon

    2002-12-01

    For final beam transport in an IFE reactor three alternatives are mainly discussed. These are neutralized ballistic transport, self-pinched transport, and plasma channel transport. Discharge plasma channels were investigated in the recent years at GSI Darmstadt and at LBNL Berkeley in a number of experiments. Different initiation mechanisms for gas discharges of up to 60 kA were studied and compared. In the Berkeley experiments laser ionization of organic vapors in a buffer gas was used to initiate and direct the discharge while at GSI laser gas heating and ion beam induced gas ionization were tested as initiation mechanisms. Measurements of temperature, electron density, gas density, and magnetic field distribution in the channels are compared with results of beam transport experiments at the GSI UNILAC accelerator and with MHD simulations of the 1D-fluidcode CYCLOPS, which was developed in Berkeley. Good agreement between plasma diagnostics results, measured ion optical properties and MHD simulations was found. Parameters that are required for a reactor application are a discharge current of 50 kA, a channel diameter below 1 cm, a pointing stability better than 500 μm, and MHD stability for more than 10 μs. These parameters have been demonstrated in the recent experiments. The results imply that transport channels work with sufficient stability, reproducibility and ion optical properties in a wide pressure range and for various discharge gases.

  20. Voltage-Gated Lipid Ion Channels

    PubMed Central

    Blicher, Andreas; Heimburg, Thomas

    2013-01-01

    Synthetic lipid membranes can display channel-like ion conduction events even in the absence of proteins. We show here that these events are voltage-gated with a quadratic voltage dependence as expected from electrostatic theory of capacitors. To this end, we recorded channel traces and current histograms in patch-experiments on lipid membranes. We derived a theoretical current-voltage relationship for pores in lipid membranes that describes the experimental data very well when assuming an asymmetric membrane. We determined the equilibrium constant between closed and open state and the open probability as a function of voltage. The voltage-dependence of the lipid pores is found comparable to that of protein channels. Lifetime distributions of open and closed events indicate that the channel open distribution does not follow exponential statistics but rather power law behavior for long open times. PMID:23823188

  1. Ion channels and anti-cancer immunity.

    PubMed

    Panyi, Gyorgy; Beeton, Christine; Felipe, Antonio

    2014-03-19

    The outcome of a malignant disease depends on the efficacy of the immune system to destroy cancer cells. Key steps in this process, for example the generation of a proper Ca(2+) signal induced by recognition of a specific antigen, are regulated by various ion channel including voltage-gated Kv1.3 and Ca(2+)-activated KCa3.1 K(+) channels, and the interplay between Orai and STIM to produce the Ca(2+)-release-activated Ca(2+) (CRAC) current required for T-cell proliferation and function. Understanding the immune cell subset-specific expression of ion channels along with their particular function in a given cell type, and the role of cancer tissue-dependent factors in the regulation of operation of these ion channels are emerging questions to be addressed in the fight against cancer disease. Answering these questions might lead to a better understanding of the immunosuppression phenomenon in cancer tissue and the development of drugs aimed at skewing the distribution of immune cell types towards killing of the tumour cells.

  2. Bubbles, Gating, and Anesthetics in Ion Channels

    PubMed Central

    Roth, Roland; Gillespie, Dirk; Nonner, Wolfgang; Eisenberg, Robert E.

    2008-01-01

    We suggest that bubbles are the bistable hydrophobic gates responsible for the on-off transitions of single channel currents. In this view, many types of channels gate by the same physical mechanism—dewetting by capillary evaporation—but different types of channels use different sensors to modulate hydrophobic properties of the channel wall and thereby trigger and control bubbles and gating. Spontaneous emptying of channels has been seen in many simulations. Because of the physics involved, such phase transitions are inherently sensitive, unstable threshold phenomena that are difficult to simulate reproducibly and thus convincingly. We present a thermodynamic analysis of a bubble gate using morphometric density functional theory of classical (not quantum) mechanics. Thermodynamic analysis of phase transitions is generally more reproducible and less sensitive to details than simulations. Anesthetic actions of inert gases—and their interactions with hydrostatic pressure (e.g., nitrogen narcosis)—can be easily understood by actions on bubbles. A general theory of gas anesthesia may involve bubbles in channels. Only experiments can show whether, or when, or which channels actually use bubbles as hydrophobic gates: direct observation of bubbles in channels is needed. Existing experiments show thin gas layers on hydrophobic surfaces in water and suggest that bubbles nearly exist in bulk water. PMID:18234836

  3. Spiking synchronization of ion channel clusters on an axon

    NASA Astrophysics Data System (ADS)

    Zeng, Shangyou; Tang, Yi; Jung, Peter

    2007-07-01

    Ion channels are distributed in clusters in squid giant axons, rat retinal nerve fiber layers, pyramidal cell dendrites of Apteronotus, etc. Ion channel clusters along the unmyelinated axon generate spontaneous spiking due to ion channel noise. Ion channel clusters are coupled by the axonal cable, and spontaneous spiking of each ion channel cluster can be synchronized. This paper considers the spiking synchronization of two ion channel clusters coupled by an axon. It is shown that axonal parameters affect the spiking synchronization exponentially and ion channel clusters have maximal spiking synchronization when they have the same size. It is further shown that there is an optimal length of the ion channel clusters with maximal spiking synchronization and the optimal length accords with the length of the node of Ranvier in the myelinated axon.

  4. 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.

  5. 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

  6. Radiative electron capture by channeled ions

    SciTech Connect

    Pitarke, J.M. . Zientzi Fakultatea); Ritchie, R.H. Tennessee Univ., Knoxville, TN . Dept. of Physics)

    1989-01-01

    Considerable experimental data have been accumulated relative to the emission of photons accompanying electron capture by swift, highly stripped atoms penetrating crystalline matter under channeling conditions. Recent data suggest that the photon energies may be less than that expected from simple considerations of transitions from the valence band of the solid to hydrogenic states on the moving ion. We have studied theoretically the impact parameter dependence of the radiative electron capture (REC) process, the effect of the ion's wake and the effect of capture from inner shells of the solid on the photon emission probability, using a statistical approach. Numerical comparisons of our results with experiment are made. 13 refs., 6 figs.

  7. Carbon-based ion and molecular channels

    NASA Astrophysics Data System (ADS)

    Sint, Kyaw; Wang, Boyang; Kral, Petr

    2008-03-01

    We design ion and molecular channels based on layered carboneous materials, with chemically-functionalized pore entrances. Our molecular dynamics simulations demonstrate that these ultra-narrow pores, with diameters around 1 nm, are highly selective to the charges and sizes of the passing (Na^+ and Cl^-) ions and short alkanes. We demonstrate that the molecular flows through these pores can be easily controlled by electrical and mechanical means. These artificial pores could be integrated in fluidic nanodevices and lab-on-a-chip techniques with numerous potential applications. [1] Kyaw Sint, Boyang Wang and Petr Kral, submitted. [2] Boyang Wang and Petr Kral, JACS 128, 15984 (2006).

  8. Ball lightning dynamics and stability at moderate ion densities

    NASA Astrophysics Data System (ADS)

    Morrow, R.

    2017-10-01

    A general mechanism is presented for the dynamics and structure of ball lightning and for the maintenance of the ball lightning structure for several seconds. Results are obtained using a spherical geometry for air at atmospheric pressure, by solving the continuity equations for electrons, positive ions and negative ions coupled with Poisson’s equation. A lightning strike can generate conditions in the lightning channel with a majority of positive nitrogen ions, and a minority of negative oxygen ions and electrons. The calculations are initiated with electrons included; however, at the moderate ion densities chosen the electrons are rapidly lost to form negative ions, and after 1 µs their influence on the ion dynamics is negligible. Further development after 1 µs is followed using a simpler set of equations involving only positive ions and negative ions, but including ion diffusion. The space-charge electric field generated by the majority positive ions drives them from the centre of the distribution and drives the minority negative ions and electrons towards the centre of the distribution. In the central region the positive and negative ion distributions eventually overlap exactly and their space-charge fields cancel resulting in zero electric field, and the plasma ball formed is quite stable for a number of seconds. The formation of such plasma balls is not critically dependent on the initial diameter of the ion distributions, or the initial density of minority negative ions. The ion densities decrease relatively slowly due to mutual neutralization of positive and negative ions. The radiation from this neutralization process involving positive nitrogen ions and negative oxygen ions is not sufficient to account for the reported luminosity of ball lightning and some other source of luminosity is shown to be required; the plasma ball model used could readily incorporate other ions in order to account for the luminosity and range of colours reported for ball

  9. Ion beam irradiated optical channel waveguides

    NASA Astrophysics Data System (ADS)

    Bányász, I.; Rajta, I.; Nagy, G. U. L.; Zolnai, Z.; Havranek, V.; Pelli, S.; Veres, M.; Himics, L.; Berneschi, S.; Nunzi-Conti, G.; Righini, G. C.

    2014-03-01

    Nowadays, in the modern optical communications systems, channel waveguides represent the core of many active and passive integrated devices, such as amplifiers, lasers, couplers and splitters. Different materials and fabrication processes were investigated in order to achieve the aforementioned optoelectronic circuits with low costs and high performance and reproducibility. Nevertheless, the 2D guiding structures fabrication continues to be a challenging task in some of optical materials due to their susceptibility to mechanical and/or chemical damages which can occur during the different steps of the fabrication process. Here we report on channel waveguides demonstration in erbium doped Tungsten - Tellurite (Er3+:TeO2-WO3) glasses and BGO crystals by means of a masked ion beam and/or direct writing processes performed at different energy MeV and ions species. The evidence of the waveguides formation was investigated by microscopy techniques and micro Raman spectroscopy.

  10. Contribution of mechanosensitive ion channels to somatosensation.

    PubMed

    Sharif-Naeini, Reza

    2015-01-01

    Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal, is a central mechanism to several physiological functions in mammals. It relies on the function of mechanosensitive ion channels (MSCs). Although the first single-channel recording from MSCs dates back to 30 years ago, the identity of the genes encoding MSCs has remained largely elusive. Because these channels have an important role in the development of mechanical hypersensitivity, a better understanding of their function may lead to the identification of selective inhibitors and generate novel therapeutic pathways in the treatment of chronic pain. Here, I will describe our current understanding of the role MSCs may play in somatosensation and the potential candidate genes proposed to encode them.

  11. Theoretical Study of Ion Transport in the Gramicidin a Channel

    NASA Astrophysics Data System (ADS)

    Roux, Benoi T.

    they fail to satisfy the compressibility theorm; a new closure consistent with the compressibility theorm is suggested. The properties of the charge density at the membrane interface between two ionic solutions are examined using the Poisson-Boltzmann theory. Statistical mechanical theory is used to examine the microscopic aspects of the Nernst-Planck diffusion equation for ion channels. Molecular dynamics simulations are used to determine the time-dependent friction for pair diffusion in an isotropic Lennard-Jones fluid as a function of the separation between two diffusing particles.

  12. Metal interactions with voltage- and receptor-activated ion channels.

    PubMed Central

    Vijverberg, H P; Oortgiesen, M; Leinders, T; van Kleef, R G

    1994-01-01

    Effects of Pb and several other metal ions on various distinct types of voltage-, receptor- and Ca-activated ion channels have been investigated in cultured N1E-115 mouse neuroblastoma cells. Experiments were performed using the whole-cell voltage clamp and single-channel patch clamp techniques. External superfusion of nanomolar to submillimolar concentrations of Pb causes multiple effects on ion channels. Barium current through voltage-activated Ca channels is blocked by micromolar concentrations of Pb, whereas voltage-activated Na current appears insensitive. Neuronal type nicotinic acetylcholine receptor-activated ion current is blocked by nanomolar concentrations of Pb and this block is reversed at micromolar concentrations. Serotonin 5-HT3 receptor-activated ion current is much less sensitive to Pb. In addition, external superfusion with micromolar concentrations of Pb as well as of Cd and aluminum induces inward current, associated with the direct activation of nonselective cation channels by these metal ions. In excised inside-out membrane patches of neuroblastoma cells, micromolar concentrations of Ca activate small (SK) and big (BK) Ca-activated K channels. Internally applied Pb activates SK and BK channels more potently than Ca, whereas Cd is approximately equipotent to Pb with respect to SK channel activation, but fails to activate BK channels. The results show that metal ions cause distinct, selective effects on the various types of ion channels and that metal ion interaction sites of ion channels may be highly selective for particular metal ions. PMID:7531139

  13. Dynamics of ponderomotive ion acceleration in a laser-plasma channel

    NASA Astrophysics Data System (ADS)

    Kovalev, V. F.; Bychenkov, V. Yu.

    2015-04-01

    Analytical solution to the Cauchy problem for the kinetic equation describing the radial acceleration of ions under the action of the ponderomotive force of a laser beam undergoing guided propagation in transparent plasma is constructed. Spatial and temporal dependences of the ion distribution function and the integral ion characteristics, such as the density, average velocity, and energy spectrum, are obtained for an axisymmetric laser-plasma channel. The formation of a density peak near the channel boundary and the effect of ion flow breaking for a quasi-stationary laser beam are described analytically.

  14. Simulations of ion current in realistic models of ion channels: the KcsA potassium channel.

    PubMed

    Burykin, A; Schutz, C N; Villá, J; Warshel, A

    2002-05-15

    Realistic studies of ion current in biologic channels present a major challenge for computer simulation approaches. All-atom molecular dynamics simulations involve serious time limitations that prevent their use in direct evaluation of ion current in channels with significant barriers. The alternative use of Brownian dynamics (BD) simulations can provide the current for simplified macroscopic models. However, the time needed for accurate calculations of electrostatic energies can make BD simulations of ion current expensive. The present work develops an approach that overcomes some of the above challenges and allows one to simulate ion currents in models of biologic channels. Our method provides a fast and reliable estimate of the energetics of the system by combining semimacroscopic calculations of the self-energy of each ion and an implicit treatment of the interactions between the ions, as well as the interactions between the ions and the protein-ionizable groups. This treatment involves the use of the semimacroscopic version of the protein dipole Langevin dipole (PDLD/S) model in its linear response approximation (LRA) implementation, which reduces the uncertainties about the value of the protein "dielectric constant." The resulting free energy surface is used to generate the forces for on-the-fly BD simulations of the corresponding ion currents. Our model is examined in a preliminary simulation of the ion current in the KcsA potassium channel. The complete free energy profile for a single ion transport reflects reasonable energetics and captures the effect of the protein-ionized groups. This calculated profile indicates that we are dealing with the channel in its closed state. Reducing the barrier at the gate region allows us to simulate the ion current in a reasonable computational time. Several limiting cases are examined, including those that reproduce the observed current, and the nature of the productive trajectories is considered. The ability to simulate

  15. [Preeclampsia, cellular migration and ion channels].

    PubMed

    Del Mónaco, Silvana M; Marino, Gabriela; Assef, Yanina; Kotsias, Basilio A

    2008-01-01

    The syncytiotrophoblast acts in human placenta as a transporting barrier regulating the transference of nutrients, solutes and water between maternal and fetal blood. This transepithelial transport involves movement of Na+ and its contribution to the osmotic pressure is an important determinant of the extracellular fluid volume. ENaC is a channel that mediates entry of Na+ from the luminal fluid into the cells in many reabsorbing epithelia; it is aldosterone, vasopressin, insulin and catecholamine-inducible, modulated by estrogens and progesterone and blocked by amiloride and its analogs. Multiple proteases are involved in the proteolytic processing and activation of ENaC subunits and aldosterone alters the protease-protease inhibitors balance. ENaC is also expressed in human placenta; although its function is not well known, the Na+ conductive properties may participate in electrolyte and extracellular volume homeostasis. The activity of ENaC channels and other ion channels and transporters is regulated by the state of actin filaments; on the other hand, changes in volume influence the actin cytoskeleton. Thus, there is an interaction between ENaC and components of the apical membrane cytoskeleton. In addition to their role in cellular homeostasis and electrical properties, Na+ currents through ENaC and other sodium channels are involved in cell migration, well documented in normal and cancer cells. In this work we presented evidences supporting the hypothesis that ENaC channels are required for the migration of BeWo cells, a human hormone-synthesizing trophoblastic cell line that express the three subunits of the ENaC channels. BeWo cell line has also been used as a model to investigate the placental transport mechanisms.

  16. Basolateral K channels in an insect epithelium. Channel density, conductance, and block by barium

    PubMed Central

    Hanrahan, JW; Wills, NK; Phillips, JE; Lewis, SA

    1986-01-01

    K channels in the basolateral membrane of insect hindgut were studied using current fluctuation analysis and microelectrodes. Locust recta were mounted in Ussing-type chambers containing Cl-free saline and cyclic AMP (cAMP). A transepithelial K current was induced by raising serosal [K] under short-circuit conditions. Adding Ba to the mucosal (luminal) side under these conditions had no effect; however, serosal Ba reversibly inhibited the short-circuit current (Isc), increased transepithelial resistance (Rt), and added a Lorentzian component to power density spectra of the Isc. A nonlinear relationship between corner frequency and serosal [Ba] was observed, which suggests that the rate constant for Ba association with basolateral channels increased as [Ba] was elevated. Microelectrode experiments revealed that the basolateral membrane hyperpolarized when Ba was added: this change in membrane potential could explain the nonlinearity of the 2 pi fc vs. [Ba] relationship if external Ba sensed about three-quarters of the basolateral membrane field. Conventional microelectrodes were used to determine the correspondence between transepithelially measured current noise and basolateral membrane conductance fluctuations, and ion-sensitive microelectrodes were used to measure intracellular K activity (acK). From the relationship between the net electrochemical potential for K across the basolateral membrane and the single channel current calculated from noise analysis, we estimate that the conductance of basolateral K channels is approximately 60 pS, and that there are approximately 180 million channels per square centimeter of tissue area. PMID:2420918

  17. Acid-sensing ion channels under hypoxia.

    PubMed

    Yingjun, Guo; Xun, Qu

    2013-01-01

    Hypoxia represents the lack of oxygen below the basic level, and the range of known channels related to hypoxia is continually increasing. Since abnormal hypoxia initiates pathological processes in numerous diseases via, to a great degree, producing acidic microenvironment, the significance of these channels in this environment has, until now, remained completely unknown. However, recent discovery of acid-sensing ion channels (ASICs) have enhanced our understanding of the hypoxic channelome. They belong to the degenerin/epithelial Na (+) channel family and function once extracellular pH decreases to a certain level. So does the ratiocination emerge that ASICs participate in many hypoxia-induced pathological processes, including pain, apoptosis, malignancy, which all appear to involve them. Since evidence suggests that activity of ASICs is altered under pathological hypoxia, future studies are needed to deeply explore the relationship between ASICs and hypoxia, which may provide a progressive understanding of hypoxic effects in cancer, arthritis, intervertebral disc degeneration, ischemic brain injury and so on.

  18. Acid-sensing ion channels under hypoxia

    PubMed Central

    Yingjun, Guo; Xun, Qu

    2013-01-01

    Hypoxia represents the lack of oxygen below the basic level, and the range of known channels related to hypoxia is continually increasing. Since abnormal hypoxia initiates pathological processes in numerous diseases via, to a great degree, producing acidic microenvironment, the significance of these channels in this environment has, until now, remained completely unknown. However, recent discovery of acid-sensing ion channels (ASICs) have enhanced our understanding of the hypoxic channelome. They belong to the degenerin/epithelial Na+ channel family and function once extracellular pH decreases to a certain level. So does the ratiocination emerge that ASICs participate in many hypoxia-induced pathological processes, including pain, apoptosis, malignancy, which all appear to involve them. Since evidence suggests that activity of ASICs is altered under pathological hypoxia, future studies are needed to deeply explore the relationship between ASICs and hypoxia, which may provide a progressive understanding of hypoxic effects in cancer, arthritis, intervertebral disc degeneration, ischemic brain injury and so on. PMID:23764948

  19. Optical control of an ion channel gate

    PubMed Central

    Lemoine, Damien; Habermacher, Chloé; Martz, Adeline; Méry, Pierre-François; Bouquier, Nathalie; Diverchy, Fanny; Taly, Antoine; Rassendren, François; Specht, Alexandre; Grutter, Thomas

    2013-01-01

    The powerful optogenetic pharmacology method allows the optical control of neuronal activity by photoswitchable ligands tethered to channels and receptors. However, this approach is technically demanding, as it requires the design of pharmacologically active ligands. The development of versatile technologies therefore represents a challenging issue. Here, we present optogating, a method in which the gating machinery of an ATP-activated P2X channel was reprogrammed to respond to light. We found that channels covalently modified by azobenzene-containing reagents at the transmembrane segments could be reversibly turned on and off by light, without the need of ATP, thus revealing an agonist-independent, light-induced gating mechanism. We demonstrate photocontrol of neuronal activity by a light-gated, ATP-insensitive P2X receptor, providing an original tool devoid of endogenous sensitivity to delineate P2X signaling in normal and pathological states. These findings open new avenues to specifically activate other ion channels independently of their natural stimulus. PMID:24297890

  20. 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.

  1. Gated Ion Channel-Based Biosensor Device

    NASA Astrophysics Data System (ADS)

    Separovic, Frances; Cornell, Bruce A.

    A biosensor device based on the ion channel gramicidin A (gA) incorporated into a bilayer membrane is described. This generic immunosensing device utilizes gA coupled to an antibody and assembled in a lipid membrane. The membrane is chemically tethered to a gold electrode, which reports on changes in the ionic conduction of the lipid bilayer. Binding of a target molecule in the bathing solution to the antibody causes the gramicidin channels to switch from predominantly conducting dimers to predominantly nonconducting monomers. Conventional a.c. impedance spectroscopy between the gold and a counter electrode in the bathing solution is used to measure changes in the ionic conductivity of the membrane. This approach permits the quantitative detection of a range of target species, including bacteria, proteins, toxins, DNA sequences, and drug molecules.

  2. 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

  3. Ion channels: molecular targets of neuroactive insecticides.

    PubMed

    Raymond-Delpech, Valérie; Matsuda, Kazuhiko; Sattelle, Benedict M; Rauh, James J; Sattelle, David B

    2005-11-01

    Many of the insecticides in current use act on molecular targets in the insect nervous system. Recently, our understanding of these targets has improved as a result of the complete sequencing of an insect genome, i.e., Drosophila melanogaster. Here we examine the recent work, drawing on genetics, genomics and physiology, which has provided evidence that specific receptors and ion channels are targeted by distinct chemical classes of insect control agents. The examples discussed include, sodium channels (pyrethroids, p,p'-dichlorodiphenyl-trichloroethane (DDT), dihydropyrazoles and oxadiazines); nicotinic acetylcholine receptors (cartap, spinosad, imidacloprid and related nitromethylenes/nitroguanidines); gamma-aminobutyric acid (GABA) receptors (cyclodienes, gamma-BHC and fipronil) and L-glutamate receptors (avermectins). Finally, we have examined the molecular basis of resistance to these molecules, which in some cases involves mutations in the molecular target, and we also consider the future impact of molecular genetic technologies in our understanding of the actions of neuroactive insecticides.

  4. High temperature ion channels and pores

    NASA Technical Reports Server (NTRS)

    Kang, Xiaofeng (Inventor); Gu, Li Qun (Inventor); Cheley, Stephen (Inventor); Bayley, Hagan (Inventor)

    2011-01-01

    The present invention includes an apparatus, system and method for stochastic sensing of an analyte to a protein pore. The protein pore may be an engineer protein pore, such as an ion channel at temperatures above 55.degree. C. and even as high as near 100.degree. C. The analyte may be any reactive analyte, including chemical weapons, environmental toxins and pharmaceuticals. The analyte covalently bonds to the sensor element to produce a detectable electrical current signal. Possible signals include change in electrical current. Detection of the signal allows identification of the analyte and determination of its concentration in a sample solution. Multiple analytes present in the same solution may also be detected.

  5. Single-Molecule Ion Channel Conformational Dynamics in Living Cells

    NASA Astrophysics Data System (ADS)

    Lu, H. Peter

    2014-03-01

    Stochastic and inhomogeneous conformational changes regulate the function and dynamics of ion channels that are crucial for cell functions, neuronal signaling, and brain functions. Such complexity makes it difficult, if not impossible, to characterize ion channel dynamics using conventional electrical recording alone since that the measurement does not specifically interrogate the associated conformational changes but rather the consequences of the conformational changes. Recently, new technology developments on single-molecule spectroscopy, and especially, the combined approaches of using single ion channel patch-clamp electrical recording and single-molecule fluorescence imaging have provided us the capability of probing ion channel conformational changes simultaneously with the electrical single channel recording. By combining real-time single-molecule fluorescence imaging measurements with real-time single-channel electric current measurements in artificial lipid bilayers and in living cell membranes, we were able to probe single ion-channel-protein conformational changes simultaneously, and thus providing an understanding the dynamics and mechanism of ion-channel proteins at the molecular level. The function-regulating and site-specific conformational changes of ion channels are now measurable under physiological conditions in real-time, one molecule at a time. We will focus our discussion on the new development and results of real-time imaging of the dynamics of gramicidin, colicin, and NMDA receptor ion channels in lipid bilayers and living cells. Our results shed light on new perspectives of the intrinsic interplay of lipid membrane dynamics, solvation dynamics, and the ion channel functions.

  6. Theory of the ion-channel laser

    SciTech Connect

    Whittum, D.H.

    1990-09-01

    A relativistic electron beam propagating through a plasma in the ion-focussed regime exhibits an electromagnetic instability with peak growth rate near a resonant frequency {omega}{approximately}2 {gamma}{sup 2} {omega}{beta}, where {gamma} is the Lorentz factor and {omega}{beta} is the betatron frequency. The physical basis for this instability is that an ensemble of relativistic simple harmonic oscillators, weakly driven by an electromagnetic wave, will lose energy to the wave through axial bunching. This bunching'' corresponds to the development of an rf component in the beam current, and a coherent centroid oscillation. The subject of this thesis is the theory of a laser capitalizing on this electromagnetic instability. A historical perspective is offered. The basic features of relativistic electron beam propagation in the ion-focussed regime are reviewed. The ion-channel laser (ICL) instability is explored theoretically through an eikonal formalism, analgous to the KMR'' formalism for the free-electron laser (FEL). The dispersion relation is derived, and the dependence of growth rate on three key parameters is explored. Finite temperature effects are assessed. From this work it is found that the typical gain length for amplification is longer than the Rayleigh length and we go on to consider three mechanisms which will tend to guide waveguide. First, we consider the effect of the ion channel as a dielectric waveguide. We consider next the use of a conducting waveguide, appropriate for a microwave amplifier. Finally, we examine a form of optical guiding'' analgous to that found in the FEL. The eikonal formalism is used to model numerically the instability through and beyond saturation. Results are compared with the numerical simulation of the full equations of motion, and with the analytic scalings. The analytical requirement on detuning spread is confirmed.

  7. Ion channels, phosphorylation and mammalian sperm capacitation

    PubMed Central

    Visconti, Pablo E; Krapf, Dario; de la Vega-Beltrán, José Luis; Acevedo, Juan José; Darszon, Alberto

    2011-01-01

    Sexually reproducing animals require an orchestrated communication between spermatozoa and the egg to generate a new individual. Capacitation, a maturational complex phenomenon that occurs in the female reproductive tract, renders spermatozoa capable of binding and fusing with the oocyte, and it is a requirement for mammalian fertilization. Capacitation encompasses plasma membrane reorganization, ion permeability regulation, cholesterol loss and changes in the phosphorylation state of many proteins. Novel tools to study sperm ion channels, image intracellular ionic changes and proteins with better spatial and temporal resolution, are unraveling how modifications in sperm ion transport and phosphorylation states lead to capacitation. Recent evidence indicates that two parallel pathways regulate phosphorylation events leading to capacitation, one of them requiring activation of protein kinase A and the second one involving inactivation of ser/thr phosphatases. This review examines the involvement of ion transporters and phosphorylation signaling processes needed for spermatozoa to achieve capacitation. Understanding the molecular mechanisms leading to fertilization is central for societies to deal with rising male infertility rates, to develop safe male gamete-based contraceptives and to preserve biodiversity through better assisted fertilization strategies. PMID:21540868

  8. 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.

  9. 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

  10. Acid-sensing ion channels and transient-receptor potential ion channels in zebrafish taste buds.

    PubMed

    Levanti, M; Randazzo, B; Viña, E; Montalbano, G; Garcia-Suarez, O; Germanà, A; Vega, J A; Abbate, F

    2016-09-01

    Sensory information from the environment is required for life and survival, and it is detected by specialized cells which together make up the sensory system. The fish sensory system includes specialized organs that are able to detect mechanical and chemical stimuli. In particular, taste buds are small organs located on the tongue in terrestrial vertebrates that function in the perception of taste. In fish, taste buds occur on the lips, the flanks, and the caudal (tail) fins of some species and on the barbels of others. In fish taste receptor cells, different classes of ion channels have been detected which, like in mammals, presumably participate in the detection and/or transduction of chemical gustatory signals. However, since some of these ion channels are involved in the detection of additional sensory modalities, it can be hypothesized that taste cells sense stimuli other than those specific for taste. This mini-review summarizes current knowledge on the presence of transient-receptor potential (TRP) and acid-sensing (ASIC) ion channels in the taste buds of teleosts, especially adult zebrafish. Up to now ASIC4, TRPC2, TRPA1, TRPV1 and TRPV4 ion channels have been found in the sensory cells, while ASIC2 was detected in the nerves supplying the taste buds.

  11. Ion channels of the mammalian urethra

    PubMed Central

    Kyle, Barry D

    2014-01-01

    The mammalian urethra is a muscular tube responsible for ensuring that urine remains in the urinary bladder until urination. In order to prevent involuntary urine leakage, the urethral musculature must be capable of constricting the urethral lumen to an extent that exceeds bladder intravesicular pressure during the urine-filling phase. The main challenge in anti-incontinence treatments involves selectively-controlling the excitability of the smooth muscles in the lower urinary tract. Almost all strategies to battle urinary incontinence involve targeting the bladder and as a result, this tissue has been the focus for the majority of research and development efforts. There is now increasing recognition of the value of targeting the urethral musculature in the treatment and management of urinary incontinence. Newly-identified and characterized ion channels and pathways in the smooth muscle of the urethra provides a range of potential therapeutic targets for the treatment of urinary incontinence. This review provides a summary of the current state of knowledge of the ion channels discovered in urethral smooth muscle cells that regulate their excitability. PMID:25483582

  12. Stochastic theory of ion movement in channels with single-ion occupancy. Application to sodium permeation of gramicidin channels.

    PubMed Central

    Jakobsson, E; Chiu, S W

    1987-01-01

    The electrodiffusion equations were solved for the one-ion channel both by the analytical method due to Levitt and also by Brownian dynamic simulations. For both types of calculations equilibration of ion distribution between the bath and the ends of the channel was assumed. Potential profiles were found that give good fits to published data on Na+ permeation of gramicidin channels. The data were best fit by profiles that have no relative energy maximum at the mouth of the channel. This finding suggests that alignment of waters or channel charged groups inside the channel in response to an ion's approach may provide an energetically favorable situation for entry sufficient to overcome the energy required for removing bulk waters of hydration. An alternative possibility is that the barrier to ion entry is situated outside the region restricted to single-ion occupancy. Replacement of valine with more polar amino acids at the No. 1 location was found to correspond to a deepening of the potential minima near the channel mouths, an increase in height of the central barrier to ion translocation across the channel, and possibly a reduction in the mobility of the ion-water complex in the channel. The Levitt theory was extended to calculate passage times for ions to cross the channel and the blocking effects of ions that entered the channel but didn't cross. These quantities were also calculated by the Brownian dynamics method. PMID:2440492

  13. Cnidarian Toxins Acting on Voltage-Gated Ion Channels

    PubMed Central

    Messerli, Shanta M.; Greenberg, Robert M.

    2006-01-01

    Voltage-gated ion channels generate electrical activity in excitable cells. As such, they are essential components of neuromuscular and neuronal systems, and are targeted by toxins from a wide variety of phyla, including the cnidarians. Here, we review cnidarian toxins known to target voltage-gated ion channels, the specific channel types targeted, and, where known, the sites of action of cnidarian toxins on different channels.

  14. Dynamic State Transitions in the Nervous System: From Ion Channels to Neurons to Networks

    NASA Astrophysics Data System (ADS)

    Århem, Peter; Braun, Hans A.; Huber, Martin T.; Liljenström, Hans

    The following sections are included: * Introduction * Ion channels: The microscopic scale * The variety of ion channels * Channel kinetics * Neurons: The mesoscopic scale * The feedback loops between membrane potential and ion currents * Neuron models: Concepts and examples * Impulse pattern modulation by ion channel densities * Oscillatory patterns * Irregular patterns * Impulse pattern modulation by subthreshold oscillations * The cold receptor model * Deterministic patterns and noise induced state-transitions on temperature scaling * Neuronal networks: The oscopic scale * Random channel events cause network state transitions * A hippocampal neural network model * Simulating noise-induced state transitions * Functional significance of oscopic neurodynamics * Conclusions * Appendix A: Computation of the neuron models * Hippocampal neuron model * The cold receptor model * Appendix B: Neural network model * References

  15. Plant Ion Channels: Gene Families, Physiology, and Functional Genomics Analyses

    PubMed Central

    Ward, John M.; Mäser, Pascal; Schroeder, Julian I.

    2016-01-01

    Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarization-and depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide–gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport. PMID:18842100

  16. DIAGNOSTICS FOR ION BEAM DRIVEN HIGH ENERGY DENSITY PHYSICS EXPERIMENTS

    SciTech Connect

    Bieniosek, F.M.; Henestroza, E.; Lidia, S.; Ni, P.A.

    2010-01-04

    Intense beams of heavy ions are capable of heating volumetric samples of matter to high energy density. Experiments are performed on the resulting warm dense matter (WDM) at the NDCX-I ion beam accelerator. The 0.3 MeV, 30-mA K{sup +} beam from NDCX-I heats foil targets by combined longitudinal and transverse neutralized drift compression of the ion beam. Both the compressed and uncompressed parts of the NDCX-I beam heat targets. The exotic state of matter (WDM) in these experiments requires specialized diagnostic techniques. We have developed a target chamber and fielded target diagnostics including a fast multi-channel optical pyrometer, optical streak camera, laser Doppler-shift interferometer (VISAR), beam transmission diagnostics, and high-speed gated cameras. We also present plans and opportunities for diagnostic development and a new target chamber for NDCX-II.

  17. Channelpedia: An Integrative and Interactive Database for Ion Channels

    PubMed Central

    Ranjan, Rajnish; Khazen, Georges; Gambazzi, Luca; Ramaswamy, Srikanth; Hill, Sean L.; Schürmann, Felix; Markram, Henry

    2011-01-01

    Ion channels are membrane proteins that selectively conduct ions across the cell membrane. The flux of ions through ion channels drives electrical and biochemical processes in cells and plays a critical role in shaping the electrical properties of neurons. During the past three decades, extensive research has been carried out to characterize the molecular, structural, and biophysical properties of ion channels. This research has begun to elucidate the role of ion channels in neuronal function and has subsequently led to the development of computational models of ion channel function. Although there have been substantial efforts to consolidate these findings into easily accessible and coherent online resources, a single comprehensive resource is still lacking. The success of these initiatives has been hindered by the sheer diversity of approaches and the variety in data formats. Here, we present “Channelpedia” (http://channelpedia.net), which is designed to store information related to ion channels and models and is characterized by an efficient information management framework. Composed of a combination of a database and a wiki-like discussion platform Channelpedia allows researchers to collaborate and synthesize ion channel information from literature. Equipped to automatically update references, Channelpedia integrates and highlights recent publications with relevant information in the database. It is web based, freely accessible and currently contains 187 annotated ion channels with 45 Hodgkin–Huxley models. PMID:22232598

  18. Hierarchical approach to predicting permeation in ion channels.

    PubMed Central

    Mashl, R J; Tang, Y; Schnitzer, J; Jakobsson, E

    2001-01-01

    A hierarchical computational strategy combining molecular modeling, electrostatics calculations, molecular dynamics, and Brownian dynamics simulations is developed and implemented to compute electrophysiologically measurable properties of the KcsA potassium channel. Models for a series of channels with different pore sizes are developed from the known x-ray structure, using insights into the gating conformational changes as suggested by a variety of published experiments. Information on the pH dependence of the channel gating is incorporated into the calculation of potential profiles for K(+) ions inside the channel, which are then combined with K(+) ion mobilities inside the channel, as computed by molecular dynamics simulations, to provide inputs into Brownian dynamics simulations for computing ion fluxes. The open model structure has a conductance of approximately 110 pS under symmetric 250 mM K(+) conditions, in reasonable agreement with experiments for the largest conducting substate. The dimensions of this channel are consistent with electrophysiologically determined size dependence of quaternary ammonium ion blocking from the intracellular end of this channel as well as with direct structural evidence that tetrabutylammonium ions can enter into the interior cavity of the channel. Realistic values of Ussing flux ratio exponents, distribution of ions within the channel, and shapes of the current-voltage and current-concentration curves are obtained. The Brownian dynamics calculations suggest passage of ions through the selectivity filter proceeds by a "knock-off" mechanism involving three ions, as has been previously inferred from functional and structural studies of barium ion blocking. These results suggest that the present calculations capture the essential nature of K(+) ion permeation in the KcsA channel and provide a proof-of-concept for the integrated microscopic/mesoscopic multitiered approach for predicting ion channel function from structure, which

  19. On the Evolution of Voltage Gated Ion Channels

    NASA Astrophysics Data System (ADS)

    Brenner, Michael

    2006-03-01

    This talk summarizes some ideas, calculations and data analysis/collection surrounding the structure and evolution of ion channels, in particular voltage gated sodium channels. The great advantage of ion channels is that they are individual proteins whose function has long been known and is readily inferred through voltage measurements. Their evolution can be tracked through the growing data base of sequences. Kinetic data is readily available, showing important differences between nearly identical channels. I will discuss our efforts to collate available functional data on voltage gated sodium channels into an 'ion channel property space' . We then use this dataset to infer underlying kinetic models, and to create evolutionary trees based on the function of the channels. Finally, I will discuss our endeavors to how ion channels evolved to be the way they are: Examples of questions we would like to answer include: to what extent do design principles dictate the details of the kinetic schemes of ion channels, such as (a) the symmetry of the sodium and potassium channels (or lack thereof), as reflected in their kinetic schemes ; (b) the coupling of sodium channel kinetics to potassium channel kinetics; or (c) activation/inactivation of the channels themselves.

  20. Modeling the Influence of Ion Channels on Neuron Dynamics in Drosophila

    PubMed Central

    Berger, Sandra D.; Crook, Sharon M.

    2015-01-01

    Voltage gated ion channels play a major role in determining a neuron's firing behavior, resulting in the specific processing of synaptic input patterns. Drosophila and other invertebrates provide valuable model systems for investigating ion channel kinetics and their impact on firing properties. Despite the increasing importance of Drosophila as a model system, few computational models of its ion channel kinetics have been developed. In this study, experimentally observed biophysical properties of voltage gated ion channels from the fruitfly Drosophila melanogaster are used to develop a minimal, conductance based neuron model. We investigate the impact of the densities of these channels on the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from integrator to resonator properties. Further, we analyze the preference to input frequency and how it depends on the channel densities and the resulting bifurcation type the system undergoes. An extension to a three dimensional model demonstrates that the inactivation kinetics of the sodium channels play an important role, allowing for firing patterns with a delayed first spike and subsequent high frequency firing as often observed in invertebrates, without altering the kinetics of the delayed rectifier current. PMID:26635592

  1. Modeling the Influence of Ion Channels on Neuron Dynamics in Drosophila.

    PubMed

    Berger, Sandra D; Crook, Sharon M

    2015-01-01

    Voltage gated ion channels play a major role in determining a neuron's firing behavior, resulting in the specific processing of synaptic input patterns. Drosophila and other invertebrates provide valuable model systems for investigating ion channel kinetics and their impact on firing properties. Despite the increasing importance of Drosophila as a model system, few computational models of its ion channel kinetics have been developed. In this study, experimentally observed biophysical properties of voltage gated ion channels from the fruitfly Drosophila melanogaster are used to develop a minimal, conductance based neuron model. We investigate the impact of the densities of these channels on the excitability of the model neuron. Changing the channel densities reproduces different in situ observed firing patterns and induces a switch from integrator to resonator properties. Further, we analyze the preference to input frequency and how it depends on the channel densities and the resulting bifurcation type the system undergoes. An extension to a three dimensional model demonstrates that the inactivation kinetics of the sodium channels play an important role, allowing for firing patterns with a delayed first spike and subsequent high frequency firing as often observed in invertebrates, without altering the kinetics of the delayed rectifier current.

  2. Density trends of negative ions at Titan

    NASA Astrophysics Data System (ADS)

    Wellbrock, A.; Coates, A. J.; Jones, G. H.; Arridge, C. S.; Lewis, G.; Sittler, E. C.; Young, D. T.

    2012-12-01

    The Electron Spectrometer part of the Cassini Plasma Spectrometer (CAPS-ELS) has revealed the existence of negative ions in Titan's ionosphere (Coates et al, 2007, Waite et al, 2007). These are observed during every encounter when the instrument points in the ram direction at altitudes between 950 and 1400 km. The heaviest ions observed so far have masses up to 13 800 amu/q. This suggests that complex hydrocarbon and nitrile chemical processes take place in Titan's upper atmosphere, probably playing a role in haze formation. Even heavier particles such as tholins can form which fall to lower altitudes and build up on Titan's surface (Coates et al., 2009). Coates et al. (2009) discussed trends in the highest masses observed with solar zenith angle (SZA), altitude and latitude. We are extending this study to density trends of different masses. With data from over 34 encounters and taking advantage of an increase in the duty cycle of measurements during recent flybys we have accumulated a large negative ion database. Groups of masses can be identified because recurrent peaks are observed in the mass-per-charge spectra of different encounters. We have updated these mass groups according to the spectra including the most recent flybys. This includes a heavy group of 625 amu/q and above. We investigate the effects of different controlling parameters such as altitude, solar zenith angle, latitude and possible seasonal effects. The aim of this study is to help constrain the chemical formation and destruction processes of negative ions in Titan's ionosphere. By studying SZA trends we can for example learn about whether nightside reactions or photochemical reactions yield higher densities for the different groups. We present the results and discuss their implications. For instance, the heaviest mass group (>625 amu/q) negative ions are only present at altitudes below 1100 km. Densities of this mass group are highest on the nightside however there are some moderate densities

  3. Self-organized enhancement of conductivity in biological ion channels

    NASA Astrophysics Data System (ADS)

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

    2013-10-01

    We discuss an example of self-organization in a biological system. It arises from long-range ion-ion interactions, and it leads us to propose a new kind of enhanced conduction in ion channels. The underlying mechanism involves charge fluctuations near the channel mouth, amplified by the mismatch between the relative permittivities of water and the protein of the channel walls. We use Brownian dynamics simulations to show that, as in conventional ‘knock on’ permeation, these interactions can strongly enhance the channel current; but unlike the conventional mechanism, the enhancement occurs without the instigating bath ion entering the channel. The transition between these two mechanisms is clearly demonstrated, emphasizing their distinction. A simple model accurately reproduces the observed phenomena. We point out that electrolyte plus protein of low relative permittivity are universal in living systems, so that long-range ion-ion correlations of the kind considered must be common.

  4. Pre-formed plasma channels for ion beam fusion

    NASA Astrophysics Data System (ADS)

    Peterson, R. R.; Olson, C. L.

    1997-04-01

    The transport of driver ions to the target in an IFE power plant is an important consideration in IFE target chamber design. Pre-formed laser-guided plasma discharge channels have been considered for light ions because they reduce the beam microdivergence constraints, allow long transport lengths, and require a target chamber fill gas that can help protect the target chamber from the target explosion. Here, pre-formed plasma discharge channels are considered for heavy ion transport. The channel formation parameters are similar to those for light ions. The allowable ion power per channel is limited by the onset of plasma instabilities and energy loss due to a reverse emf from the rapid channel expansion driven by the ion beam.

  5. United in diversity: mechanosensitive ion channels in plants.

    PubMed

    Hamilton, Eric S; Schlegel, Angela M; Haswell, Elizabeth S

    2015-01-01

    Mechanosensitive (MS) ion channels are a common mechanism for perceiving and responding to mechanical force. This class of mechanoreceptors is capable of transducing membrane tension directly into ion flux. In plant systems, MS ion channels have been proposed to play a wide array of roles, from the perception of touch and gravity to the osmotic homeostasis of intracellular organelles. Three families of plant MS ion channels have been identified: the MscS-like (MSL), Mid1-complementing activity (MCA), and two-pore potassium (TPK) families. Channels from these families vary widely in structure and function, localize to multiple cellular compartments, and conduct chloride, calcium, and/or potassium ions. However, they are still likely to represent only a fraction of the MS ion channel diversity in plant systems.

  6. United in Diversity: Mechanosensitive Ion Channels in Plants

    PubMed Central

    Hamilton, Eric S.; Schlegel, Angela M.; Haswell, Elizabeth S.

    2015-01-01

    Mechanosensitive (MS) ion channels are a common mechanism for perceiving and responding to mechanical force. This class of mechanoreceptors is capable of transducing membrane tension directly into ion flux. In plant systems, MS ion channels have been proposed to play a wide array of roles, from the perception of touch and gravity to the osmotic homeostasis of intracellular organelles. Three families of plant MS ion channels have been identified: the MscS-like (MSL), Mid1-complementing activity (MCA), and two-pore potassium (TPK) families. Channels from these families vary widely in structure and function, localize to multiple cellular compartments, and conduct chloride, calcium, and/or potassium ions. However, they are still likely to represent only a fraction of the MS ion channel diversity in plant systems. PMID:25494462

  7. The effect of cell size and channel density on neuronal information encoding and energy efficiency.

    PubMed

    Sengupta, Biswa; Faisal, A Aldo; Laughlin, Simon B; Niven, Jeremy E

    2013-09-01

    Identifying the determinants of neuronal energy consumption and their relationship to information coding is critical to understanding neuronal function and evolution. Three of the main determinants are cell size, ion channel density, and stimulus statistics. Here we investigate their impact on neuronal energy consumption and information coding by comparing single-compartment spiking neuron models of different sizes with different densities of stochastic voltage-gated Na(+) and K(+) channels and different statistics of synaptic inputs. The largest compartments have the highest information rates but the lowest energy efficiency for a given voltage-gated ion channel density, and the highest signaling efficiency (bits spike(-1)) for a given firing rate. For a given cell size, our models revealed that the ion channel density that maximizes energy efficiency is lower than that maximizing information rate. Low rates of small synaptic inputs improve energy efficiency but the highest information rates occur with higher rates and larger inputs. These relationships produce a Law of Diminishing Returns that penalizes costly excess information coding capacity, promoting the reduction of cell size, channel density, and input stimuli to the minimum possible, suggesting that the trade-off between energy and information has influenced all aspects of neuronal anatomy and physiology.

  8. Circadian regulation of ion channels and their functions

    PubMed Central

    Ko, Gladys Y.-P.; Shi, Liheng; Ko, Michael L.

    2010-01-01

    Ion channels are the gatekeepers to neuronal excitability. Retinal neurons of vertebrates and invertebrates, neurons of the suprachiasmatic nucleus (SCN) of vertebrates, and pinealocytes of non-mammalian vertebrates display daily rhythms in their activities. The interlocking transcription–translation feedback loops with specific post-translational modulations within individual cells form the molecular clock, the basic mechanism that maintains the autonomic ~24-h rhythm. The molecular clock regulates downstream output signaling pathways that further modulate activities of various ion channels. Ultimately, it is the circadian regulation of ion channel properties that govern excitability and behavior output of these neurons. In this review, we focus on the recent development of research in circadian neurobiology mainly from 1980 forward. We will emphasize the circadian regulation of various ion channels, including cGMP-gated cation channels, various voltage-gated calcium and potassium channels, Na+/K+-ATPase, and a long-opening cation channel. The cellular mechanisms underlying the circadian regulation of these ion channels and their functions in various tissues and organisms will also be discussed. Despite the magnitude of chronobiological studies in recent years, the circadian regulation of ion channels still remains largely unexplored. Through more investigation and understanding of the circadian regulation of ion channels, the future development of therapeutic strategies for the treatment of sleep disorders, cardiovascular diseases, and other illnesses linked to circadian misalignment will benefit. PMID:19549279

  9. Engineered ion channels as emerging tools for chemical biology.

    PubMed

    Mayer, Michael; Yang, Jerry

    2013-12-17

    Over the last 25 years, researchers have developed exogenously expressed, genetically engineered, semi-synthetic, and entirely synthetic ion channels. These structures have sufficient fidelity to serve as unique tools that can reveal information about living organisms. One of the most exciting success stories is optogenetics: the use of light-gated channels to trigger action potentials in specific neurons combined with studies of the response from networks of cells or entire live animals. Despite this breakthrough, the use of molecularly engineered ion channels for studies of biological systems is still in its infancy. Historically, researchers studied ion channels in the context of their own function in single cells or in multicellular signaling and regulation. Only recently have researchers considered ion channels and pore-forming peptides as responsive tools to report on the chemical and physical changes produced by other biochemical processes and reactions. This emerging class of molecular probes has a number of useful characteristics. For instance, these structures can greatly amplify the signal of chemical changes: the binding of one molecule to a ligand-gated ion channel can result in flux of millions of ions across a cell membrane. In addition, gating occurs on sub-microsecond time scales, resulting in fast response times. Moreover, the signal is complementary to existing techniques because the output is ionic current rather than fluorescence or radioactivity. And finally, ion channels are also localized at the membrane of cells where essential processes such as signaling and regulation take place. This Account highlights examples, mostly from our own work, of uses of ion channels and pore-forming peptides such as gramicidin in chemical biology. We discuss various strategies for preparing synthetically tailored ion channels that range from de novo designed synthetic molecules to genetically engineered or simply exogenously expressed or reconstituted wild

  10. Stochastic Ion Channel Gating in Dendritic Neurons: Morphology Dependence and Probabilistic Synaptic Activation of Dendritic Spikes

    PubMed Central

    Nolan, Matthew F.

    2010-01-01

    Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites. PMID:20711353

  11. Trails of kilovolt ions created by subsurface channeling.

    PubMed

    Redinger, Alex; Standop, Sebastian; Michely, Thomas; Rosandi, Yudi; Urbassek, Herbert M

    2010-02-19

    Using scanning tunneling microscopy, we observe the damage trails produced by keV noble-gas ions incident at glancing angles onto Pt(111). Surface vacancies and adatoms aligned along the ion trajectory constitute the ion trails. Atomistic simulations reveal that these straight trails are produced by nuclear (elastic) collisions with surface layer atoms during subsurface channeling of the projectiles. In a small energy window around 5 keV, Xe+ ions create vacancy grooves that mark the ion trajectory with atomic precision. The asymmetry of the adatom production on the two sides of the projectile path is traced back to the asymmetry of the ion's subsurface channel.

  12. Trails of Kilovolt Ions Created by Subsurface Channeling

    SciTech Connect

    Redinger, Alex; Standop, Sebastian; Michely, Thomas; Rosandi, Yudi; Urbassek, Herbert M.

    2010-02-19

    Using scanning tunneling microscopy, we observe the damage trails produced by keV noble-gas ions incident at glancing angles onto Pt(111). Surface vacancies and adatoms aligned along the ion trajectory constitute the ion trails. Atomistic simulations reveal that these straight trails are produced by nuclear (elastic) collisions with surface layer atoms during subsurface channeling of the projectiles. In a small energy window around 5 keV, Xe{sup +} ions create vacancy grooves that mark the ion trajectory with atomic precision. The asymmetry of the adatom production on the two sides of the projectile path is traced back to the asymmetry of the ion's subsurface channel.

  13. The Control of Male Fertility by Spermatozoan Ion Channels

    PubMed Central

    Lishko, Polina V.; Kirichok, Yuriy; Ren, Dejian; Navarro, Betsy; Chung, Jean-Ju

    2014-01-01

    Ion channels control the sperm ability to fertilize the egg by regulating sperm maturation in the female reproductive tract and by triggering key sperm physiological responses required for successful fertilization such as hyperactivated motility, chemotaxis, and the acrosome reaction. CatSper, a pH-regulated, calcium-selective ion channel, and KSper (Slo3) are core regulators of sperm tail calcium entry and sperm hyperactivated motility. Many other channels had been proposed as regulating sperm activity without direct measurements. With the development of the sperm patch-clamp technique, CatSper and KSper have been confirmed as the primary spermatozoan ion channels. In addition, the voltage-gated proton channel Hv1 has been identified in human sperm tail, and the P2X2 ion channel has been identified in the midpiece of mouse sperm. Mutations and deletions in sperm-specific ion channels affect male fertility in both mice and humans without affecting other physiological functions. The uniqueness of sperm ion channels makes them ideal pharmaceutical targets for contraception. In this review we discuss how ion channels regulate sperm physiology. PMID:22017176

  14. Potassium channels as multi-ion single-file pores

    PubMed Central

    1978-01-01

    A literature review reveals many lines of evidence that both delayed rectifier and inward rectifier potassium channels are multi-ion pores. These include unidirectional flux ratios given by the 2--2.5 power of the electrochemical activity ratio, very steeply voltage-dependent block with monovalent blocking ions, relief of block by permeant ions added to the side opposite from the blocking ion, rectification depending on E--EK, and a minimum in the reversal potential or conductance as external K+ ions are replaced by an equivalent concentration of T1+ ions. We consider a channel with a linear sequence of energy barriers and binding sites. The channel can be occupied by more than one ion at a time, and ions hop in single file into vacant sites with rate constants that depend on barrier heights, membrane potential, and interionic repulsion. Such multi-ion models reproduce qualitatively the special flux properties of potassium channels when the barriers for hopping out of the pore are larger than for hopping between sites within the pore and when there is repulsion between ions. These conditions also produce multiple maxima in the conductance-ion activity relationship. In agreement with Armstrong's hypothesis (1969. J. Gen. Physiol. 54:553--575), inward rectification may be understood in terms of block by an internal blocking cation. Potassium channels must have at least three sites and often contain at least two ions at a time. PMID:722275

  15. High gluon densities in heavy ion collisions

    NASA Astrophysics Data System (ADS)

    Blaizot, Jean-Paul

    2017-03-01

    The early stages of heavy ion collisions are dominated by high density systems of gluons that carry each a small fraction x of the momenta of the colliding nucleons. A distinguishing feature of such systems is the phenomenon of ‘saturation’ which tames the expected growth of the gluon density as the energy of the collision increases. The onset of saturation occurs at a particular transverse momentum scale, the ‘saturation momentum’, that emerges dynamically and that marks the onset of non-linear gluon interactions. At high energy, and for large nuclei, the saturation momentum is large compared to the typical hadronic scale, making high density gluons amenable to a description with weak coupling techniques. This paper reviews some of the challenges faced in the study of such dense systems of small x gluons, and of the progress made in addressing them. The focus is on conceptual issues, and the presentation is both pedagogical, and critical. Examples where high gluon density could play a visible role in heavy ion collisions are briefly discussed at the end, for illustration purpose.

  16. Ion Channeling Analysis of Gallium Nitride Implanted with Deuterium

    SciTech Connect

    Myers, S.M.; Wampler, W.R.

    1998-12-23

    Ion channeling and transmission electron microscopy were used to examine the microstructure of GaN implanted with deuterium (D) at high (>1 at. %) and low (< 0.1 at. %) D concentrations. At high concentrations, bubbles and basal-plane stacking faults were observed. Ion channeling showed the D was disordered relative to the GaN lattice, consistent with precipitation of D2 into bubbles. At low D concentrations, bubbles and stacking faults are absent and ion channeling shows that a large fraction of the D occupies sites near the center of the c-axis channel.

  17. Ion flow in the bath and flux interactions between channels.

    PubMed Central

    Ramanan, S V; Mesimeris, V; Brink, P R

    1994-01-01

    We present an exact solution to the linearized Nernst-Planck-Poisson equation for spherically symmetric current flow. This solution differs from Levitt's solution (Levitt, D. G. 1992. Biophys. J., Eq. A5) by its dependence on an additional parameter, which is equal to the net ion flux for monovalent ion-selective channels. For ion-selective channels, this solution may provide better boundary conditions to modelling the flow in the channel pore itself, although only at low salt concentrations. We use the solution to estimate the effects of flux interaction between closely packed channels. PMID:7518706

  18. Physiological and pathological functions of mechanosensitive ion channels.

    PubMed

    Gu, Yuanzheng; Gu, Chen

    2014-10-01

    Rapid sensation of mechanical stimuli is often mediated by mechanosensitve ion channels. Their opening results from conformational changes induced by mechanical forces. It leads to membrane permeation of selected ions and thereby to electrical signaling. Newly identified mechanosensitive ion channels are emerging at an astonishing rate, including some that are traditionally assigned for completely different functions. In this review, we first provide a brief overview of ion channels that are known to play a role in mechanosensation. Next, we focus on three representative ones, including the transient receptor potential channel V4 (TRPV4), Kv1.1 voltage-gated potassium (Kv) channel, and Piezo channels. Their structures, biophysical properties, expression and targeting patterns, and physiological functions are highlighted. The potential role of their mechanosensation in related diseases is further discussed. In sum, mechanosensation appears to be achieved in a variety of ways by different proteins and plays a fundamental role in the function of various organs under normal and abnormal conditions.

  19. Studying mechanosensitive ion channels with an automated patch clamp.

    PubMed

    Barthmes, Maria; Jose, Mac Donald F; Birkner, Jan Peter; Brüggemann, Andrea; Wahl-Schott, Christian; Koçer, Armağan

    2014-03-01

    Patch clamp electrophysiology is the main technique to study mechanosensitive ion channels (MSCs), however, conventional patch clamping is laborious and success and output depends on the skills of the operator. Even though automated patch systems solve these problems for other ion channels, they could not be applied to MSCs. Here, we report on activation and single channel analysis of a bacterial mechanosensitive ion channel using an automated patch clamp system. With the automated system, we could patch not only giant unilamellar liposomes but also giant Escherichia coli (E. coli) spheroplasts. The tension sensitivity and channel kinetics data obtained in the automated system were in good agreement with that obtained from the conventional patch clamp. The findings will pave the way to high throughput fundamental and drug screening studies on mechanosensitive ion channels.

  20. Flow-activated ion channels in vascular endothelium.

    PubMed

    Gautam, Mamta; Gojova, Andrea; Barakat, Abdul I

    2006-01-01

    The ability of vascular endothelial cells (ECs) to respond to fluid mechanical forces associated with blood flow is essential for flow-mediated vasoregulation and arterial wall remodeling. Abnormalities in endothelial responses to flow also play a role in the development of atherosclerosis. Although our understanding of the endothelial signaling pathways stimulated by flow has greatly increased over the past two decades, the mechanisms by which ECs sense flow remain largely unknown. Activation of flow-sensitive ion channels is among the fastest known endothelial responses to flow; therefore, these ion channels have been proposed as candidate flow sensors. This review focuses on: 1) describing the various types of flow-sensitive ion channels that have been reported in ECs, 2) discussing the implications of activation of these ion channels for endothelial function, and 3) proposing candidate mechanisms for activation of flow-sensitive ion channels.

  1. Large fraction of crystal directions leads to ion channeling

    NASA Astrophysics Data System (ADS)

    Nordlund, K.; Djurabekova, F.; Hobler, G.

    2016-12-01

    It is well established that when energetic ions are moving in crystals, they may penetrate much deeper if they happen to be directed in some specific crystal directions. This `channeling' effect is utilized for instance in certain ion beam analysis methods and has been described by analytical theories and atomistic computer simulations. However, there have been very few systematic studies of channeling in directions other than the principal low-index ones. We present here a molecular dynamics-based approach to calculate ion channeling systematically over all crystal directions, providing ion `channeling maps' that easily show in which directions channeling is expected. The results show that channeling effects can be quite significant even at energies below 1 keV, and that in many cases, significant planar channeling occurs also in a wide range of crystal directions between the low-index principal ones. In all of the cases studied, a large fraction (˜20 -60 % ) of all crystal directions show channeling. A practical implication of this is that modern experiments on randomly oriented nanostructures will have a large probability of channeling. It also means that when ion irradiations are carried out on polycrystalline samples, channeling effects on the results cannot a priori be assumed to be negligible. The maps allow for easy selection of good `nonchanneling' directions in experiments or alternatively finding wide channels for beneficial uses of channeling. We implement channeling theory to also give the fraction of channeling directions in a manner directly comparable to the simulations. The comparison shows good qualitative agreement. In particular, channeling theory is very good at predicting which channels are active at a given energy. This is true down to sub-keV energies, provided the penetration depth is not too small.

  2. Ion Channels, Cell Volume, Cell Proliferation and Apoptotic Cell Death

    NASA Astrophysics Data System (ADS)

    Lang, Florian; Gulbins, Erich; Szabo, Ildiko; Vereninov, Alexey; Huber, Stephan M.

    At some stage cell proliferation requires an increase in cell volume and a typical hallmark of apoptotic cell death is cell shrinkage. The respective alterations of cell volume are accomplished by altered regulation of ion transport including ion channels. Thus, cell proliferation and apoptosis are both paralleled by altered activity of ion channels, which play an active part in these fundamental cellular mechanisms. Activation of anion channels allows exit of Cl?, osmolyte and HCO3 ? leading to cell shrinkage and acidification of the cytosol. K+ exit through K+ channels leads to cell shrinkage and a decrease in intracellular K+ concentration. K+ channel activity is further important for maintenance of the cell membrane potential - a critical determinant of Ca2+ entry through Ca2+ channels. Cytosolic Ca2+ may both activate mechanisms required for cell proliferation and stimulate enzymes executing apoptosis. The effect of enhanced cytosolic Ca2+ activity depends on the magnitude and temporal organisation of Ca2+ entry. Moreover, a given ion channel may support both cell proliferation and apoptosis, and specific ion channel blockers may abrogate both fundamental cellular mechanisms, depending on cell type, regulatory environment and condition of the cell. Clearly, further experimental effort is needed to clarify the role of ion channels in the regulation of cell proliferation and apoptosis.

  3. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    PubMed Central

    Vasconcelos, Luiz H. C.; Souza, Iara L. L.; Pinheiro, Lílian S.; Silva, Bagnólia A.

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  4. Transportation behavior of alkali ions through a cell membrane ion channel. A quantum chemical description of a simplified isolated model.

    PubMed

    Billes, Ferenc; Mohammed-Ziegler, Ildikó; Mikosch, Hans

    2012-08-01

    Quantum chemical model calculations were carried out for modeling the ion transport through an isolated ion channel of a cell membrane. An isolated part of a natural ion channel was modeled. The model channel was a calixarene derivative, hydrated sodium and potassium ions were the models of the transported ion. The electrostatic potential of the channel and the energy of the channel-ion system were calculated as a function of the alkali ion position. Both attractive and repulsive ion-channel interactions were found. The calculations - namely the dependence of the system energy and the atomic charges of the water molecules with respect to the position of the alkali ion in the channel - revealed the molecular-structural background of the potassium selectivity of this artificial ion channel. It was concluded that the studied ion channel mimics real biological ion channel quite well.

  5. Novel screening techniques for ion channel targeting drugs

    PubMed Central

    Obergrussberger, Alison; Stölzle-Feix, Sonja; Becker, Nadine; Brüggemann, Andrea; Fertig, Niels; Möller, Clemens

    2015-01-01

    Ion channels are integral membrane proteins that regulate the flux of ions across the cell membrane. They are involved in nearly all physiological processes, and malfunction of ion channels has been linked to many diseases. Until recently, high-throughput screening of ion channels was limited to indirect, e.g. fluorescence-based, readout technologies. In the past years, direct label-free biophysical readout technologies by means of electrophysiology have been developed. Planar patch-clamp electrophysiology provides a direct functional label-free readout of ion channel function in medium to high throughput. Further electrophysiology features, including temperature control and higher-throughput instruments, are continually being developed. Electrophysiological screening in a 384-well format has recently become possible. Advances in chip and microfluidic design, as well as in cell preparation and handling, have allowed challenging cell types to be studied by automated patch clamp. Assays measuring action potentials in stem cell-derived cardiomyocytes, relevant for cardiac safety screening, and neuronal cells, as well as a large number of different ion channels, including fast ligand-gated ion channels, have successfully been established by automated patch clamp. Impedance and multi-electrode array measurements are particularly suitable for studying cardiomyocytes and neuronal cells within their physiological network, and to address more complex physiological questions. This article discusses recent advances in electrophysiological technologies available for screening ion channel function and regulation. PMID:26556400

  6. 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

  7. Ion conduction pore is conserved among potassium channels

    NASA Astrophysics Data System (ADS)

    Lu, Zhe; Klem, Angela M.; Ramu, Yajamana

    2001-10-01

    Potassium channels, a group of specialized membrane proteins, enable K+ ions to flow selectively across cell membranes. Transmembrane K+ currents underlie electrical signalling in neurons and other excitable cells. The atomic structure of a bacterial K+ channel pore has been solved by means of X-ray crystallography. To the extent that the prokaryotic pore is representative of other K+ channels, this landmark achievement has profound implications for our general understanding of K+ channels. But serious doubts have been raised concerning whether the prokaryotic K+ channel pore does actually represent those of eukaryotes. Here we have addressed this fundamental issue by substituting the prokaryotic pore into eukaryotic voltage-gated and inward-rectifier K+ channels. The resulting chimaeras retain the respective functional hallmarks of the eukaryotic channels, which indicates that the ion conduction pore is indeed conserved among K+ channels.

  8. Ion transport in graphene nanofluidic channels.

    PubMed

    Xie, Quan; Xin, Fang; Park, Hyung Gyu; Duan, Chuanhua

    2016-12-01

    Carbon nanofluidic structures made of carbon nanotubes or graphene/graphene oxide have shown great promise in energy and environment applications due to the newly discovered fast and selective mass transport. However, they have yet to be utilized in nanofluidic devices for lab-on-a-chip applications because of great challenges in their fabrication and integration. Herein we report the fabrication of two-dimensional planar graphene nanochannel devices and the study of ion transport inside a graphene nanochannel array. A MEMS fabrication process that includes controlled nanochannel etching, graphene wet transfer, and vacuum anodic bonding is developed to fabricate graphene nanochannels where graphene conformally coats the channel surfaces. We observe higher ionic conductance inside the graphene nanochannels compared with silica nanochannels with the same geometries at low electrolyte concentrations (10(-6) M-10(-2) M). Enhanced electroosmotic flow due to the boundary slip at graphene surfaces is attributed to the measured higher conductance in the graphene nanochannels. Our results also suggest that the surface charge on the graphene surface, originating from the dissociation of oxygen-containing functional groups, is crucial to the enhanced electroosmotic flow inside the nanochannels.

  9. Electrical Heart Defibrillation with Ion Channel Blockers

    NASA Astrophysics Data System (ADS)

    Feeney, Erin; Clark, Courtney; Puwal, Steffan

    Heart disease is the leading cause of mortality in the United States. Rotary electrical waves within heart muscle underlie electrical disorders of the heart termed fibrillation; their propagation and breakup leads to a complex distribution of electrical activation of the tissue (and of the ensuing mechanical contraction that comes from electrical activation). Successful heart defibrillation has, thus far, been limited to delivering large electrical shocks to activate the entire heart and reset its electrical activity. In theory, defibrillation of a system this nonlinear should be possible with small electrical perturbations (stimulations). A successful algorithm for such a low-energy defibrillator continues to elude researchers. We propose to examine in silica whether low-energy electrical stimulations can be combined with antiarrhythmic, ion channel-blocking drugs to achieve a higher rate of defibrillation and whether the antiarrhythmic drugs should be delivered before or after electrical stimulation has commenced. Progress toward a more successful, low-energy defibrillator will greatly minimize the adverse effects noted in defibrillation and will assist in the development of pediatric defibrillators.

  10. Surface dynamics of voltage-gated ion channels

    PubMed Central

    Heine, Martin; Ciuraszkiewicz, Anna; Voigt, Andreas; Heck, Jennifer; Bikbaev, Arthur

    2016-01-01

    ABSTRACT Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks. PMID:26891382

  11. Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels.

    PubMed

    Zhao, Qiancheng; Wu, Kun; Geng, Jie; Chi, Shaopeng; Wang, Yanfeng; Zhi, Peng; Zhang, Mingmin; Xiao, Bailong

    2016-03-16

    Piezo proteins have been proposed as the long-sought-after mechanosensitive cation channels in mammals that play critical roles in various mechanotransduction processes. However, the molecular bases that underlie their ion permeation and mechanotransduction have remained functionally undefined. Here we report our finding of the miniature pore-forming module of Piezo1 that resembles the pore architecture of other trimeric channels and encodes the essential pore properties. We further identified specific residues within the pore module that determine unitary conductance, pore blockage and ion selectivity for divalent and monovalent cations and anions. The non-pore-containing region of Piezo1 confers mechanosensitivity to mechano-insensitive trimeric acid-sensing ion channels, demonstrating that Piezo1 channels possess intrinsic mechanotransduction modules separate from their pore modules. In conclusion, this is the first report on the bona fide pore module and mechanotransduction components of Piezo channels, which define their ion-conducting properties and gating by mechanical stimuli, respectively.

  12. High throughput electrophysiology: new perspectives for ion channel drug discovery.

    PubMed

    Willumsen, Niels J; Bech, Morten; Olesen, Søren-Peter; Jensen, Bo Skaaning; Korsgaard, Mads P G; Christophersen, Palle

    2003-01-01

    Proper function of ion channels is crucial for all living cells. Ion channel dysfunction may lead to a number of diseases, so-called channelopathies, and a number of common diseases, including epilepsy, arrhythmia, and type II diabetes, are primarily treated by drugs that modulate ion channels. A cornerstone in current drug discovery is high throughput screening assays which allow examination of the activity of specific ion channels though only to a limited extent. Conventional patch clamp remains the sole technique with sufficiently high time resolution and sensitivity required for precise and direct characterization of ion channel properties. However, patch clamp is a slow, labor-intensive, and thus expensive, technique. New techniques combining the reliability and high information content of patch clamping with the virtues of high throughput philosophy are emerging and predicted to make a number of ion channel targets accessible for drug screening. Specifically, genuine HTS parallel processing techniques based on arrays of planar silicon chips are being developed, but also lower throughput sequential techniques may be of value in compound screening, lead optimization, and safety screening. The introduction of new powerful HTS electrophysiological techniques is predicted to cause a revolution in ion channel drug discovery.

  13. Pathophysiological and protective roles of mitochondrial ion channels

    PubMed Central

    O’Rourke, Brian

    2000-01-01

    Mitochondria possess a highly permeable outer membrane and an inner membrane that was originally thought to be relatively impermeable to ions to prevent dissipation of the electrochemical gradient for protons. Although recent evidence has revealed a rich diversity of ion channels in both membranes, the purpose of these channels remains incompletely determined. Pores in the outer membrane are fundamental participants in apoptotic cell death, and this process may also involve permeability transition pores on the inner membrane. Novel functions are now being assigned to other ion channels of the inner membrane. Examples include protection against ischaemic injury by mitochondrial KATP channels and the contribution of inner membrane anion channels to spontaneous mitochondrial oscillations in cardiac myocytes. The central role of mitochondria in both the normal function of the cell and in its demise makes these channels prime targets for future research and drug development. PMID:11080248

  14. Ion Channels as Drug Targets in Central Nervous System Disorders

    PubMed Central

    Waszkielewicz, A.M; Gunia, A; Szkaradek, N; Słoczyńska, K; Krupińska, S; Marona, H

    2013-01-01

    Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na+ channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 – for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Cav1.1-Cav3.3, with even newer nomenclature α1A-α1I and α1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs. PMID:23409712

  15. Ion channels in genetic and acquired forms of epilepsy

    PubMed Central

    Lerche, Holger; Shah, Mala; Beck, Heinz; Noebels, Jeff; Johnston, Dan; Vincent, Angela

    2013-01-01

    Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na+ channels of inhibitory neurons, or GABAA receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K+ channels, hyperpolarization-activated cation channels and T-type Ca2+ channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K+ channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. PMID:23090947

  16. Guiding supersonic projectiles using optically generated air density channels

    NASA Astrophysics Data System (ADS)

    Johnson, Luke A.; Sprangle, Phillip

    2015-09-01

    We investigate the feasibility of using optically generated channels of reduced air density to provide trajectory correction (guiding) for a supersonic projectile. It is shown that the projectile experiences a force perpendicular to its direction of motion as one side of the projectile passes through a channel of reduced air density. A single channel of reduced air density can be generated by the energy deposited from filamentation of an intense laser pulse. We propose changing the laser pulse energy from shot-to-shot to build longer effective channels. Current femtosecond laser systems with multi-millijoule pulses could provide trajectory correction of several meters on 5 km trajectories for sub-kilogram projectiles traveling at Mach 3.

  17. Through the channel and around the channel: Validating and comparing microscopic approaches for the evaluation of free energy profiles for ion penetration through ion channels.

    PubMed

    Kato, Mitsunori; Warshel, Arieh

    2005-10-20

    Microscopic calculations of free energy profiles for ion transport through biological ion channels present a very serious challenge to modern simulation approaches. The main problem is due to the major convergence problems associated with the heterogeneous landscape of the electrostatic environment in ion channels and with the need to evaluate the profile associated with the transfer of the ion from bulk water to the channel environment. This problem is compounded by the lack of reliable and relevant benchmarks that can discriminate between alternative approaches. The present study is aimed at reducing the above problems by defining benchmarks that are directly relevant to ion channels and can also give converging results. This is done by constructing a series of models of a truncated gramicidin channel with different numbers of water molecules and by comparing the profiles for going around the channel and through the channel. These discriminating models are then used to validate and compare the adiabatic charging free energy perturbation (FEP) approach combined with an umbrella sampling approach (Warshel, A. J. Phys. Chem. 1982, 86, 2218) and the potential of mean force (PMF) approach used frequently in studies of ion channels. It is found that both approaches work quite well until one moves to the case of the fully solvated channel. In this limit, the PMF approach may give different results for the overall work of going through the channel and around the channel, while the FEP approach gives physically consistent results. The present benchmark also indicates that the weighted histogram analysis method (WHAM) approach does not offer a significant advantage over earlier approaches at least as much as studies of ion channels are concerned. Finally, it is concluded that the FEP approach may be more useful in evaluating the overall barrier for moving ions from water to ion channels and that in some cases it might be beneficial to use the FEP approach for selective

  18. Diversity of folds in animal toxins acting on ion channels.

    PubMed Central

    Mouhat, Stéphanie; Jouirou, Besma; Mosbah, Amor; De Waard, Michel; Sabatier, Jean-Marc

    2004-01-01

    Animal toxins acting on ion channels of excitable cells are principally highly potent short peptides that are present in limited amounts in the venoms of various unrelated species, such as scorpions, snakes, sea anemones, spiders, insects, marine cone snails and worms. These toxins have been used extensively as invaluable biochemical and pharmacological tools to characterize and discriminate between the various ion channel types that differ in ionic selectivity, structure and/or cell function. Alongside the huge molecular and functional diversity of ion channels, a no less impressive structural diversity of animal toxins has been indicated by the discovery of an increasing number of polypeptide folds that are able to target these ion channels. Indeed, it appears that these peptide toxins have evolved over time on the basis of clearly distinct architectural motifs, in order to adapt to different ion channel modulating strategies (pore blockers compared with gating modifiers). Herein, we provide an up-to-date overview of the various types of fold from animal toxins that act on ion channels selective for K+, Na+, Ca2+ or Cl- ions, with special emphasis on disulphide bridge frameworks and structural motifs associated with these peptide folds. PMID:14674883

  19. Detection of single ion channel activity with carbon nanotubes

    PubMed Central

    Zhou, Weiwei; Wang, Yung Yu; Lim, Tae-Sun; Pham, Ted; Jain, Dheeraj; Burke, Peter J.

    2015-01-01

    Many processes in life are based on ion currents and membrane voltages controlled by a sophisticated and diverse family of membrane proteins (ion channels), which are comparable in size to the most advanced nanoelectronic components currently under development. Here we demonstrate an electrical assay of individual ion channel activity by measuring the dynamic opening and closing of the ion channel nanopores using single-walled carbon nanotubes (SWNTs). Two canonical dynamic ion channels (gramicidin A (gA) and alamethicin) and one static biological nanopore (α-hemolysin (α-HL)) were successfully incorporated into supported lipid bilayers (SLBs, an artificial cell membrane), which in turn were interfaced to the carbon nanotubes through a variety of polymer-cushion surface functionalization schemes. The ion channel current directly charges the quantum capacitance of a single nanotube in a network of purified semiconducting nanotubes. This work forms the foundation for a scalable, massively parallel architecture of 1d nanoelectronic devices interrogating electrophysiology at the single ion channel level. PMID:25778101

  20. Detection of single ion channel activity with carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Zhou, Weiwei; Wang, Yung Yu; Lim, Tae-Sun; Pham, Ted; Jain, Dheeraj; Burke, Peter J.

    2015-03-01

    Many processes in life are based on ion currents and membrane voltages controlled by a sophisticated and diverse family of membrane proteins (ion channels), which are comparable in size to the most advanced nanoelectronic components currently under development. Here we demonstrate an electrical assay of individual ion channel activity by measuring the dynamic opening and closing of the ion channel nanopores using single-walled carbon nanotubes (SWNTs). Two canonical dynamic ion channels (gramicidin A (gA) and alamethicin) and one static biological nanopore (α-hemolysin (α-HL)) were successfully incorporated into supported lipid bilayers (SLBs, an artificial cell membrane), which in turn were interfaced to the carbon nanotubes through a variety of polymer-cushion surface functionalization schemes. The ion channel current directly charges the quantum capacitance of a single nanotube in a network of purified semiconducting nanotubes. This work forms the foundation for a scalable, massively parallel architecture of 1d nanoelectronic devices interrogating electrophysiology at the single ion channel level.

  1. What is the optimal channel density for transmyocardial laser revascularization?

    PubMed

    Mouli, Samdeep K; Fronza, Jeffrey; Greene, Rodney; Robert, Emmanuel S; Horvath, Keith A

    2004-10-01

    Transmyocardial laser revascularization (TMR) has demonstrated reproducible relief of angina in patients with end-stage coronary disease. However, the optimum dose or channel density has not been elucidated. Using a porcine model of chronic myocardial ischemia, 14 animals were treated with CO2 TMR and randomized as follows: group 1 was 1 channel per 2 cm2; group 2 was 1 channel per 1 cm2; and group 3 was 2 channels per 1 cm2. Left ventricular myocardial viability and function were assessed by magnetic resonance imaging (MRI) and echocardiography pretreatment, and repeated 6 weeks later. The MRI assessment of group 1 (1 channel/2 cm2) and group 2 (1 channel/cm2) demonstrated similar improvement in segmental contractility posttreatment of 12.11% +/- 5.15% and 12.47% +/- 9.51%, respectively. In contrast, group 3 (2 channels/cm2) showed significantly worse segmental contractility posttreatment: -18.52% +/- 7.16% (p = 0.01). Echocardiographic imaging revealed significant improvements in wall thickening in the ischemic zone for group 1 at 0.91 +/- 0.07 cm pretreatment versus 1.30 +/- 0.09 cm posttreatment, (p = 0.01); and for group 2 at 0.93 +/- 0.11 cm versus 1.42 +/- 0.18 cm, (p = 0.01). No significant improvement in wall thickening was seen in group 3 (0.84 +/- 0.06 cm versus 0.88 +/- 0.09 cm, p = n.s.). These data corroborate the empiric finding of an effective therapeutic dose range for TMR, 1 channel per 1 to 2 cm2. These results also demonstrate a detrimental effect when channel density is increased above the clinical standard of 1 channel per cm2 to a density of 2 channels per 1 cm2.

  2. HIGH ENERGY DENSITY PHYSICS EXPERIMENTS WITH INTENSE HEAVY ION BEAMS

    SciTech Connect

    Henestroza, E.; Leitner, M.; Logan, B.G.; More, R.M.; Roy, P.K.; Ni, P.; Seidl, P.A.; Waldron, W.L.; Barnard, J.J.

    2010-03-16

    The US heavy ion fusion science program has developed techniques for heating ion-beam-driven warm dense matter (WDM) targets. The WDM conditions are to be achieved by combined longitudinal and transverse space-charge neutralized drift compression of the ion beam to provide a hot spot on the target with a beam spot size of about 1 mm, and pulse length about 1-2 ns. As a technique for heating volumetric samples of matter to high energy density, intense beams of heavy ions are capable of delivering precise and uniform beam energy deposition dE/dx, in a relatively large sample size, and the ability to heat any solid-phase target material. Initial experiments use a 0.3 MeV K+ beam (below the Bragg peak) from the NDCX-I accelerator. Future plans include target experiments using the NDCX-II accelerator, which is designed to heat targets at the Bragg peak using a 3-6 MeV lithium ion beam. The range of the beams in solid matter targets is about 1 micron, which can be lengthened by using porous targets at reduced density. We have completed the fabrication of a new experimental target chamber facility for WDM experiments, and implemented initial target diagnostics to be used for the first target experiments in NDCX-1. The target chamber has been installed on the NDCX-I beamline. The target diagnostics include a fast multi-channel optical pyrometer, optical streak camera, VISAR, and high-speed gated cameras. Initial WDM experiments will heat targets by compressed NDCX-I beams and will explore measurement of temperature and other target parameters. Experiments are planned in areas such as dense electronegative targets, porous target homogenization and two-phase equation of state.

  3. Scorpion toxin peptide action at the ion channel subunit level.

    PubMed

    Housley, David M; Housley, Gary D; Liddell, Michael J; Jennings, Ernest A

    2016-10-10

    This review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes. The identification and functional characterisation of these SCTX peptides has tremendous potential for development of novel pharmaceuticals that advance knowledge of ion channels and establish lead compounds for treatment of excitable tissue disorders. This review delineates the unique specificities of 320 individual SCTX peptides that collectively act on 41 ion channel subclasses. Thus the SCTX research field has significant translational implications for pathophysiology spanning neurotransmission, neurohumoral signalling, sensori-motor systems and excitation-contraction coupling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Homology modeling of transporter proteins (carriers and ion channels).

    PubMed

    Ravna, Aina Westrheim; Sylte, Ingebrigt

    2012-01-01

    Transporter proteins are divided into channels and carriers and constitute families of membrane proteins of physiological and pharmacological importance. These proteins are targeted by several currently prescribed drugs, and they have a large potential as targets for new drug development. Ion channels and carriers are difficult to express and purify in amounts for X-ray crystallography and nuclear magnetic resonance (NMR) studies, and few carrier and ion channel structures are deposited in the PDB database. The scarcity of atomic resolution 3D structures of carriers and channels is a problem for understanding their molecular mechanisms of action and for designing new compounds with therapeutic potentials. The homology modeling approach is a valuable approach for obtaining structural information about carriers and ion channels when no crystal structure of the protein of interest is available. In this chapter, computational approaches for constructing homology models of carriers and transporters are reviewed.

  5. Ion channels in control of pancreatic stellate cell migration

    PubMed Central

    Storck, Hannah; Hild, Benedikt; Schimmelpfennig, Sandra; Sargin, Sarah; Nielsen, Nikolaj; Zaccagnino, Angela; Budde, Thomas; Novak, Ivana; Kalthoff, Holger; Schwab, Albrecht

    2017-01-01

    Pancreatic stellate cells (PSCs) play a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC). Once activated, PSCs support proliferation and metastasis of carcinoma cells. PSCs even co-metastasise with carcinoma cells. This requires the ability of PSCs to migrate. In recent years, it has been established that almost all “hallmarks of cancer” such as proliferation or migration/invasion also rely on the expression and function of ion channels. So far, there is only very limited information about the function of ion channels in PSCs. Yet, there is growing evidence that ion channels in stromal cells also contribute to tumor progression. Here we investigated the function of KCa3.1 channels in PSCs. KCa3.1 channels are also found in many tumor cells of different origin. We revealed the functional expression of KCa3.1 channels by means of Western blot, immunofluorescence and patch clamp analysis. The impact of KCa3.1 channel activity on PSC function was determined with live-cell imaging and by measuring the intracellular Ca2+ concentration ([Ca2+]i). KCa3.1 channel blockade or knockout prevents the stimulation of PSC migration and chemotaxis by reducing the [Ca2+]i and calpain activity. KCa3.1 channels functionally cooperate with TRPC3 channels that are upregulated in PDAC stroma. Knockdown of TRPC3 channels largely abolishes the impact of KCa3.1 channels on PSC migration. In summary, our results clearly show that ion channels are crucial players in PSC physiology and pathophysiology. PMID:27903970

  6. Ion Concentration-Dependent Ion Conduction Mechanism of a Voltage-Sensitive Potassium Channel

    PubMed Central

    Kasahara, Kota; Shirota, Matsuyuki; Kinoshita, Kengo

    2013-01-01

    Voltage-sensitive potassium ion channels are essential for life, but the molecular basis of their ion conduction is not well understood. In particular, the impact of ion concentration on ion conduction has not been fully studied. We performed several micro-second molecular dynamics simulations of the pore domain of the Kv1.2 potassium channel in KCl solution at four different ion concentrations, and scrutinized each of the conduction events, based on graphical representations of the simulation trajectories. As a result, we observed that the conduction mechanism switched with different ion concentrations: at high ion concentrations, potassium conduction occurred by Hodgkin and Keynes' knock-on mechanism, where the association of an incoming ion with the channel is tightly coupled with the dissociation of an outgoing ion, in a one-step manner. On the other hand, at low ion concentrations, ions mainly permeated by a two-step association/dissociation mechanism, in which the association and dissociation of ions were not coupled, and occurred in two distinct steps. We also found that this switch was triggered by the facilitated association of an ion from the intracellular side within the channel pore and by the delayed dissociation of the outermost ion, as the ion concentration increased. PMID:23418558

  7. Calculating Conductance of Ion Channels - Linking Molecular Dynamics and Electrophysiology

    NASA Astrophysics Data System (ADS)

    Wilson, Michael A.; Pohorille, Andrew

    2015-01-01

    Molecular dynamics computer simulations were combined with an electrodiffusion model to compute conduction of simple ion channels. The main assumptions of the model, and the consistency, efficiency and accuracy of the ion current calculations were tested and found satisfactory. The calculated current-voltage dependence for a synthetic peptide channel is in agreement with experiments and correctly captures the asymmetry of current with respect to applied field.

  8. Antibody therapeutics targeting ion channels: are we there yet?

    PubMed Central

    Sun, Han; Li, Min

    2013-01-01

    The combination of technological advances, genomic sequences and market success is catalyzing rapid development of antibody-based therapeutics. Cell surface receptors and ion channel proteins are well known drug targets, but the latter has seen less success. The availability of crystal structures, better understanding of gating biophysics and validation of physiological roles now form an excellent foundation to pursue antibody-based therapeutics targeting ion channels to treat a variety of diseases. PMID:23381110

  9. Antibody therapeutics targeting ion channels: are we there yet?

    PubMed

    Sun, Han; Li, Min

    2013-02-01

    The combination of technological advances, genomic sequences and market success is catalyzing rapid development of antibody-based therapeutics. Cell surface receptors and ion channel proteins are well known drug targets, but the latter has seen less success. The availability of crystal structures, better understanding of gating biophysics and validation of physiological roles now form an excellent foundation to pursue antibody-based therapeutics targeting ion channels to treat a variety of diseases.

  10. Ion channels, long QT syndrome and arrhythmogenesis in ageing.

    PubMed

    Jeevaratnam, Kamalan; Chadda, Karan R; Salvage, Samantha C; Valli, Haseeb; Ahmad, Shiraz; Grace, Andrew A; Huang, Christopher L-H

    2016-12-26

    Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias particularly after 40 years of age consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing WT murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration. This article is

  11. Permeation of ions across the potassium channel: Brownian dynamics studies.

    PubMed

    Chung, S H; Allen, T W; Hoyles, M; Kuyucak, S

    1999-11-01

    The physical mechanisms underlying the transport of ions across a model potassium channel are described. The shape of the model channel corresponds closely to that deduced from crystallography. From electrostatic calculations, we show that an ion permeating the channel, in the absence of any residual charges, encounters an insurmountable energy barrier arising from induced surface charges. Carbonyl groups along the selectivity filter, helix dipoles near the oval chamber, and mouth dipoles near the channel entrances together transform the energy barrier into a deep energy well. Two ions are attracted to this well, and their presence in the channel permits ions to diffuse across it under the influence of an electric field. Using Brownian dynamics simulations, we determine the magnitude of currents flowing across the channel under various conditions. The conductance increases with increasing dipole strength and reaches its maximum rapidly; a further increase in dipole strength causes a steady decrease in the channel conductance. The current also decreases systematically when the effective dielectric constant of the channel is lowered. The conductance with the optimal choice of dipoles reproduces the experimental value when the dielectric constant of the channel is assumed to be 60. The current-voltage relationship obtained with symmetrical solutions is linear when the applied potential is less than approximately 100 mV but deviates from Ohm's law at a higher applied potential. The reversal potentials obtained with asymmetrical solutions are in agreement with those predicted by the Nernst equation. The conductance exhibits the saturation property observed experimentally. We discuss the implications of these findings for the transport of ions across the potassium channels and membrane channels in general.

  12. Channelopathies: ion channel defects linked to heritable clinical disorders

    PubMed Central

    Felix, R.

    2000-01-01

    Electrical signals are critical for the function of neurones, muscle cells, and cardiac myocytes. Proteins that regulate electrical signalling in these cells, including voltage gated ion channels, are logical sites where abnormality might lead to disease. Genetic and biophysical approaches are being used to show that several disorders result from mutations in voltage gated ion channels. Understanding gained from early studies on the pathogenesis of a group of muscle diseases that are similar in their episodic nature (periodic paralysis) showed that these disorders result from mutations in a gene encoding a voltage gated Na+ channel. Their characterisation as channelopathies has served as a paradigm for other episodic disorders. For example, migraine headache and some forms of epilepsy have been shown to result from mutations in voltage gated Ca2+ channel genes, while long QT syndrome is known to result from mutations in either K+ or Na+ channel genes. This article reviews progress made in the complementary fields of molecular genetics and cellular electrophysiology which has led to a better understanding of voltage gated ion channelopathies in humans and mice.


Keywords: ion channel genetics; ion channel physiopathology; channelopathies; hereditary diseases PMID:11015449

  13. 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.

  14. Pore architecture and ion sites in acid-sensing ion channels and P2X receptors.

    PubMed

    Gonzales, Eric B; Kawate, Toshimitsu; Gouaux, Eric

    2009-07-30

    Acid-sensing ion channels are proton-activated, sodium-selective channels composed of three subunits, and are members of the superfamily of epithelial sodium channels, mechanosensitive and FMRF-amide peptide-gated ion channels. These ubiquitous eukaryotic ion channels have essential roles in biological activities as diverse as sodium homeostasis, taste and pain. Despite their crucial roles in biology and their unusual trimeric subunit stoichiometry, there is little knowledge of the structural and chemical principles underlying their ion channel architecture and ion-binding sites. Here we present the structure of a functional acid-sensing ion channel in a desensitized state at 3 A resolution, the location and composition of the approximately 8 A 'thick' desensitization gate, and the trigonal antiprism coordination of caesium ions bound in the extracellular vestibule. Comparison of the acid-sensing ion channel structure with the ATP-gated P2X(4) receptor reveals similarity in pore architecture and aqueous vestibules, suggesting that there are unanticipated yet common structural and mechanistic principles.

  15. The 13th Annual Aurora Biomed Ion Channel Retreat: Three Days of Research, Technology, and Networking.

    PubMed

    Magee, Kaylee E A; Stanwood, Shawna R

    2016-03-01

    The 13th Annual Ion Channel Retreat was held by Aurora Biomed in Vancouver, Canada from July 7 to 9, 2015. The meeting showcased prominent current research including cardiac safety and pharmacology; ion channel structure, function and engineering; transporters and ion pumps; screening technologies; ion channels as disease targets; alcohol, tobacco, and ion channels; and ion channels as pain targets. This report summarizes the work presented at the retreat.

  16. Multiplexed four-channel rectilinear ion trap mass spectrometer.

    PubMed

    Kothari, Sameer; Song, Qingyu; Xia, Yu; Fico, Miriam; Taylor, Dennis; Amy, Jonathan W; Stafford, George; Cooks, R Graham

    2009-02-15

    A four-channel multiplexed mass spectrometer with rectilinear ion trap (RIT) mass analyzers was designed, constructed, and characterized. The system consists of four parallel atmospheric pressure ion (API) sources, four RIT mass analyzers, four sets of ion optical elements, and four conversion dynode detectors. The complete instrument is housed in a single vacuum manifold with a common vacuum system. It has a relatively small footprint, and costs and complexity were minimized and controls simplified by sharing the electronics and control modules among different channels. Each channel of the instrument can be operated in either positive or negative ion mode with a choice of ionization methods to improve the information content from an experiment. Also, the instrument is equipped with simultaneous data acquisition capabilities from all four channels, but the use of a common RF electronics system limits the degree to which the analyzer channels can be scanned independently. The instrument was characterized over the mass/charge range of 150 to 1300 Th. Mass misassignments in different ion traps because of machining and assembly tolerances were avoided by the application of supplementary direct current signals to each mass analyzer to correct mass offsets. A multiplexed automatic gain control (AGC) scheme was developed to control the ion population in each of the traps independently. These two features allow tandem mass spectrometry to be performed with an isolation window of 1 Th so trapping identical ions in all four channels. There are two principal modes of operation. In one, the same sample is analyzed in all four channels using different ionization methods to increase the information content of the analysis. In the other mode of operation, different samples are analyzed in all four channels with the same ionization method, so providing higher throughput. These capabilities were demonstrated by examining lipids produced by Escherichia coli and complex mixtures

  17. Rediscovering sperm ion channels with the patch-clamp technique

    PubMed Central

    Kirichok, Yuriy; Lishko, Polina V.

    2011-01-01

    Upon ejaculation, mammalian spermatozoa have to undergo a sequence of physiological transformations within the female reproductive tract that will allow them to reach and fertilize the egg. These include initiation of motility, hyperactivation of motility and perhaps chemotaxis toward the egg, and culminate in the acrosome reaction that permits sperm to penetrate the protective vestments of the egg. These physiological responses are triggered through the activation of sperm ion channels that cause elevations of sperm intracellular pH and Ca2+ in response to certain cues within the female reproductive tract. Despite their key role in sperm physiology and their absolute requirement for the process of fertilization, sperm ion channels remain poorly understood due to the extreme difficulty in application of the patch-clamp technique to spermatozoa. This review covers the topic of sperm ion channels in the following order: first, we discuss how the intracellular Ca2+ and pH signaling mediated by sperm ion channels controls sperm behavior during the process of fertilization. Then, we briefly cover the history of the methodology to study sperm ion channels, which culminated in the recent development of a reproducible whole-cell patch-clamp technique for mouse and human cells. We further discuss the main approaches used to patch-clamp mature mouse and human spermatozoa. Finally, we focus on the newly discovered sperm ion channels CatSper, KSper (Slo3) and HSper (Hv1), identified by the sperm patch-clamp technique. We conclude that the patch-clamp technique has markedly improved and shifted our understanding of the sperm ion channels, in addition to revealing significant species-specific differences in these channels. This method is critical for identification of the molecular mechanisms that control sperm behavior within the female reproductive tract and make fertilization possible. PMID:21642646

  18. Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification.

    PubMed

    Curran, Jerry; Mohler, Peter J

    2015-01-01

    Channelopathies are a diverse set of disorders associated with defects in ion channel (and transporter) function. Although the vast majority of channelopathies are linked with inherited mutations that alter ion channel biophysical properties, another group of similar disorders has emerged that alter ion channel synthesis, membrane trafficking, and/or posttranslational modifications. In fact, some electrical and episodic disorders have now been identified that are not defects in the ion channel but instead reflect dysfunction in an ion channel (or transporter) regulatory protein. This review focuses on alternative paradigms for physiological disorders associated with protein biosynthesis, folding, trafficking, and membrane retention. Furthermore, the review highlights the role of aberrant posttranslational modifications in acquired channelopathies.

  19. Mass-dependent channel electron multiplier operation. [for ion detection

    NASA Technical Reports Server (NTRS)

    Fields, S. A.; Burch, J. L.; Oran, W. A.

    1977-01-01

    The absolute counting efficiency and pulse height distributions of a continuous-channel electron multiplier used in the detection of hydrogen, argon and xenon ions are assessed. The assessment technique, which involves the post-acceleration of 8-eV ion beams to energies from 100 to 4000 eV, provides information on counting efficiency versus post-acceleration voltage characteristics over a wide range of ion mass. The charge pulse height distributions for H2 (+), A (+) and Xe (+) were measured by operating the experimental apparatus in a marginally gain-saturated mode. It was found that gain saturation occurs at lower channel multiplier operating voltages for light ions such as H2 (+) than for the heavier ions A (+) and Xe (+), suggesting that the technique may be used to discriminate between these two classes of ions in electrostatic analyzers.

  20. Ion Channels that Control Fertility in Mammalian Spermatozoa

    PubMed Central

    Navarro, Betsy; Kirichok, Yuriy; Chung, Jean-Ju; Clapham, David E.

    2015-01-01

    Whole-cell voltage clamp of mammalian spermatozoa was first achieved in 2006. This technical advance, combined with genetic deletion strategies, makes unambiguous identification of sperm ion channel currents possible. This review summarizes the ion channel currents that have been directly measured in mammalian sperm, and their physiological roles in fertilization. The predominant currents are 1) a Ca2+-selective current requiring expression of the 4 mCatSper genes, and 2) a delayed rectifier K+ current with properties most similar to mSlo3. Intracellular alkalinization activates both channels and induces hyperactivated motility. PMID:18649274

  1. Small Ion Channel Linking Molecular Simulations and Electrophysiology

    NASA Technical Reports Server (NTRS)

    Pohorille, Andrzej

    2017-01-01

    Ion channels are pore-forming protein assemblies that mediate the transport of small ions across cell membranes. Otherwise, membrane bilayers would be almost impermeable to ions incapable to traverse the low dielectric constant, hydrophobic membrane core. Ion channels are ubiquitous to all life forms. In humans and other higher organisms they play the central role in conducting nerve impulses, cardiac functions, muscle contraction and apoptosis. On the other extreme of biological complexity, viral ion channels (viroporins) influence many stages of the virus infection cycle either through regulating virus replication, such as entry, assembly and release or modulating the electrochemical balance in the subcellular compartments of host cells. Ion channels were crucial components of protocells. Their emergence facilitated adaptation of nascent life to different environmental conditions. The earliest ion channels must have been much simpler than most of their modern ancestors. Viral channels are among only a few naturally occurring models to study the structure, function and evolution of primordial channels. Experimental studies of these properties are difficult and often unreliable. In principle, computational methods, and molecular dynamics (MD) simulations in particular, can aid in providing information about both the structure and the function of ion channels. However, MD suffers from its own problems, such as inability to access sufficiently long time scales or limited accuracy of force fields. It is, therefore, essential to determine the reliability of MD simulations. We propose to do so on the basis of two criteria. One is channel stability on time scales that extend for several microseconds or longer. The other is the ability to reproduce the measured ionic conductance as a function of applied voltage. If both the stability and the calculated ionic conductance are satisfactory it will greatly increase our confidence that the structure and the function of a

  2. Effect of Cytoskeletal Reagents on Stretch Activated Ion Channels

    DTIC Science & Technology

    1992-11-12

    transduction. Biophys J59: 1143-1145, 1991. 23. SACHS, F., W. SIGURDSON, A. RUKNUDIN, AND C. BOWMAN. Single- channel mechanosensitive currents. Science 253: 800... mechanosensitive ion channels . In: Advances in Comparative and Environmental Physiology, v0C, edited by F. Ito. Berlin: Springer-Verlag, 1992, p. 55-77. Report of Inventions: None 4 ...EFFECT OF CYTOSKELETAL REAGENTS ON STRETCH ACTIVATED ION CHANNELS b lfli..3-f-I’- o0*’t 6. AUTHOR(S) Dr.-Frederick Sachs DI 7. PERFORMING ORGANIZATION NAME

  3. Electron-beam guiding by a reduced-density channel

    NASA Astrophysics Data System (ADS)

    Welch, D. R.; Bieniosek, F. M.; Godfrey, B. B.

    1990-12-01

    A new regime of density-channel guiding of a relativistic electron beam in air has been found using a three-dimensional charged-particle simulation code, and confirmed in a double-pulse electron-beam experiment. The guiding results from the temperature dependence of the electron-neutral momentum-transfer frequency nu(m). The mechanism does not require a deep channel to obtain a significant guiding force. For the 13-kA MEDEA II (and beams of similar parameters), guiding persists 10 nsec into the beam pulse, with the force per channel displacement as high as 4 G/cm.

  4. Combining molecular dynamics and an electrodiffusion model to calculate ion channel conductance.

    PubMed

    Wilson, Michael A; Nguyen, Thuy Hien; Pohorille, Andrew

    2014-12-14

    Establishing the relation between the structures and functions of protein ion channels, which are protein assemblies that facilitate transmembrane ion transport through water-filled pores, is at the forefront of biological and medical sciences. A reliable way to determine whether our understanding of this relation is satisfactory is to reproduce the measured ionic conductance over a broad range of applied voltages. This can be done in molecular dynamics simulations by way of applying an external electric field to the system and counting the number of ions that traverse the channel per unit time. Since this approach is computationally very expensive we develop a markedly more efficient alternative in which molecular dynamics is combined with an electrodiffusion equation. This alternative approach applies if steady-state ion transport through channels can be described with sufficient accuracy by the one-dimensional diffusion equation in the potential given by the free energy profile and applied voltage. The theory refers only to line densities of ions in the channel and, therefore, avoids ambiguities related to determining the surface area of the channel near its endpoints or other procedures connecting the line and bulk ion densities. We apply the theory to a simple, model system based on the trichotoxin channel. We test the assumptions of the electrodiffusion equation, and determine the precision and consistency of the calculated conductance. We demonstrate that it is possible to calculate current/voltage dependence and accurately reconstruct the underlying (equilibrium) free energy profile, all from molecular dynamics simulations at a single voltage. The approach developed here applies to other channels that satisfy the conditions of the electrodiffusion equation.

  5. Turning a Poor Ion Channel into a Good Pump

    NASA Astrophysics Data System (ADS)

    Astumian, Dean

    2003-05-01

    We consider a membrane protein that can exist in two configurations, either one of which acts as a poor ion channel, allowing ions to slowly leak across the membrane from high to low elctrochemical potential. We show that random external fluctuations can provide the energy to turn this poor channel into a good pump that drives ion transport from low to high electrochemical potential. We discuss this result in terms of a gambling analogy, and point to possible implications for fields as far ranging as population biology, economics, and actuarial science.

  6. 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

  7. Emerging approaches to probing ion channel structure and function.

    PubMed

    Li, Wei-Guang; Xu, Tian-Le

    2012-08-01

    Ion channels, as membrane proteins, are the sensors of the cell. They act as the first line of communication with the world beyond the plasma membrane and transduce changes in the external and internal environments into unique electrical signals to shape the responses of excitable cells. Because of their importance in cellular communication, ion channels have been intensively studied at the structural and functional levels. Here, we summarize the diverse approaches, including molecular and cellular, chemical, optical, biophysical, and computational, used to probe the structural and functional rearrangements that occur during channel activation (or sensitization), inactivation (or desensitization), and various forms of modulation. The emerging insights into the structure and function of ion channels by multidisciplinary approaches allow the development of new pharmacotherapies as well as new tools useful in controlling cellular activity.

  8. Ions channels/transporters and chloroplast regulation.

    PubMed

    Finazzi, Giovanni; Petroutsos, Dimitris; Tomizioli, Martino; Flori, Serena; Sautron, Emeline; Villanova, Valeria; Rolland, Norbert; Seigneurin-Berny, Daphné

    2015-07-01

    Ions play fundamental roles in all living cells and their gradients are often essential to fuel transports, to regulate enzyme activities and to transduce energy within and between cells. Their homeostasis is therefore an essential component of the cell metabolism. Ions must be imported from the extracellular matrix to their final subcellular compartments. Among them, the chloroplast is a particularly interesting example because there, ions not only modulate enzyme activities, but also mediate ATP synthesis and actively participate in the building of the photosynthetic structures by promoting membrane-membrane interaction. In this review, we first provide a comprehensive view of the different machineries involved in ion trafficking and homeostasis in the chloroplast, and then discuss peculiar functions exerted by ions in the frame of photochemical conversion of absorbed light energy.

  9. [Ion channel abnormalities ("channelopathies") in neurologic diseases].

    PubMed

    Masson, C

    2002-02-16

    THE ROLE OF IONIC CHANNEL DYSFUNCTION: During various neurological diseases has been evoked for many years on electro-physiological data. Molecular biology has led to great progress in neurology, and can be considered "functional" since it is surpasses the classical anatomo-clinical methods. IONIC CHANNEL DYSFUNCTION: Can be determined genetically, resulting from the mutation of a gene code of a channel sub-unit. CHANNELOPATHIES ARE RESPONSIBLE: For muscular diseases (myotonia, familial periodic paralysis, malignant hyperthermia and congenital myasthenia), but also for central nervous system disorders such as familial hemiplegic migraine, hereditary paroxystic ataxia and certain forms of Mendel's law hereditary epilepsy. ACQUIRED IONIC CHANNEL DYSFUNCTION: Resulting from auto-immune aggression is implied in diseases such as Lambert-Eaton's myasthenic syndrome and Isaac's neuromyotonia syndrome. It probably plays a part in the clinical, and particularly the sensitive expression (paresthesia and pain) of some peripheral neuropathies and certain central nervous system affections, such as multiple sclerosis.

  10. Hodgkin-Huxley neurons with defective and blocked ion channels

    NASA Astrophysics Data System (ADS)

    Pang, James Christopher S.; Bantang, Johnrob Y.

    2015-03-01

    We utilize the original Hodgkin-Huxley (HH) model to consider the effects of defective ion channels to the temporal response of neurons. Statistics of firing rate and inter-spike interval (ISI) reveal that production of action potentials (APs) in neurons is not sensitive to changes in membrane conductance for sodium and potassium ions, as well as to the reversal potential for sodium ions, as long as the relevant parameters do not exceed 13% from their normal levels. We also found that blockage of a critical fraction of either sodium or potassium channels (dependent on constant input current) respectively limits the firing activity or increases spontaneous spiking activity of neurons. Our model may be used to guide experiment designs related to ion channel control drug development.

  11. Channeling, channel density and mass recovery in aquifer transport, with application to the MADE experiment

    NASA Astrophysics Data System (ADS)

    Fiori, A.

    2014-12-01

    Channeling effects in heterogeneous formations are studied through a new quantity denoted as channel density a(x,t). Focusing on advection only, a(x,t) is defined as the relative number of streamtubes (or channels) containing solute between x and x + dx at a given time t, regardless of the mass that they carry. The channel density generally differs from the widely employed longitudinal mass distribution m(x,t), and their difference increases with time and the degree of heterogeneity. The difference between a and m reflects the nonuniformity of mass distribution relative to the plume geometry. In particular, the "fast" channels typically carry a larger fraction of mass than their share in their relative volume, which in turn can be rather small. Detecting such channels by a network of monitoring wells may be a challenging task, which might explain the poor solute recovery of some field experiments at increasing times. After application of the proposed concepts to the simple case of stratified formations, we model the channel density and mass distribution pertaining to the MADE experiment, which exhibited poor mass recovery at large times. The results presented in this study emphasize the possible channeling effects at MADE and the general difficulty in sampling the leading edge of the plume, which in turn may contain a significant fraction of the plume mass.

  12. [Acid-Sensing Ion Channels (ASICs) in pain].

    PubMed

    Lingueglia, Eric

    2014-01-01

    The discovery of new drug targets represents a real opportunity for developing fresh strategies against pain. Ion channels are interesting targets because they are directly involved in the detection and the transmission of noxious stimuli by sensory fibres of the peripheral nervous system and by neurons of the spinal cord. Acid-Sensing Ion Channels (ASICs) have emerged as important players in the pain pathway. They are neuronal, voltage-independent depolarizing sodium channels activated by extracellular protons. The ASIC family comprises several subunits that need to associate into homo- or hetero-trimers to form a functional channel. The ASIC1 and ASIC3 isoforms are particularly important in sensory neurons, whereas ASIC1a, alone or in association with ASIC2, is essential in the central nervous system. The potent analgesic effects associated with their inhibition in animals (which can be comparable to those of morphine) and data suggesting a role in human pain illustrate the therapeutic potential of these channels.

  13. Ion transport through a T-intersection of nanofluidic channels.

    PubMed

    Daiguji, Hirofumi; Adachi, Takuma; Tatsumi, Naoya

    2008-08-01

    Ion transport through a T-intersection of two silica nanochannels (a main channel, 5-mum long and 30-nm wide, and a subchannel, 5-microm long and 15-nm wide) with a surface charge distribution was investigated based on continuum dynamics calculations. The surface charge within 250 nm of the intersection in the main channel and the entire subchannel was positive and that in the main channel outside this intersection region was negative. This nanofluidic system is analogous to a p-n-p transistor. The calculation results revealed that, by adjusting the electric potentials at the ends of the nanochannels, the ionic current could be (1) cut off, (2) regulated in the main channel, (3) diverged into the main and subchannels, (4) turned from the main channel to the subchannel, and (5) merged into the subchannel. A series connection of this nanofluidic system can therefore be used in biotechnological applications for electrophoretic separation and for sorting of ions and biomolecules.

  14. Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction

    PubMed Central

    Kasahara, Kota; Shirota, Matsuyuki; Kinoshita, Kengo

    2016-01-01

    The mechanism of ion conduction by potassium channels is one of the central issues in physiology. In particular, it is still unclear how the ion concentration and the membrane voltage drive ion conduction. We have investigated the dynamics of the ion conduction processes in the Kv1.2 pore domain, by molecular dynamics (MD) simulations with several different voltages and ion concentrations. By focusing on the detailed ion movements through the pore including selectivity filter (SF) and cavity, we found two major conduction mechanisms, called the III-IV-III and III-II-III mechanisms, and the balance between the ion concentration and the voltage determines the mechanism preference. In the III-IV-III mechanism, the outermost ion in the pore is pushed out by a new ion coming from the intracellular fluid, and four-ion states were transiently observed. In the III-II-III mechanism, the outermost ion is pulled out first, without pushing by incoming ions. Increases in the ion concentration and voltage accelerated ion conductions, but their mechanisms were different. The increase in the ion concentrations facilitated the III-IV-III conductions, while the higher voltages increased the III-II-III conductions, indicating that the pore domain of potassium channels permeates ions by using two different driving forces: a push by intracellular ions and a pull by voltage. PMID:26950215

  15. Ion Concentration- and Voltage-Dependent Push and Pull Mechanisms of Potassium Channel Ion Conduction.

    PubMed

    Kasahara, Kota; Shirota, Matsuyuki; Kinoshita, Kengo

    2016-01-01

    The mechanism of ion conduction by potassium channels is one of the central issues in physiology. In particular, it is still unclear how the ion concentration and the membrane voltage drive ion conduction. We have investigated the dynamics of the ion conduction processes in the Kv1.2 pore domain, by molecular dynamics (MD) simulations with several different voltages and ion concentrations. By focusing on the detailed ion movements through the pore including selectivity filter (SF) and cavity, we found two major conduction mechanisms, called the III-IV-III and III-II-III mechanisms, and the balance between the ion concentration and the voltage determines the mechanism preference. In the III-IV-III mechanism, the outermost ion in the pore is pushed out by a new ion coming from the intracellular fluid, and four-ion states were transiently observed. In the III-II-III mechanism, the outermost ion is pulled out first, without pushing by incoming ions. Increases in the ion concentration and voltage accelerated ion conductions, but their mechanisms were different. The increase in the ion concentrations facilitated the III-IV-III conductions, while the higher voltages increased the III-II-III conductions, indicating that the pore domain of potassium channels permeates ions by using two different driving forces: a push by intracellular ions and a pull by voltage.

  16. Emergence of ion channel modal gating from independent subunit kinetics.

    PubMed

    Bicknell, Brendan A; Goodhill, Geoffrey J

    2016-09-06

    Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca(2+) concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

  17. Emergence of ion channel modal gating from independent subunit kinetics

    PubMed Central

    Bicknell, Brendan A.

    2016-01-01

    Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior. PMID:27551100

  18. Electrostatic calculations for an ion channel. I. Energy and potential profiles and interactions between ions.

    PubMed Central

    Levitt, D G

    1978-01-01

    The electrostatic energy profile of one, two, or three ions in an aqueous channel through a lipid membrane is calculated. It is shown that the previous solution to this problem (based on the assumption that the channel is infinitely long) significantly overestimates the electrostatic energy barrier. For example, for a 3-A radius pore, the energy is 16 kT for the infinite channel and 6.7 kT for an ion in the center of a channel 25 A long. The energy as a function of the position of the ion is also determined. With this energy profile, the rate of crossing the membrane (using the Nernst-Planck equation) was estimated and found to be compatible with the maximum conductance observed for the gramicidin A channel. The total electrostatic energy (as a function of position) required to place two or three ions in the channel is also calculated. The electrostatic interaction is small for two ions at opposite ends of the channel and large for any positioning of the three ions. Finally, the gradient through the channel of an applied potential is calculated. The solution to these problems is based on solving an equivalent problem in which an appropriate surface charge is placed on the boundary between the lipid and aqueous regions. The magnitude of the surface charge is obtained from the numerical solution for a system of coupled integral equations. PMID:656542

  19. A golden approach to ion channel inhibition☆

    PubMed Central

    Jarvis, Gavin E.; Thompson, Andrew J.

    2013-01-01

    Drugs are often used in combination and, for pharmacologists, the manner of their interactions can cast light on drug mechanisms and biological processes. Here we provide simplified descriptions of commonly used analytical methods for analysing drug combinations and describe a new and practical experimental solution to address the mechanistic question: ‘Do two channel-blocking drugs bind at the same site?’ We define two simple mathematical models that describe the effects of two channel blockers acting simultaneously at either the same (Syntopic Model) or different (Allotopic Model) binding sites within a channel pore. We find that the optimum concentrations of two drugs for distinguishing between the two models are related to the mathematical Golden Ratio. PMID:23972927

  20. The 22nd Ion Channel Meeting, September 2011, France

    PubMed Central

    Goaillard, Jean-Marc; Groc, Laurent; Lévi, Sabine; Mantegazza, Massimo; Matifat, Fabrice; Morel, Jean-Luc; Baron-Forster, Anne

    2012-01-01

    The 22nd Ion Channel Meeting was organized by the French Ion Channel Society (Association Canaux Ioniques) from the 25th to the 28th of September 2011 on the French Riviera (Giens). This year again, more than one hundred researchers from France, Europe and extra-European countries gathered to present and discuss their recent advances and future challenges in the ion channels and transporters field. The scientific committee organized a plenary lecture and five thematic symposia by inviting international researchers to present their recent outstanding work on themes as diverse as muscular channelopathies, regulation of channels by extracellular matrix, receptor-channels interactions, localization and distribution of ion channels, their involvement in the cell life and death, and finally how they participate in the evolution and adaptability of cellular excitability. These presentations are summarized in this meeting report. Two sessions of oral communications selected from submitted abstracts and two poster sessions were also organized to present the ongoing work of young researchers worldwide. PMID:22647366

  1. Ion channels in human erythroblasts. Modulation by erythropoietin.

    PubMed Central

    Cheung, J Y; Elensky, M B; Brauneis, U; Scaduto, R C; Bell, L L; Tillotson, D L; Miller, B A

    1992-01-01

    To investigate the mechanism of intracellular Ca2+ ([Cai]) increase in human burst-forming unit-erythroid-derived erythroblasts by erythropoietin, we measured [Cai] with digital video imaging, cellular phosphoinositides with high performance liquid chromatography, and plasma membrane potential and currents with whole cell patch clamp. Chelation of extracellular free Ca2+ abolished [Cai] increase induced by erythropoietin. In addition, the levels of inositol-1,4,5-trisphosphate did not increase in erythropoietin-treated erythroblasts. These results indicate that in erythropoietin-stimulated cells, Ca2+ influx rather than intracellular Ca2+ mobilization was responsible for [Cai] rise. Both Ni2+ and moderately high doses of nifedipine blocked [Cai] increase, suggesting involvement of ion channels. Resting membrane potential in human erythroblasts was -10.9 +/- 1.0 mV and was not affected by erythropoietin, suggesting erythropoietin modulated a voltage-independent ion channel permeable to Ca2+. No voltage-dependent ion channel but a Ca(2+)-activated K+ channel was detected in human erythroblasts. The magnitude of erythropoietin-induced [Cai] increase, however, was insufficient to open Ca(2+)-activated K+ channels. Our data suggest erythropoietin modulated a voltage-independent ion channel permeable to Ca2+, resulting in sustained increases in [Cai]. PMID:1385476

  2. General anesthesia mediated by effects on ion channels

    PubMed Central

    Zhou, Cheng; Liu, Jin; Chen, Xiang-Dong

    2012-01-01

    Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties such as hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels. PMID:24701405

  3. Physiological and Pathological Functions of Mechanosensitive Ion Channels

    PubMed Central

    Gu, Yuanzheng; Gu, Chen

    2014-01-01

    Rapid sensation of mechanical stimuli is often mediated by mechanosensitve ion channels. Their opening results from conformational changes induced by mechanical forces. It leads to membrane permeation of selected ions and thereby to electrical signaling. Newly identified mechanosensitive ion channels are emerging at an astonishing rate, including some that are traditionally assigned for completely different functions. In this review, we first provide a brief overview of ion channels that are known to play a role in mechanosensation. Next, we focus on three representative ones, including the transient receptor potential channel V4 (TRPV4), Kv1.1 voltage-gated potassium (Kv) channel, and Piezo channels. Their structures, biophysical properties, expression and targeting patterns, and physiological functions are highlighted. The potential role of their mechanosensation in related diseases is further discussed. In sum, mechanosensation appears to be achieved in a variety of ways by different proteins and plays a fundamental role in the function of various organs under normal and abnormal conditions. PMID:24532247

  4. Cocaine withdrawal and neuro-adaptations in ion channel function.

    PubMed

    Hu, Xiu-Ti

    2007-02-01

    Chronic exposure to psychostimulants induces neuro-adaptations in ion channel function of dopamine (DA)-innervated cells localized within the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Although neuroplasticity in ion channel function is initially found in drug-sensitized animals, it has recently been believed to underlie the withdrawal effects of cocaine, including craving that leads to relapse in human addicts. Recent studies have also revealed remarkable differences in altered ion channel activities between mPFC pyramidal neurons and medium spiny NAc neurons in cocaine-withdrawn animals. In response to psychostimulant or certain "excitatory" stimuli, increased intrinsic excitability is found in mPFC pyramidal neurons, whereas decreased excitability is observed in medium spiny NAc cells in drug-withdrawn animals compared to drug-free control animals. These changes in ion channel function are modulated by interrupted DA/Ca2+ signaling with decreased DA D2 receptor function but increased D1 receptor signaling. More importantly, they are correlated to behavioral changes in cocaine-withdrawn human addicts and sensitized animals. Based on growing evidence, researchers have proposed that cocaine-induced neuro-adaptations in ion channel activity and DA/Ca2+ signaling in mPFC pyramidal neurons and medium spiny NAc cells may be the fundamental cellular mechanism underlying the cocaine withdrawal effects observed in human addicts.

  5. Ion/water channels for embryo implantation barrier.

    PubMed

    Liu, Xin-Mei; Zhang, Dan; Wang, Ting-Ting; Sheng, Jian-Zhong; Huang, He-Feng

    2014-05-01

    Successful implantation involves three distinct processes, namely the embryo apposition, attachment, and penetration through the luminal epithelium of the endometrium to establish a vascular link to the mother. After penetration, stromal cells underlying the epithelium differentiate and surround the embryo to form the embryo implantation barrier, which blocks the passage of harmful substances to the embryo. Many ion/water channel proteins were found to be involved in the process of embryo implantation. First, ion/water channel proteins play their classical role in establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane. Second, most of ion/water channel proteins are regulated by steroid hormone (estrogen or progesterone), which may have important implications to the embryo implantation. Last but not least, these proteins do not limit themselves as pure channels but also function as an initiator of a series of consequences once activated by their ligand/stimulator. Herein, we discuss these new insights in recent years about the contribution of ion/water channels to the embryo implantation barrier construction during early pregnancy.

  6. Influence of ion channels on the proliferation of human chondrocytes.

    PubMed

    Wohlrab, David; Lebek, Susanne; Krüger, Thomas; Reichel, Heiko

    2002-01-01

    The goal of the study was to examine connections between ion channel activity and the proliferation of human chondrocytes. Chondrocytes were isolated form human osteoarthritic knee joint cartilage. In this study the concentration-dependent influence of the ion channel modulators tetraethylammonium (TEA), 4-aminopyridine (4-AP), 4',4' diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS), 4-acetamido-4'-isothiocyano-2,2'-disulfonic acid stilbene (SITS), verapamil (vp) and lidocaine (lido) on the membrane potential and the proliferation of human chondrocytes was investigated using flow cytometry and the measurement of (3)H-thymidine incorporation as measure for the cell proliferation. The results show an effect of the used ion channel modulators causing a change of the membrane potential of human chondrocytes. The maximal measurable effects of the membrane potential were listed with 0.25 mmol/l verapamil (-18%) and 0.1 mmol/l lidocaine (+20%). When measuring DNA distribution, it became apparent that the human chondrocytes are diploid cells with a very low proliferation tendency. After 12 days culture duration, lidocaine and 4-AP cause an increase of the DNA synthesis rate being a limited effect. These results allow the conclusion of an influence of ion channel modulators on chondrocyte proliferation. To gain knowledge of the regulation of chondrocyte proliferation via ion channel modulators could serve the research of new osteoarthritis treatment concepts.

  7. Ion Channels and Signaling in the Pituitary Gland

    PubMed Central

    Stojilkovic, Stanko S.; Tabak, Joël; Bertram, Richard

    2010-01-01

    Endocrine pituitary cells are neuronlike; they express numerous voltage-gated sodium, calcium, potassium, and chloride channels and fire action potentials spontaneously, accompanied by a rise in intracellular calcium. In some cells, spontaneous electrical activity is sufficient to drive the intracellular calcium concentration above the threshold for stimulus-secretion and stimulus-transcription coupling. In others, the function of these action potentials is to maintain the cells in a responsive state with cytosolic calcium near, but below, the threshold level. Some pituitary cells also express gap junction channels, which could be used for intercellular Ca2+ signaling in these cells. Endocrine cells also express extracellular ligand-gated ion channels, and their activation by hypothalamic and intrapituitary hormones leads to amplification of the pacemaking activity and facilitation of calcium influx and hormone release. These cells also express numerous G protein-coupled receptors, which can stimulate or silence electrical activity and action potential-dependent calcium influx and hormone release. Other members of this receptor family can activate calcium channels in the endoplasmic reticulum, leading to a cell type-specific modulation of electrical activity. This review summarizes recent findings in this field and our current understanding of the complex relationship between voltage-gated ion channels, ligand-gated ion channels, gap junction channels, and G protein-coupled receptors in pituitary cells. PMID:20650859

  8. Ion channel gates: comparative analysis of energy barriers.

    PubMed

    Tai, Kaihsu; Haider, Shozeb; Grottesi, Alessandro; Sansom, Mark S P

    2009-04-01

    The energetic profile of an ion translated along the axis of an ion channel should reveal whether the structure corresponds to a functionally open or closed state of the channel. In this study, we explore the combined use of Poisson-Boltzmann electrostatic calculations and evaluation of van der Waals interactions between ion and pore to provide an initial appraisal of the gating state of a channel. This approach is exemplified by its application to the bacterial inward rectifier potassium channel KirBac3.1, where it reveals the closed gate to be formed by a ring of leucine (L124) side chains. We have extended this analysis to a comparative survey of gating profiles, including model hydrophobic nanopores, the nicotinic acetylcholine receptor, and a number of potassium channel structures and models. This enables us to identify three gating regimes, and to show the limitation of this computationally inexpensive method. For a (closed) gate radius of 0.4 nm < R < 0.8 nm, a hydrophobic gate may be present. For a gate radius of 0.2 nm < R < 0.4 nm, both electrostatic and van der Waals interactions will contribute to the barrier height. Below R = 0.2 nm, repulsive van der Waals interactions are likely to dominate, resulting in a sterically occluded gate. In general, the method is more useful when the channel is wider; for narrower channels, the flexibility of the protein may allow otherwise-unsurmountable energetic barriers to be overcome.

  9. Multiple Scales in the Simulation of Ion Channels and Proteins

    PubMed Central

    Eisenberg, Bob

    2010-01-01

    Computation of living processes creates great promise for the everyday life of mankind and great challenges for physical scientists. Simulations molecular dynamics have great appeal to biologists as a natural extension of structural biology. Once a biologist sees a structure, she/he wants to see it move. Molecular biology has shown that a small number of atoms, sometimes even one messenger ion, like Ca2+, can control biological function on the scale of cells, organs, tissues, and organisms. Enormously concentrated ions—at number densities of ~20 M—in protein channels and enzymes are responsible for many of the characteristics of living systems, just as highly concentrated ions near electrodes are responsible for many of the characteristics of electrochemical systems. Here we confront the reality of the scale differences of ions. We show that the scale differences needed to simulate all the atoms of biological cells are 107 in linear dimension, 1021 in three dimensions, 109 in resolution, 1011 in time, and 1013 in particle number (to deal with concentrations of Ca2+). These scales must be dealt with simultaneously if the simulation is to deal with most biological functions. Biological function extends across all of them, all at once in most cases. We suggest a computational approach using explicit multiscale analysis instead of implicit simulation of all scales. The approach is based on an energy variational principle EnVarA introduced by Chun Liu to deal with complex fluids. Variational methods deal automatically with multiple interacting components and scales. When an additional component is added to the system, the resulting Euler Lagrange field equations change form automatically—by algebra alone—without additional unknown parameters. Multifaceted interactions are solutions of the resulting equations. We suggest that ionic solutions should be viewed as complex fluids with simple components. Highly concentrated solutions—dominated by interactions of

  10. Dependence of the beam-channel interaction force on the radial profiles of a relativistic electron beam and an ion channel in the ion-focusing regime

    NASA Astrophysics Data System (ADS)

    Kolesnikov, E. K.; Manuilov, A. S.

    2017-02-01

    We have derived the formulas for calculating the force of the interaction of a relativistic electron beam with an ion plasma channel in the case of the beam transportation during ion focusing. The dependence of the difference in radial profiles of the beam and the ion channel on this force for different amplitudes of beam deviations from the channel symmetry axis has been studied.

  11. 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

  12. Electronic capture and excitation of highly charged channeled ions

    NASA Astrophysics Data System (ADS)

    Andriamonje, S.; Blank, B.; Del Moral, R.; Dufour, J. P.; Faux, L.; Fleury, A.; Pravikoff, M. S.; Röhl, C.; Chevallier, M.; Dauvergne, D.; Kirsch, R.; Poizat, J. C.; Remillieux, J.; Cohen, C.; Girard, Y.; L'Hoir, A.; Rozet, J. P.; Schmaus, D.; Vernhet, D.; Dural, J.; Rothard, H.; Toulemonde, M.; Quéré, Y.; Cue, N.

    1994-04-01

    Two aspects of heavy ion channeling are presented. The first aspect is related to the fact that channeled ions interact only with the most loosely bound target electrons. One can take benefit of this feature to study processes such as radiative electron capture (REC) and resonant transfer and excitation (RTE) in a dense quasi-free electron gas. The experimental work, performed at GANIL, devoted to these two processes is described. A possible extension to Nuclear RTE or NEEC (nuclear excitation by electron capture) studies is also described. The second aspect discussed is related to the periodicity of the potential experienced by channeled ions. We show that in a well chosen case this could lead to a significant and detectable coherent excitation of the projectile nucleus.

  13. Modification of cardiovascular ion channels by gene therapy.

    PubMed

    Telemaque, Sabine; Marsh, James D

    2009-08-01

    Delivery of genes to the heart and vasculature for therapeutic purposes is an exciting strategy that is approaching clinical reality. Abnormalities of expression or function of ion channels is central to many cardiovascular diseases and gene delivery to modify ion channels is an appealing alternative to traditional therapy with small-molecule drugs. Potential therapeutic targets include hypertrophy and heart failure, atrioventricular node modification in atrial fibrillation, ventricular tachycardia and hypertension. Numerous approaches for gene delivery are under development, including use of tissue-specific promoters in viral vectors. For other applications, such as development of biological pacemakers, cells can be transduced with pacemaker genes in vitro, and then the cells implanted within the heart. There are short-term hurdles to therapeutic gene delivery to modify cardiovascular ion channels, but in the intermediate and longer term, the outlook is promising.

  14. Divalent ion trapping inside potassium channels of human T lymphocytes

    PubMed Central

    1989-01-01

    Using the patch-clamp whole-cell recording technique, we investigated the influence of external Ca2+, Ba2+, K+, Rb+, and internal Ca2+ on the rate of K+ channel inactivation in the human T lymphocyte-derived cell line, Jurkat E6-1. Raising external Ca2+ or Ba2+, or reducing external K+, accelerated the rate of the K+ current decay during a depolarizing voltage pulse. External Ba2+ also produced a use-dependent block of the K+ channels by entering the open channel and becoming trapped inside. Raising internal Ca2+ accelerated inactivation at lower concentrations than external Ca2+, but increasing the Ca2+ buffering with BAPTA did not affect inactivation. Raising [K+]o or adding Rb+ slowed inactivation by competing with divalent ions. External Rb+ also produced a use-dependent removal of block of K+ channels loaded with Ba2+ or Ca2+. From the removal of this block we found that under normal conditions approximately 25% of the channels were loaded with Ca2+, whereas under conditions with 10 microM internal Ca2+ the proportion of channels loaded with Ca2+ increased to approximately 50%. Removing all the divalent cations from the external and internal solution resulted in the induction of a non-selective, voltage-independent conductance. We conclude that Ca2+ ions from the outside or the inside can bind to a site at the K+ channel and thereby block the channel or accelerate inactivation. PMID:2786551

  15. Ion channels: Key elements in sea urchin sperm physiology

    NASA Astrophysics Data System (ADS)

    Darszon, Alberto; de De Latorre, Lucia; Vargas, Irma; Liévano, Arturo; Beltrán, Carmen; Santi, Celia; Labarca, Pedro; Zapata, Otilia

    1995-08-01

    Ion channels are deeply involved in sea urchin sperm activation, motility, chemotaxis and in the acrosome reaction. Unraveling ion channel function and regulation in sperm behavior has required a combination of complementary approaches since spermatozoa are very tiny cells. Planar bilayer and patch clamp techniques have allowed us to detect, for the first time, the activity of single channels in the plasma membrane of these cells. Unlike intact sperm, swollen sperm can be much more easily patch clamped and single channel activity recorded. These techniques, together with studies of membrane potential, intracellular Ca2+ and pH in whole sperm, have established the presence of K+, Ca2+, and Cl- channels in this cell. The strategies developed to study sea urchin sperm channels are applicable to mammalian spermatozoa. We recently detected a Ca2+ channel resembling one found in S. purpuratus sperm in planar bilayers containing mouse sperm plasma membranes. The presence of this Ca2+ channel in such diverse species suggests it is important in sperm function.

  16. Ion channels in artificial bolaamphiphile membranes deposited on sensor chips: optical detection in an ion-channel-based biosensor

    NASA Astrophysics Data System (ADS)

    Schalkhammer, Thomas G. M.; Weiss-Wichert, Christof; Smetazko, Michaela M.; Valina-Saba, Miriam

    1997-06-01

    Signal amplification using labels should be replaced by a technique monitoring the biochemical binding event directly. The use of a ligand coupled to an artificial gated membrane ion channel is a new promising strategy. Binding of protein- or DNA/RNA-analytes at ligand modified peptide channels results in an on/off-response of the channel current due to channel closure or distortion. The sensor consists of stable transmembrane channels with a ligand bound covalently at the peptide channel entrance, a sensor chip with a photostructurized hydrophobic polymer frame, a hydrophilic ion conducting membrane support, a lipid membrane incorporating the engineered ion channels, and a current amplifier or a sensitive fluorescence monitor. Detection of channel opening or closure can ether be obtained by directly monitoring membrane conductivity or a transient change of pH or ion concentration within the membrane compartment. This change can be induced by electrochemical or optical means and its decay is directly correlated to the permeability of the membrane. The ion concentration in the sub membrane compartment was monitored by incorporation of fluorescent indicator dyes. To obtain the stable sensor membrane the lipid layer had to be attached on a support and the floating of the second lipid membrane on top of the first one had to be prevented. Both problems do not occur using our new circular C44-C76 bolaamphiphilic lipids consisting of a long hydrophobic core region and two hydrophilic heads. Use of maleic ester-head groups enabled us to easily modify the lipids with amines, thioles, alcohols, phosphates, boronic acid as well as fluorescent dyes. The properties of these membranes were studied using LB and fluorescence techniques. Based on this detection principle miniaturized sensor chips with significantly enhanced sensitivity and large multi analyte arrays are under construction.

  17. Identification and characterization of a bacterial hydrosulphide ion channel

    SciTech Connect

    Czyzewski, Bryan K.; Wang, Da-Neng

    2012-10-26

    The hydrosulphide ion (HS{sup -}) and its undissociated form, hydrogen sulphide (H{sub 2}S), which are believed to have been critical to the origin of life on Earth, remain important in physiology and cellular signalling. As a major metabolite in anaerobic bacterial growth, hydrogen sulphide is a product of both assimilatory and dissimilatory sulphate reduction. These pathways can reduce various oxidized sulphur compounds including sulphate, sulphite and thiosulphate. The dissimilatory sulphate reduction pathway uses this molecule as the terminal electron acceptor for anaerobic respiration, in which process it produces excess amounts of H{sub 2}S. The reduction of sulphite is a key intermediate step in all sulphate reduction pathways. In Clostridium and Salmonella, an inducible sulphite reductase is directly linked to the regeneration of NAD{sup +}, which has been suggested to have a role in energy production and growth, as well as in the detoxification of sulphite. Above a certain concentration threshold, both H{sub 2}S and HS{sup -} inhibit cell growth by binding the metal centres of enzymes and cytochrome oxidase, necessitating a release mechanism for the export of this toxic metabolite from the cell. Here we report the identification of a hydrosulphide ion channel in the pathogen Clostridium difficile through a combination of genetic, biochemical and functional approaches. The HS{sup -} channel is a member of the formate/nitrite transport family, in which about 50 hydrosulphide ion channels form a third subfamily alongside those for formate (FocA) and for nitrite (NirC). The hydrosulphide ion channel is permeable to formate and nitrite as well as to HS{sup -} ions. Such polyspecificity can be explained by the conserved ion selectivity filter observed in the channel's crystal structure. The channel has a low open probability and is tightly regulated, to avoid decoupling of the membrane proton gradient.

  18. Briefing in application of machine learning methods in ion channel prediction.

    PubMed

    Lin, Hao; Chen, Wei

    2015-01-01

    In cells, ion channels are one of the most important classes of membrane proteins which allow inorganic ions to move across the membrane. A wide range of biological processes are involved and regulated by the opening and closing of ion channels. Ion channels can be classified into numerous classes and different types of ion channels exhibit different functions. Thus, the correct identification of ion channels and their types using computational methods will provide in-depth insights into their function in various biological processes. In this review, we will briefly introduce and discuss the recent progress in ion channel prediction using machine learning methods.

  19. From toxins targeting ligand gated ion channels to therapeutic molecules.

    PubMed

    Nasiripourdori, Adak; Taly, Valérie; Grutter, Thomas; Taly, Antoine

    2011-03-01

    Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted.

  20. Desensitization mechanism in prokaryotic ligand-gated ion channel.

    PubMed

    Velisetty, Phanindra; Chakrapani, Sudha

    2012-05-25

    Crystal structures of Gloeobacter violaceus ligand-gated ion channel (GLIC), a proton-gated prokaryotic homologue of pentameric ligand-gated ion channel (LGIC) from G. violaceus, have provided high-resolution models of the channel architecture and its role in selective ion conduction and drug binding. However, it is still unclear which functional states of the LGIC gating scheme these crystal structures represent. Much of this uncertainty arises from a lack of thorough understanding of the functional properties of these prokaryotic channels. To elucidate the molecular events that constitute gating, we have carried out an extensive characterization of GLIC function and dynamics in reconstituted proteoliposomes by patch clamp measurements and EPR spectroscopy. We find that GLIC channels show rapid activation upon jumps to acidic pH followed by a time-dependent loss of conductance because of desensitization. GLIC desensitization is strongly coupled to activation and is modulated by voltage, permeant ions, pore-blocking drugs, and membrane cholesterol. Many of these properties are parallel to functions observed in members of eukaryotic LGIC. Conformational changes in loop C, measured by site-directed spin labeling and EPR spectroscopy, reveal immobilization during desensitization analogous to changes in LGIC and acetylcholine binding protein. Together, our studies suggest conservation of mechanistic aspects of desensitization among LGICs of prokaryotic and eukaryotic origin.

  1. Modeling ion channel dynamics through reflected stochastic differential equations

    NASA Astrophysics Data System (ADS)

    Dangerfield, Ciara E.; Kay, David; Burrage, Kevin

    2012-05-01

    Ion channels are membrane proteins that open and close at random and play a vital role in the electrical dynamics of excitable cells. The stochastic nature of the conformational changes these proteins undergo can be significant, however current stochastic modeling methodologies limit the ability to study such systems. Discrete-state Markov chain models are seen as the “gold standard,” but are computationally intensive, restricting investigation of stochastic effects to the single-cell level. Continuous stochastic methods that use stochastic differential equations (SDEs) to model the system are more efficient but can lead to simulations that have no biological meaning. In this paper we show that modeling the behavior of ion channel dynamics by a reflected SDE ensures biologically realistic simulations, and we argue that this model follows from the continuous approximation of the discrete-state Markov chain model. Open channel and action potential statistics from simulations of ion channel dynamics using the reflected SDE are compared with those of a discrete-state Markov chain method. Results show that the reflected SDE simulations are in good agreement with the discrete-state approach. The reflected SDE model therefore provides a computationally efficient method to simulate ion channel dynamics while preserving the distributional properties of the discrete-state Markov chain model and also ensuring biologically realistic solutions. This framework could easily be extended to other biochemical reaction networks.

  2. The Structure and Transport of Water and Hydrated Ions Within Hydrophobic, Nanoscale Channels

    SciTech Connect

    Holt, J K; Herberg, J L; Wu, Y; Schwegler, E; Mehta, A

    2009-06-15

    The purpose of this project includes an experimental and modeling investigation into water and hydrated ion structure and transport at nanomaterials interfaces. This is a topic relevant to understanding the function of many biological systems such as aquaporins that efficiently shuttle water and ion channels that permit selective transport of specific ions across cell membranes. Carbon nanotubes (CNT) are model nanoscale, hydrophobic channels that can be functionalized, making them artificial analogs for these biological channels. This project investigates the microscopic properties of water such as water density distributions and dynamics within CNTs using Nuclear Magnetic Resonance (NMR) and the structure of hydrated ions at CNT interfaces via X-ray Absorption Spectroscopy (XAS). Another component of this work is molecular simulation, which can predict experimental measurables such as the proton relaxation times, chemical shifts, and can compute the electronic structure of CNTs. Some of the fundamental questions this work is addressing are: (1) what is the length scale below which nanoscale effects such as molecular ordering become important, (2) is there a relationship between molecular ordering and transport?, and (3) how do ions interact with CNT interfaces? These are questions of interest to the scientific community, but they also impact the future generation of sensors, filters, and other devices that operate on the nanometer length scale. To enable some of the proposed applications of CNTs as ion filtration media and electrolytic supercapacitors, a detailed knowledge of water and ion structure at CNT interfaces is critical.

  3. Mechanistic and therapeutic perspectives for cardiac arrhythmias: beyond ion channels.

    PubMed

    Wu, Yufei; Li, Jun; Xu, Liang; Lin, Li; Chen, Yi-Han

    2017-03-24

    Cardiac arrhythmias are among the most common causes of death in the world. Foundational studies established the critical role of ion channel disorders in arrhythmias, yet defects in ion channels themselves, such as mutations, may not account for all arrhythmias. Despite the progress made in recent decades, the antiarrhythmic drugs currently available have limited effectiveness, and the majority of these drugs can have proarrhythmic effects. This review describes novel knowledge on cellular mechanisms that cause cardiac arrhythmias, focuses on the dysfunction of subcellular organelles and intracellular logistics, and discusses potential strategies and challenges for developing novel, safe and effective treatments for arrhythmias.

  4. Mitochondrial Ion Channels: Gatekeepers of Life and Death

    PubMed Central

    O'Rourke, Brian; Cortassa, Sonia; Aon, Miguel A.

    2009-01-01

    Continuous generation of ATP by mitochondrial oxidative phosphorylation is essential to maintain function in mechanically active cells such as cardiomyocytes. Emerging evidence indicates that mitochondrial ion channels activated by reactive oxygen species can induce a mitochondrial "critical" state, which can scale to cause electrical and contractile dysfunction of the cardiac cell and, ultimately, the whole heart. Here we focus on how mitochondrial ion channels participate in life-and-death decisions of the cell and discuss the challenges ahead for translating recent findings into novel therapeutic applications. PMID:16174870

  5. Ferroelectric active models of ion channels in biomembranes.

    PubMed

    Bystrov, V S; Lakhno, V D; Molchanov, M

    1994-06-21

    Ferroactive models of ion channels in the theory of biological membranes are presented. The main equations are derived and their possible solutions are shown. The estimates of some experimentally measured parameters are given. Possible physical consequences of the suggested models are listed and the possibility of their experimental finding is discussed. The functioning of the biomembrane's ion channel is qualitatively described on the basis of the suggested ferroactive models. The main directions and prospects for development of the ferroactive approach to the theory of biological membranes and their structures are indicated.

  6. Ion channels and the transduction of light signals

    NASA Technical Reports Server (NTRS)

    Spalding, E. P.; Evans, M. L. (Principal Investigator)

    2000-01-01

    Studies of biological light-sensing mechanisms are revealing important roles for ion channels. Photosensory transduction in plants is no exception. In this article, the evidence that ion channels perform such signal-transducing functions in the complex array of mechanisms that bring about plant photomorphogenesis will be reviewed and discussed. The examples selected for discussion range from light-gradient detection in unicellular algae to the photocontrol of stem growth in Arabidopsis. Also included is some discussion of the technical aspects of studies that combine electrophysiology and photobiology.

  7. Ion channels and the transduction of light signals

    NASA Technical Reports Server (NTRS)

    Spalding, E. P.; Evans, M. L. (Principal Investigator)

    2000-01-01

    Studies of biological light-sensing mechanisms are revealing important roles for ion channels. Photosensory transduction in plants is no exception. In this article, the evidence that ion channels perform such signal-transducing functions in the complex array of mechanisms that bring about plant photomorphogenesis will be reviewed and discussed. The examples selected for discussion range from light-gradient detection in unicellular algae to the photocontrol of stem growth in Arabidopsis. Also included is some discussion of the technical aspects of studies that combine electrophysiology and photobiology.

  8. Energetics of Multi-Ion Conduction Pathways in Potassium Ion Channels.

    PubMed

    Fowler, Philip W; Abad, Enrique; Beckstein, Oliver; Sansom, Mark S P

    2013-11-12

    Potassium ion channels form pores in cell membranes, allowing potassium ions through while preventing the passage of sodium ions. Despite numerous high-resolution structures, it is not yet possible to relate their structure to their single molecule function other than at a qualitative level. Over the past decade, there has been a concerted effort using molecular dynamics to capture the thermodynamics and kinetics of conduction by calculating potentials of mean force (PMF). These can be used, in conjunction with the electro-diffusion theory, to predict the conductance of a specific ion channel. Here, we calculate seven independent PMFs, thereby studying the differences between two potassium ion channels, the effect of the CHARMM CMAP forcefield correction, and the sensitivity and reproducibility of the method. Thermodynamically stable ion-water configurations of the selectivity filter can be identified from all the free energy landscapes, but the heights of the kinetic barriers for potassium ions to move through the selectivity filter are, in nearly all cases, too high to predict conductances in line with experiment. This implies it is not currently feasible to predict the conductance of potassium ion channels, but other simpler channels may be more tractable.

  9. Crystal orientation mapping via ion channeling: An alternative to EBSD.

    PubMed

    Langlois, C; Douillard, T; Yuan, H; Blanchard, N P; Descamps-Mandine, A; Van de Moortèle, B; Rigotti, C; Epicier, T

    2015-10-01

    A new method, which we name ion CHanneling ORientation Determination (iCHORD), is proposed to obtain orientation maps on polycrystals via ion channeling. The iChord method exploits the dependence between grain orientation and ion beam induced secondary electron image contrast. At each position of the region of interest, intensity profiles are obtained from a series of images acquired with different orientations with respect to the ion beam. The profiles are then compared to a database of theoretical profiles of known orientation. The Euler triplet associated to the most similar theoretical profile gives the orientation at that position. The proof-of-concept is obtained on a titanium nitride sample. The potentialities of iCHORD as an alternative to EBSD are then discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Contribution of Automated Technologies to Ion Channel Drug Discovery.

    PubMed

    Picones, Arturo; Loza-Huerta, Arlet; Segura-Chama, Pedro; Lara-Figueroa, Cesar O

    2016-01-01

    Automated technologies are now resolving the historical relegation that ion channels have endured as targets for the new drug discovery and development global efforts. The richness and adequacy of functional assay methodologies, remarkably fluorescence-based detection of ions fluxes and patch-clamp electrophysiology recording of ionic currents, are now automated and increasingly employed for the analysis of ion channel activity. While the former is currently the most commonly applied, the latter is finally reaching the throughput capacity to be engaged in the primary screening of chemical libraries conformed by hundreds of thousands of compounds. The use of automated instrumentation for the study of ion channel functionality (and dysfunctionality), particularly in the search for novel pharmacological agents with therapeutic purposes, has now reached out beyond the industrial setting, its original natural enclave, and is making its way into a growing number of academic labs and core facilities. The present chapter reviews the increasing contributions accomplished by a variety of different key automated technologies which have revolutionized the strategies to approach the discovery and development of new drugs targeting ion channels. © 2016 Elsevier Inc. All rights reserved.

  11. Ion channel activity in lobster skeletal muscle membrane.

    PubMed

    Worden, M K; Rahamimoff, R; Kravitz, E A

    1993-09-01

    Ion channel activity in the sarcolemmal membrane of muscle fibers is critical for regulating the excitability, and therefore the contractility, of muscle. To begin the characterization of the biophysical properties of the sarcolemmal membrane of lobster exoskeletal muscle fibers, recordings were made from excised patches of membrane from enzymatically induced muscle fiber blebs. Blebs formed as evaginations of the muscle sarcolemmal membrane and were sufficiently free of extracellular debris to allow the formation of gigaohm seals. Under simple experimental conditions using bi-ionic symmetrical recording solutions and maintained holding potentials, a variety of single channel types with conductances in the range 32-380 pS were detected. Two of these ion channel species are described in detail, both are cation channels selective for potassium. They can be distinguished from each other on the basis of their single-channel conductance and gating properties. The results suggest that current flows through a large number of ion channels that open spontaneously in bleb membranes in the absence of exogenous metabolites or hormones.

  12. 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.

  13. Ion channels at the nucleus: electrophysiology meets the genome.

    PubMed

    Matzke, Antonius J M; Weiger, Thomas M; Matzke, Marjori

    2010-07-01

    The nuclear envelope is increasingly viewed from an electrophysiological perspective by researchers interested in signal transduction pathways that influence gene transcription and other processes in the nucleus. Here, we describe evidence for ion channels and transporters in the nuclear membranes and for possible ion gating by the nuclear pores. We argue that a systems-level understanding of cellular regulation is likely to require the assimilation of nuclear electrophysiology into molecular and biochemical signaling pathways.

  14. Ion channel diversity, channel expression and function in the choroid plexuses

    PubMed Central

    Millar, Ian D; Bruce, Jason IE; Brown, Peter D

    2007-01-01

    Knowledge of the diversity of ion channel form and function has increased enormously over the last 25 years. The initial impetus in channel discovery came with the introduction of the patch clamp method in 1981. Functional data from patch clamp experiments have subsequently been augmented by molecular studies which have determined channel structures. Thus the introduction of patch clamp methods to study ion channel expression in the choroid plexus represents an important step forward in our knowledge understanding of the process of CSF secretion. Two K+ conductances have been identified in the choroid plexus: Kv1 channel subunits mediate outward currents at depolarising potentials; Kir 7.1 carries an inward-rectifying conductance at hyperpolarising potentials. Both K+ channels are localised at the apical membrane where they may contribute to maintenance of the membrane potential while allowing the recycling of K+ pumped in by Na+-K+ ATPase. Two anion conductances have been identified in choroid plexus. Both have significant HCO3- permeability, and may play a role in CSF secretion. One conductance exhibits inward-rectification and is regulated by cyclic AMP. The other is carried by an outward-rectifying channel, which is activated by increases in cell volume. The molecular identity of the anion channels is not known, nor is it clear whether they are expressed in the apical or basolateral membrane. Recent molecular evidence indicates that choroid plexus also expresses the non-selective cation channels such as transient receptor potential channels (TRPV4 and TRPM3) and purinoceptor type 2 (P2X) receptor operated channels. In conclusion, good progress has been made in identifying the channels expressed in the choroid plexus, but determining the precise roles of these channels in CSF secretion remains a challenge for the future. PMID:17883837

  15. Single-Walled Carbon Nanotubes: Mimics of Biological Ion Channels.

    PubMed

    Amiri, Hasti; Shepard, Kenneth L; Nuckolls, Colin; Hernández Sánchez, Raúl

    2017-02-08

    Here we report on the ion conductance through individual, small diameter single-walled carbon nanotubes. We find that they are mimics of ion channels found in natural systems. We explore the factors governing the ion selectivity and permeation through single-walled carbon nanotubes by considering an electrostatic mechanism built around a simplified version of the Gouy-Chapman theory. We find that the single-walled carbon nanotubes preferentially transported cations and that the cation permeability is size-dependent. The ionic conductance increases as the absolute hydration enthalpy decreases for monovalent cations with similar solid-state radii, hydrated radii, and bulk mobility. Charge screening experiments using either the addition of cationic or anionic polymers, divalent metal cations, or changes in pH reveal the enormous impact of the negatively charged carboxylates at the entrance of the single-walled carbon nanotubes. These observations were modeled in the low-to-medium concentration range (0.1-2.0 M) by an electrostatic mechanism that mimics the behavior observed in many biological ion channel-forming proteins. Moreover, multi-ion conduction in the high concentration range (>2.0 M) further reinforces the similarity between single-walled carbon nanotubes and protein ion channels.

  16. Single-Walled Carbon Nanotubes: Mimics of Biological Ion Channels

    PubMed Central

    2017-01-01

    Here we report on the ion conductance through individual, small diameter single-walled carbon nanotubes. We find that they are mimics of ion channels found in natural systems. We explore the factors governing the ion selectivity and permeation through single-walled carbon nanotubes by considering an electrostatic mechanism built around a simplified version of the Gouy–Chapman theory. We find that the single-walled carbon nanotubes preferentially transported cations and that the cation permeability is size-dependent. The ionic conductance increases as the absolute hydration enthalpy decreases for monovalent cations with similar solid-state radii, hydrated radii, and bulk mobility. Charge screening experiments using either the addition of cationic or anionic polymers, divalent metal cations, or changes in pH reveal the enormous impact of the negatively charged carboxylates at the entrance of the single-walled carbon nanotubes. These observations were modeled in the low-to-medium concentration range (0.1–2.0 M) by an electrostatic mechanism that mimics the behavior observed in many biological ion channel-forming proteins. Moreover, multi-ion conduction in the high concentration range (>2.0 M) further reinforces the similarity between single-walled carbon nanotubes and protein ion channels. PMID:28103039

  17. Structural determinants of ion permeation in CRAC channels

    PubMed Central

    McNally, Beth A.; Yamashita, Megumi; Engh, Anita; Prakriya, Murali

    2009-01-01

    CRAC channels generate Ca2+ signals critical for the activation of immune cells and exhibit an intriguing pore profile distinguished by extremely high Ca2+ selectivity, low Cs+ permeability, and small unitary conductance. To identify the ion conduction pathway and gain insight into the structural bases of these permeation characteristics, we introduced cysteine residues in the CRAC channel pore subunit, Orai1, and probed their accessibility to various thiol-reactive reagents. Our results indicate that the architecture of the ion conduction pathway is characterized by a flexible outer vestibule formed by the TM1-TM2 loop, which leads to a narrow pore flanked by residues of a helical TM1 segment. Residues in TM3, and specifically, E190, a residue considered important for ion selectivity, are not close to the pore. Moreover, the outer vestibule does not significantly contribute to ion selectivity, implying that Ca2+ selectivity is conferred mainly by E106. The ion conduction pathway is sufficiently narrow along much of its length to permit stable coordination of Cd2+ by several TM1 residues, which likely explains the slow flux of ions within the restrained geometry of the pore. These results provide a structural framework to understand the unique permeation properties of CRAC channels. PMID:20018736

  18. Finite element simulation of the gating mechanism of mechanosensitive ion channels

    NASA Astrophysics Data System (ADS)

    Bavi, Navid; Qin, Qinghua; Martinac, Boris

    2013-08-01

    In order to eliminate limitations of existing experimental or computational methods (such as patch-clamp technique or molecular dynamic analysis) a finite element (FE) model for multi length-scale and time-scale investigation on the gating mechanism of mechanosensitive (MS) ion channels has been established. Gating force value (from typical patch clamping values) needed to activate Prokaryotic MS ion channels was applied as tensional force to the FE model of the lipid bilayer. Making use of the FE results, we have discussed the effects of the geometrical and the material properties of the Escherichia coli MscL mechanosensitive ion channel opening in relation to the membrane's Young's modulus (which will vary depending on the cell type or cholesterol density in an artificial membrane surrounding the MscL ion channel). The FE model has shown that when the cell membrane stiffens the required channel activation force increases considerably. This is in agreement with experimental results taken from the literature. In addition, the present study quantifies the relationship between the membrane stress distribution around a `hole' for modeling purposes and the stress concentration in the place transmembrane proteins attached to the hole by applying an appropriate mesh refinement as well as well defining contact condition in these areas.

  19. Scorpion venom components that affect ion-channels function

    PubMed Central

    Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.F.; Possani, L.D.

    2014-01-01

    SUMMARY The number and types of venom components that affect ion-channel function are reviewed. These are the most important venom components responsible for human intoxication, deserving medical attention, often requiring the use of specific anti-venoms. Special emphasis is given to peptides that recognize Na+-, K+- and Ca++-channels of excitable cells. Knowledge generated by direct isolation of peptides from venom and components deduced from cloned genes, whose amino acid sequences are deposited into databanks are now adays in the order of 1.5 thousands, out of an estimate biodiversity closed to 300,000. Here the diversity of components is briefly reviewed with mention to specific references. Structural characteristic are discussed with examples taken from published work. The principal mechanisms of action of the three different types of peptides are also reviewed. Na+-channel specific venom components usually are modifier of the open and closing kinetic mechanisms of the ion-channels, whereas peptides affecting K+-channels are normally pore blocking agents. The Ryanodine Ca++-channel specific peptides are known for causing sub-conducting stages of the channels conductance and some were shown to be able to internalize penetrating inside the muscle cells. PMID:23891887

  20. High baryon density from relativistic heavy ion collisions

    SciTech Connect

    Pang, Y.; Kahana, S.H.; Schlagel, T.J. |

    1993-10-01

    A quantitative model, based on hadronic physics, is developed and applied to heavy ion collisions at BNL-AGS energies. This model is in excellent agreement with observed particle spectra in heavy ion collisions using Si beams, where baryon densities of three and four times the normal nuclear matter density ({rho}{sub 0}) are reached. For Au on Au collisions, the authors predict the formation of matter at very high densities (up to 10 {rho}{sub 0}).

  1. Ion channels and transporters in cancer. 3. Ion channels in the tumor cell-microenvironment cross talk.

    PubMed

    Arcangeli, Annarosa

    2011-10-01

    The traditional view of cancer as a collection of proliferating cells must be reconsidered, and cancer must be viewed as a "tissue" constituted by both transformed cells and a heterogeneous microenvironment, that tumor cells construct and remodel during multistep tumorigenesis. The "tumor microenvironment" (TM) is formed by mesenchymal, endothelial, and immune cells immersed in a network of extracellular matrix (ECM) proteins and soluble factors. The TM strongly contributes to tumor progression, through long distance, cell-to-cell or cell-to-matrix signals, which influence different aspects of tumor cell behavior. Understanding the relationships among the different components of the cancer tissue is crucial to design and develop new therapeutic strategies. Ion channels are emerging as relevant players in the cross talk between tumor cells and their TM. Ion channels are expressed on tumor cells, as well as in the different cellular components of the TM. In all these cells, ion channels are in a strategic position to sense and transmit extracellular signals into the intracellular machinery. Often, this transmission is mediated by integrin adhesion receptors, which can be functional partners of ion channels since they form molecular complexes with the channel protein in the context of the plasma membrane. The same relevant role is exerted by ion transporters, which also contribute to determine two facets of the cancer tissue: hypoxia and the acidic extracellular pH. On the whole, it is conceivable to prospect the targeting of ion channels for new therapeutic strategies aimed at better controlling the malignant progression of the cancer tissue.

  2. Protein 4.1 and the control of ion channels.

    PubMed

    Baines, Anthony J; Bennett, Pauline M; Carter, Edward W; Terracciano, Cesare

    2009-01-01

    The classical function of 4.1R in red blood cells is to contribute to the mechanochemical properties of the membrane by promoting the interaction between spectrin and actin. More recently, it has been recognized that 4.1R is required for the stable cell surface accumulation of a number of erythrocyte membrane proteins. 4.1R is one member of the mammalian 4.1 family - the others being 4.1N, 4.1G and 4.1B - and is expressed in many cell types other than erythrocytes. Recently we have examined the phenotype of hearts from 4.1R knockout mice. Although they had a generally normal morphology, these hearts exhibited bradycardia, and prolongation of both action potentials and QT intervals. Electrophysiological analysis revealed anomalies in a range of ion channel activities. In addition, the immunoreactivity of voltage-gated Na(+) channel NaV1.5 was reduced, indicating a role for 4.1R in the cellular accumulation of this ion channel. 4.1 proteins also have roles in the accumulation of at least two other classes of ion channel. In epithelia, 4.1 interacts with the store-operated channel TRPC4. In neurons, the ligand-gated channels GluR1 and GluR4 require 4.1 proteins for cell surface accumulation. The spectrum of transmembrane proteins that bind to 4.1 proteins overlaps with that of ankyrin. A hypothesis to investigate in the future is that differential regulation of 4.1 and ankyrins (e.g. by PIP(2)) allows highly selective control of cell surface accumulation and transport activity of a specific range of ion channels.

  3. Mouse Middle Ear Ion Homeostasis Channels and Intercellular Junctions

    PubMed Central

    Morris, Lisa M.; DeGagne, Jacqueline M.; Kempton, J. Beth; Hausman, Frances; Trune, Dennis R.

    2012-01-01

    Hypothesis The middle ear contains homeostatic mechanisms that control the movement of ions and fluids similar to those present in the inner ear, and are altered during inflammation. Background The normal middle ear cavity is fluid-free and air-filled to allow for effective sound transmission. Within the inner ear, the regulation of fluid and ion movement is essential for normal auditory and vestibular function. The same ion and fluid channels active in the inner ear may have similar roles with fluid regulation in the middle ear. Methods Middle and inner ears from BALB/c mice were processed for immunohistochemistry of 10 specific ion homeostasis factors to determine if similar transport and barrier mechanisms are present in the tympanic cavity. Examination also was made of BALB/c mice middle ears after transtympanic injection with heat-killed Haemophilus influenza to determine if these channels are impacted by inflammation. Results The most prominent ion channels in the middle ear included aquaporins 1, 4 and 5, claudin 3, ENaC and Na+,K+-ATPase. Moderate staining was found for GJB2, KCNJ10 and KCNQ1. The inflamed middle ear epithelium showed increased staining due to expected cellular hypertrophy. Localization of ion channels was preserved within the inflamed middle ear epithelium. Conclusions The middle ear epithelium is a dynamic environment with intrinsic mechanisms for the control of ion and water transport to keep the middle ear clear of fluids. Compromise of these processes during middle ear disease may underlie the accumulation of effusions and suggests they may be a therapeutic target for effusion control. PMID:22720014

  4. A kinetic model of NMDA ion channel under varying noise

    NASA Astrophysics Data System (ADS)

    Wang, Rubin; Chen, Hao; Zhang, Zhikang

    2004-05-01

    It is well known that when transmitters are applied to the postsynaptic membrane, the resulting depolarization is noisy that is due to the random opening and closing of the ion channels activated by the transmitters[1]. In other words, the energy of noise is associated with changes in ion channels. On the base of these ideas, we explore a model of relationship between NMDA (n-methyl-D-aspartate) ion channels and LTP (long-term synaptic potentiation). We have proved that NMDA ion channel and calcium-dependent protein kinases, which are the triggers for the inducement of LTP, could be regarded as "molecular machines". In this system all of these molecules require energy and the energy of the system is supplied from the random motion of water molecules generated through heat energy of ATP hydrolysis[2]. So the appropriate framework to describe them comes from bioenergetics. Models of LTP previously reported are all on the macroscopic level [3-7]. Instead, we research a model at the molecular level by applying energy parameters [8].

  5. Role of Ca++ Influx via Epidermal TRP Ion Channels

    DTIC Science & Technology

    2014-10-01

    moisturization parameters in response to modulation of TRPV1 , 3 and 4 and TRPA1 in normal human skin as it is subjected to mechanical stress. (2) to assess...subjected it to reverse transcriptase, followed by quantitative PCR. We detected all TRP ion channels under study ( TRPV1 , TRPV3, TRPV4, TRPA1) as well as

  6. Ion channel networks in the control of cerebral blood flow

    PubMed Central

    Longden, Thomas A; Hill-Eubanks, David C

    2015-01-01

    One hundred and twenty five years ago, Roy and Sherrington made the seminal observation that neuronal stimulation evokes an increase in cerebral blood flow.1 Since this discovery, researchers have attempted to uncover how the cells of the neurovascular unit—neurons, astrocytes, vascular smooth muscle cells, vascular endothelial cells and pericytes—coordinate their activity to control this phenomenon. Recent work has revealed that ionic fluxes through a diverse array of ion channel species allow the cells of the neurovascular unit to engage in multicellular signaling processes that dictate local hemodynamics. In this review we center our discussion on two major themes: (1) the roles of ion channels in the dynamic modulation of parenchymal arteriole smooth muscle membrane potential, which is central to the control of arteriolar diameter and therefore must be harnessed to permit changes in downstream cerebral blood flow, and (2) the striking similarities in the ion channel complements employed in astrocytic endfeet and endothelial cells, enabling dual control of smooth muscle from either side of the blood–brain barrier. We conclude with a discussion of the emerging roles of pericyte and capillary endothelial cell ion channels in neurovascular coupling, which will provide fertile ground for future breakthroughs in the field. PMID:26661232

  7. Insight toward epithelial Na+ channel mechanism revealed by the acid-sensing ion channel 1 structure.

    PubMed

    Stockand, James D; Staruschenko, Alexander; Pochynyuk, Oleh; Booth, Rachell E; Silverthorn, Dee U

    2008-09-01

    The epithelial Na(+) channel/degenerin (ENaC/DEG) protein family includes a diverse group of ion channels, including nonvoltage-gated Na(+) channels of epithelia and neurons, and the acid-sensing ion channel 1 (ASIC1). In mammalian epithelia, ENaC helps regulate Na(+) and associated water transport, making it a critical determinant of systemic blood pressure and pulmonary mucosal fluidity. In the nervous system, ENaC/DEG proteins are related to sensory transduction. While the importance and physiological function of these ion channels are established, less is known about their structure. One hallmark of the ENaC/DEG channel family is that each channel subunit has only two transmembrane domains connected by an exceedingly large extracellular loop. This subunit structure was recently confirmed when Jasti and colleagues determined the crystal structure of chicken ASIC1, a neuronal acid-sensing ENaC/DEG channel. By mapping ENaC to the structural coordinates of cASIC1, as we do here, we hope to provide insight toward ENaC structure. ENaC, like ASIC1, appears to be a trimeric channel containing 1alpha, 1beta, and 1gamma subunit. Heterotrimeric ENaC and monomeric ENaC subunits within the trimer possibly contain many of the major secondary, tertiary, and quaternary features identified in cASIC1 with a few subtle but critical differences. These differences are expected to have profound effects on channel behavior. In particular, they may contribute to ENaC insensitivity to acid and to its constitutive activity in the absence of time- and ligand-dependent inactivation. Experiments resulting from this comparison of cASIC1 and ENaC may help clarify unresolved issues related to ENaC architecture, and may help identify secondary structures and residues critical to ENaC function.

  8. Electrical pumping of potassium ions against an external concentration gradient in a biological ion channel

    NASA Astrophysics Data System (ADS)

    Queralt-Martín, María; García-Giménez, Elena; Aguilella, Vicente M.; Ramirez, Patricio; Mafe, Salvador; Alcaraz, Antonio

    2013-07-01

    We show experimentally and theoretically that significant currents can be obtained with a biological ion channel, the OmpF porin of Escherichia coli, using zero-average potentials as driving forces. The channel rectifying properties can be used to pump potassium ions against an external concentration gradient under asymmetric pH conditions. The results are discussed in terms of the ionic selectivity and rectification ratio of the channel. The physical concepts involved may be applied to separation processes with synthetic nanopores and to bioelectrical phenomena.

  9. The tenth annual Ion Channel Retreat, Vancouver, Canada, June 25-27, 2012.

    PubMed

    Kimlicka, Lynn; Jamieson, Ashley Lauren; Liang, Sophia; Brugger, Saranna; Liang, Dong

    2013-05-01

    Ten years after Aurora Biomed (Vancouver, British Columbia, Canada) hosted the inaugural Ion Channel Retreat, this event is recognized as a leading conference for ion channel researchers. Held annually in Vancouver, this meeting consistently provides an outlet for researchers to share their findings while learning about new concepts, methods, and technologies. Researchers use this forum to discuss and debate a spectrum of topics from ion channel research and technology to drug discovery and safety. The Retreat covered key subjects in the ion channel industry, including ion channels as disease targets, transient receptor protein channels as pain and disease targets, ion channels as pain targets, ion channel structure and function, ion channel screening technologies, cardiac safety and toxicology, and cardiac function and pharmacology.

  10. The ninth annual Ion Channel Retreat, Vancouver, Canada, June 27-29, 2011.

    PubMed

    Brugger, Saranna; Garate, Marco; Papaianni, Gina; Volnoukhin, Maria; Zhan, Chris; Gill, Sikander; Liang, Sophia; Liang, Dong

    2011-12-01

    Nine years ago Aurora Biomed Inc. (Vancouver, Canada) committed to gathering the brightest minds and the most innovative research companies at one conference. The Ion Channel Retreat provides a podium for scientific discourse spanning a wide range of ion channel disciplines. This conference has consistently provided a venue for people to share knowledge, exchange ideas, and establish partnerships. This conference continues to expand and grow each year, demonstrating the value of such a conference. Attendees at the 2011 Ion Channel retreat presented ion channel research from 12 different countries, representing research groups located on 5 of the 7 continents. Aurora Biomed's 2011 Retreat covered a variety of topics including Ion Channels as Disease Targets, Ion Channels as Pain Targets, TRP-channels, Ion Channel Screening Technologies, Cardiac Function and Pharmacology, Cardiac Safety and Toxicology, and Structure and Function of Ion Channels.

  11. The Tenth Annual Ion Channel Retreat, Vancouver, Canada, June 25–27, 2012

    PubMed Central

    Kimlicka, Lynn; Liang, Sophia; Brugger, Saranna; Liang, Dong

    2013-01-01

    Abstract Ten years after Aurora Biomed (Vancouver, British Columbia, Canada) hosted the inaugural Ion Channel Retreat, this event is recognized as a leading conference for ion channel researchers. Held annually in Vancouver, this meeting consistently provides an outlet for researchers to share their findings while learning about new concepts, methods, and technologies. Researchers use this forum to discuss and debate a spectrum of topics from ion channel research and technology to drug discovery and safety. The Retreat covered key subjects in the ion channel industry, including ion channels as disease targets, transient receptor protein channels as pain and disease targets, ion channels as pain targets, ion channel structure and function, ion channel screening technologies, cardiac safety and toxicology, and cardiac function and pharmacology. PMID:23679851

  12. Ligand-Gated Ion Channels: Permeation and Activation1

    NASA Astrophysics Data System (ADS)

    Lynch, Joseph W.; Barry, Peter H.

    Ligand-gated ion channels (LGICs) are fast-responding channels in which the receptor, which binds the activating molecule (the ligand), and the ion channel are part of the same nanomolecular protein complex. This chapter will describe the properties and functions of the nicotinic acetylcholine LGIC superfamily, which play a critical role in the fast chemical transmission of electrical signals between nerve cells at synapses and between nerve and muscle cells at endplates. All the processing functions of the brain and the resulting behavioral output depend on chemical transmission across such neuronal interconnections. To describe the properties of the channels of this LGIC superfamily,we will mainly use two examples of this family of channels: the excitatory nicotinic acetylcholine receptor (nAChR) and the inhibitory glycine receptor (GlyR) channels. In the chemical transmission of electrical signals, the arrival of an electrical signal at the synaptic terminal of a nerve causes the release of a chemical signal—a neurotransmitter molecule (the ligand, also referred to as the agonist). The neurotransmitter rapidly diffuses across the very narrow 20-40 nm synaptic gap between the cells and binds to the LGIC receptors in the membrane of the target (postsynaptic) cell and generates a new electrical signal in that cell (e.g., Kandel et al., 2000). How this chemical signal is converted into an electrical one depends on the fundamental properties of LGICs and the ionic composition of the postsynaptic cell and its external solution.

  13. 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.

  14. Influence of planar oscillations on scattered ion energy distributions in transmission ion channeling

    NASA Astrophysics Data System (ADS)

    Bailes, A. A.; Seiberling, L. E.

    1999-06-01

    Utilizing the transmission ion channeling technique and a Monte Carlo simulation of the channeling of He ions in Si, we have been able to determine surface structure by comparing experimental to simulated scattered ion energy distributions. In analyzing data for {110} beam incidence, we have found that planar oscillations persist well past 2000 Å in our Monte Carlo simulations. These oscillations yield no benefit to this method of data analysis but can make analysis more difficult by the requirement for more accurate Si thickness determination.

  15. Ion channel noise can explain firing correlation in auditory nerves.

    PubMed

    Moezzi, Bahar; Iannella, Nicolangelo; McDonnell, Mark D

    2016-10-01

    Neural spike trains are commonly characterized as a Poisson point process. However, the Poisson assumption is a poor model for spiking in auditory nerve fibres because it is known that interspike intervals display positive correlation over long time scales and negative correlation over shorter time scales. We have therefore developed a biophysical model based on the well-known Meddis model of the peripheral auditory system, to produce simulated auditory nerve fibre spiking statistics that more closely match the firing correlations observed in empirical data. We achieve this by introducing biophysically realistic ion channel noise to an inner hair cell membrane potential model that includes fractal fast potassium channels and deterministic slow potassium channels. We succeed in producing simulated spike train statistics that match empirically observed firing correlations. Our model thus replicates macro-scale stochastic spiking statistics in the auditory nerve fibres due to modeling stochasticity at the micro-scale of potassium channels.

  16. A microscopic view of ion conduction through the K+ channel

    NASA Astrophysics Data System (ADS)

    Bernèche, Simon; Roux, Benoît

    2003-07-01

    Recent results from x-ray crystallography and molecular dynamics free-energy simulations have revealed the existence of a number of specific cation-binding sites disposed along the narrow pore of the K+ channel from Streptomyces lividans (KcsA), suggesting that K+ ions might literally "hop" in single file from one binding site to the next as permeation proceeds. In support of this view, it was found that the ion configurations correspond to energy wells of similar depth and that ion translocation is opposed only by small energy barriers. Although such features of the multiion potential energy surface are certainly essential for achieving a high throughput rate, diffusional and dissipative dynamical factors must also be taken into consideration to understand how rapid conduction of K+ is possible. To elucidate the mechanism of ion conduction, we established a framework theory enabling the direct simulation of nonequilibrium fluxes by extending the results of molecular dynamics over macroscopically long times. In good accord with experimental measurements, the simulated maximum conductance of the channel at saturating concentration is on the order of 550 and 360 pS for outward and inward ions flux, respectively, with a unidirectional flux-ratio exponent of 3. Analysis of the ion-conduction process reveals a lack of equivalence between the cation-binding sites in the selectivity filter. molecular dynamics | Brownian dynamics | potential of mean force | membrane potential | Poisson-Boltzmann equation

  17. 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.

  18. Plasma channel and Z-pinch dynamics for heavy ion transport

    SciTech Connect

    Ponce-Marquez, David

    2002-01-01

    A self stabilized, free standing, z-pinch plasma channel has been proposed to deliver the high intensity heavy ion beam from the end of a driver to the fuel target in a heavy ion inertial fusion power plant. The z-pinch relaxes emittance and energy spread requirements requiring a lower cost driver. A z-pinch transport would reduce the number of beam entry port holes to the target chamber from over a hundred to four as compared to neutralized ballistic focusing thus reducing the driver hardware exposure to neutron flux. Experiments where a double pulse discharge technique is used, z-pinch plasma channels with enhanced stability are achieved. Typical parameters are 7 kV pre-pulse discharge and 30 kV main bank discharge with 50 kA of channel current in a 7 torr background gas atmosphere. This work is an experimental study of these plasma channels examining the relevant physics necessary to understand and model such plasmas. Laser diagnostics measured the dynamical properties of neutrals and plasma. Schlieren and phase contrast techniques probe the pre-pulse gas dynamics and infrared interferometry and faraday effect polarimetry are used on the z-pinch to study its electron density and current distribution. Stability and repeatability of the z-pinch depend on the initial conditions set by the pre-pulse. Results show that the z-pinch channel is wall stabilized by an on-axis gas density depression created by the pre-pulse through hydrodynamic expansion where the ratio of the initial gas density to the final gas density is > 10/1. The low on-axis density favors avalanching along the desired path for the main bank discharge. Pinch time is around 2 s from the main bank discharge initiation with a FWHM of ~ 2 cm. Results also show that typical main bank discharge plasma densities reach 1017 cm-3 peak on axis for a 30 kV, 7 torr gas nitrogen discharge. Current rise time is limited by the circuit-channel inductance with the highest contribution to the

  19. Epithelial Sodium and Acid-Sensing Ion Channels

    NASA Astrophysics Data System (ADS)

    Kellenberger, Stephan

    The epithelial Na+ channel (ENaC) and acid-sensing ion channels (ASICs) are non-voltage-gated Na+ channels that form their own subfamilies within the ENaC/degenerin ion channel family. ASICs are sensors of extracellular pH, and ENaC, whose main function is trans-epithelial Na+ transport, can sense extra- and intra-cellular Na+. In aldosterone-responsive epithelial cells of the kidney, ENaC plays a critical role in the control of sodium balance, blood volume and blood pressure. In airway epithelia, ENaC has a distinct role in controlling fluid reabsorption at the air-liquid interface, thereby determining the rate of mucociliary transport. In taste receptor cells of the tongue, ENaC is involved in salt taste sensation. ASICs have emerged as key sensors for extracellular protons in central and peripheral neurons. Although not all of their physiological and pathological functions are firmly established yet, there is good evidence for a role of ASICs in the brain in learning, expression of fear, and in neurodegeneration after ischaemic stroke. In sensory neurons, ASICs are involved in nociception and mechanosensation. ENaC and ASIC subunits share substantial sequence homology and the conservation of several functional domains. This chapter summarises our current understanding of the physiological functions and of the mechanisms of ion permeation, gating and regulation of ENaC and ASICs.

  20. Convergence of ion channel genome content in early animal evolution

    PubMed Central

    Liebeskind, Benjamin J.; Hillis, David M.; Zakon, Harold H.

    2015-01-01

    Multicellularity has evolved multiple times, but animals are the only multicellular lineage with nervous systems. This fact implies that the origin of nervous systems was an unlikely event, yet recent comparisons among extant taxa suggest that animal nervous systems may have evolved multiple times independently. Here, we use ancestral gene content reconstruction to track the timing of gene family expansions for the major families of ion-channel proteins that drive nervous system function. We find that animals with nervous systems have broadly similar complements of ion-channel types but that these complements likely evolved independently. We also find that ion-channel gene family evolution has included large loss events, two of which were immediately followed by rounds of duplication. Ctenophores, cnidarians, and bilaterians underwent independent bouts of gene expansion in channel families involved in synaptic transmission and action potential shaping. We suggest that expansions of these family types may represent a genomic signature of expanding nervous system complexity. Ancestral nodes in which nervous systems are currently hypothesized to have originated did not experience large expansions, making it difficult to distinguish among competing hypotheses of nervous system origins and suggesting that the origin of nerves was not attended by an immediate burst of complexity. Rather, the evolution of nervous system complexity appears to resemble a slow fuse in stem animals followed by many independent bouts of gene gain and loss. PMID:25675537

  1. Crotalphine desensitizes TRPA1 ion channels to alleviate inflammatory hyperalgesia.

    PubMed

    Bressan, Elisangela; Touska, Filip; Vetter, Irina; Kistner, Katrin; Kichko, Tatjana I; Teixeira, Nathália B; Picolo, Gisele; Cury, Yara; Lewis, Richard J; Fischer, Michael J M; Zimmermann, Katharina; Reeh, Peter W

    2016-11-01

    Crotalphine is a structural analogue to a novel analgesic peptide that was first identified in the crude venom from the South American rattlesnake Crotalus durissus terrificus. Although crotalphine's analgesic effect is well established, its direct mechanism of action remains unresolved. The aim of the present study was to investigate the effect of crotalphine on ion channels in peripheral pain pathways. We found that picomolar concentrations of crotalphine selectively activate heterologously expressed and native TRPA1 ion channels. TRPA1 activation by crotalphine required intact N-terminal cysteine residues and was followed by strong and long-lasting desensitization of the channel. Homologous desensitization of recombinant TRPA1 and heterologous desensitization in cultured dorsal root ganglia neurons was observed. Likewise, crotalphine acted on peptidergic TRPA1-expressing nerve endings ex vivo as demonstrated by suppression of calcitonin gene-related peptide release from the trachea and in vivo by inhibition of chemically induced and inflammatory hypersensitivity in mice. The crotalphine-mediated desensitizing effect was abolished by the TRPA1 blocker HC030031 and absent in TRPA1-deficient mice. Taken together, these results suggest that crotalphine is the first peptide to mediate antinociception selectively and at subnanomolar concentrations by targeting TRPA1 ion channels.

  2. Mechanical transduction by ion channels: A cautionary tale

    PubMed Central

    Sachs, Frederick

    2016-01-01

    Mechanical transduction by ion channels occurs in all cells. The physiological functions of these channels have just begun to be elaborated, but if we focus on the upper animal kingdom, these channels serve the common sensory services such as hearing and touch, provide the central nervous system with information on the force and position of muscles and joints, and they provide the autonomic system with information about the filling of hollow organs such as blood vessels. However, all cells of the body have mechanosensitive channels (MSCs), including red cells. Most of these channels are cation selective and are activated by bilayer tension. There are also K+ selective MSCs found commonly in neurons where they may be responsible for both general anesthesia and knockout punches in the boxing ring by hyperpolarizing neurons to reduce excitability. The cationic MSCs are typically inactive under normal mechanical stress, but open under pathologic stress. The channels are normally inactive because they are shielded from stress by the cytoskeleton. The cationic MSCs are specifically blocked by the externally applied peptide GsMtx4 (aka, AT-300). This is the first drug of its class and provides a new approach to many pathologies since it is nontoxic, non-immunogenic, stable in a biological environment and has a long pharmacokinetic lifetime. Pathologies involving excessive stress are common. They produce cardiac arrhythmias, contraction in stretched dystrophic muscle, xerocytotic and sickled red cells, etc. The channels seem to function primarily as “fire alarms”, providing feedback to the cytoskeleton that a region of the bilayer is under excessive tension and needs reinforcing. The eukaryotic forms of MSCs have only been cloned in recent years and few people have experience working with them. “Newbies” need to become aware of the technology, potential artifacts, and the fundamentals of mechanics. The most difficult problem in studying MSCs is that the actual

  3. Mechanism of Ion Permeation in Skeletal Muscle Chloride Channels

    PubMed Central

    Fahlke, Christoph; Dürr, Christine; George, Alfred L.

    1997-01-01

    Voltage-gated Cl− channels belonging to the ClC family exhibit unique properties of ion permeation and gating. We functionally probed the conduction pathway of a recombinant human skeletal muscle Cl− channel (hClC-1) expressed both in Xenopus oocytes and in a mammalian cell line by investigating block by extracellular or intracellular I− and related anions. Extracellular and intracellular I− exert blocking actions on hClC-1 currents that are both concentration and voltage dependent. Similar actions were observed for a variety of other halide (Br−) and polyatomic (SCN−, NO3−, CH3SO3−) anions. In addition, I− block is accompanied by gating alterations that differ depending on which side of the membrane the blocker is applied. External I− causes a shift in the voltage-dependent probability that channels exist in three definable kinetic states (fast deactivating, slow deactivating, nondeactivating), while internal I− slows deactivation. These different effects on gating properties can be used to distinguish two functional ion binding sites within the hClC-1 pore. We determined KD values for I− block in three distinct kinetic states and found that binding of I− to hClC-1 is modulated by the gating state of the channel. Furthermore, estimates of electrical distance for I− binding suggest that conformational changes affecting the two ion binding sites occur during gating transitions. These results have implications for understanding mechanisms of ion selectivity in hClC-1, and for defining the intimate relationship between gating and permeation in ClC channels. PMID:9348327

  4. Targeting ion channels in leukemias: a new challenge for treatment.

    PubMed

    Arcangeli, A; Pillozzi, S; Becchetti, A

    2012-01-01

    Leukemias, as other cancers, bear several genetic alterations of tumor-related genes, such as point mutations, translocations, epigenetic modifications, often accompanied by gene amplification or inactivation. The identification of tumor-related genes provides considerable insight into the biology of leukemias and opens the way to more specific pharmacological treatments. These genes comprise several ion channels and pumps, as the transport mechanisms associated with volume control, proliferation and apoptosis are often altered in cancers. In leukemic cells, such changes are observed as early as the stem cell stage. Ion channels can regulate other malignant features, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The role of certain voltage-gated K(+) channels, such as K(v)11.1 (also known as hERG1) can be largely attributed to modulation of cell adhesion to the extracellular matrix (ECM). K(v)11.1 exerts pleiotropic regulatory effects by forming multiprotein membrane complexes with integrin receptors in both acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). By recruiting growth factor and chemokine receptors, these complexes form signaling hubs that control neoplastic progression. Work in mice shows that blocking K(v)11.1 has a protective effect in acute leukemias. Ion channels are most promising targets for anti-leukemic therapy, because of their accessibility from the extracellular side and the thorough understanding of their pharmacology. In ALL cells, K(v)11.1 inhibitors abrogate the protective effect of bone marrow stromal cells and enhance the cytotoxicity of some common antileukemic drugs. Hence, ion channel modulators could overcome chemoresistance in acute leukemias, a major hindrance to therapeutic success.

  5. Redox Regulation of Ion Channels in the Pulmonary Circulation

    PubMed Central

    Weir, Edward Kenneth

    2015-01-01

    Abstract Significance: The pulmonary circulation is a low-pressure, low-resistance, highly compliant vasculature. In contrast to the systemic circulation, it is not primarily regulated by a central nervous control mechanism. The regulation of resting membrane potential due to ion channels is of integral importance in the physiology and pathophysiology of the pulmonary vasculature. Recent Advances: Redox-driven ion conductance changes initiated by direct oxidation, nitration, and S-nitrosylation of the cysteine thiols and indirect phosphorylation of the threonine and serine residues directly affect pulmonary vascular tone. Critical Issues: Molecular mechanisms of changes in ion channel conductance, especially the identification of the sites of action, are still not fully elucidated. Future Directions: Further investigation of the interaction between redox status and ion channel gating, especially the physiological significance of S-glutathionylation and S-nitrosylation, could result in a better understanding of the physiological and pathophysiological importance of these mediators in general and the implications of such modifications in cellular functions and related diseases and their importance for targeted treatment strategies. Antioxid. Redox Signal. 22, 465–485. PMID:24702125

  6. Are ion channels voltage-dependent "transfer-enzymes"?

    NASA Astrophysics Data System (ADS)

    Nelson, Peter Hugo

    2002-04-01

    The known structure of the KcsA channel selectivity filter is used to derive a novel ion permeation theory for K channels. The simplified model has only two adjustable parameters: a maximum ion transfer rate and a binding coefficient - that explicitly appear in the Michaelis-Menten equation governing the concentration dependence of the zero-voltage conductivity. A third parameter is the relative distance between two K+ ions in the selectivity filter of KcsA. This parameter is obtained directly from the X-ray structure [Doyle et al., Science 280 (1998) 69-77] and successfully predicts the experimentally observed voltage dependence of K+ ion permeation [Meuser et al., FEBS Lett. 462 (1999) 447-452][LeMasurier et al., J. Gen. Physiol. 118 (2001) 303-313], suggesting a quantitative relationship between the KcsA X-ray structure and its function. The same theory also successfully models all experimentally observed aspects of Cl- and SCN- permeation through GlyR and GABAR channels [Bormann et al., J. Physiol. 385 (1987) 243-286] including the so-called 'anomalous mole fraction effect'. This work is supported by NIH Post-Doctoral Fellowship GM20584.

  7. Stormtime Subauroral Density Troughs: Ion-Molecule Kinetics Effects

    DTIC Science & Technology

    2007-11-02

    trap to measure the total ion density (ni); and (4) a coincided with an increase in the energy and intensity of spherical Langmuir probe to measure...Experiments Figure 3. Rate coefficients for the reaction (RI). Circles in a high-temperature flowing afterglow device (HTFA) and squares show the HTFA and...poleward part coincided with strong wave structures, energetic (ring current) ion precipitations, and enhanced vertical ion flows . One or several narrow

  8. Identified ion channels in the squid nervous system.

    PubMed

    Rosenthal, J J C; Gilly, W F

    2003-01-01

    Our modern understanding of channels as discrete voltage-sensitive and ion-selective entities comes largely from a series of classical studies using the squid giant axon. This system has also been critical for understanding how transporters and synaptic transmission operate. This review outlines attempts to assign molecular identities to the extensively studied physiological properties of this system. As it turns out, this is no simple task. Molecular candidates for voltage-gated Na(+), K(+), and Ca(2+) channels, as well as ion transporters have been isolated from the squid nervous system. Both physiological and molecular approaches have been used to equate these cloned gene products with their native counterparts. In the case of the delayed rectifier K(+) conductance, the most thoroughly studied example, two major issues further complicate the equation. First, the ability of K(+) channel monomers to form heteromultimers with unique properties must be considered. Second, squid K(+) channel mRNAs are extensively edited, a process that can generate a wide variety of channel proteins from a common gene. The giant axon system is beginning to play an important role in understanding the biological relevance of this latter process. Copyright 2003 S. Karger AG, Basel

  9. Impact of intracellular ion channels on cancer development and progression.

    PubMed

    Peruzzo, Roberta; Biasutto, Lucia; Szabò, Ildikò; Leanza, Luigi

    2016-10-01

    Cancer research is nowadays focused on the identification of possible new targets in order to try to develop new drugs for curing untreatable tumors. Ion channels have emerged as "oncogenic" proteins, since they have an aberrant expression in cancers compared to normal tissues and contribute to several hallmarks of cancer, such as metabolic re-programming, limitless proliferative potential, apoptosis-resistance, stimulation of neo-angiogenesis as well as cell migration and invasiveness. In recent years, not only the plasma membrane but also intracellular channels and transporters have arisen as oncological targets and were proposed to be associated with tumorigenesis. Therefore, the research is currently focusing on understanding the possible role of intracellular ion channels in cancer development and progression on one hand and, on the other, on developing new possible drugs able to modulate the expression and/or activity of these channels. In a few cases, the efficacy of channel-targeting drugs in reducing tumors has already been demonstrated in vivo in preclinical mouse models.

  10. Ion transport through a T-intersection of nanofluidic channels

    NASA Astrophysics Data System (ADS)

    Daiguji, Hirofumi; Adachi, Takuma; Tatsumi, Naoya

    2008-08-01

    Ion transport through a T-intersection of two silica nanochannels (a main channel, 5-μm long and 30-nm wide, and a subchannel, 5-μm long and 15-nm wide) with a surface charge distribution was investigated based on continuum dynamics calculations. The surface charge within 250nm of the intersection in the main channel and the entire subchannel was positive and that in the main channel outside this intersection region was negative. This nanofluidic system is analogous to a p-n-p transistor. The calculation results revealed that, by adjusting the electric potentials at the ends of the nanochannels, the ionic current could be (1) cut off, (2) regulated in the main channel, (3) diverged into the main and subchannels, (4) turned from the main channel to the subchannel, and (5) merged into the subchannel. A series connection of this nanofluidic system can therefore be used in biotechnological applications for electrophoretic separation and for sorting of ions and biomolecules.

  11. Ion-number-density-dependent effects on hyperfine transition of trapped 199Hg+ ions in quadrupole linear ion traps

    NASA Astrophysics Data System (ADS)

    Yang, Zhihui; Chen, Yihe; Yan, Bibo; Wang, Man; Wan, Yongquan; Liu, Hao; She, Lei; Li, Jiaomei

    2017-04-01

    The ion-number-density-dependent frequency offsets and broadening of the ground state hyperfine transition spectra of trapped 199Hg+ ions were measured as a function of the end-cap voltage of the quadrupole linear ion trap. The number density of trapped 199Hg+ ions in the quadrupole linear trap was controlled by the end-cap voltage. The fractional frequency stability of 199Hg+ hyperfine transition to the 1 mV end-cap voltage variation was preliminary estimated to be less than 1 ×10-16. The causes of the ion-number-density-dependent frequency shift and spectrum broadening were analyzed theoretically and explained.

  12. Divalent ions are potential permeating blockers of the non-selective NaK ion channel: combined QM and MD based investigations.

    PubMed

    Sadhu, Biswajit; Sundararajan, Mahesh; Bandyopadhyay, Tusar

    2017-10-05

    The bacterial NaK ion channel is distinctly different from other known ion channels due to its inherent non-selective feature. One of the unexplored and rather interesting features is its ability to permeate divalent metal ions (such as Ca(2+) and Ba(2+)) and not monovalent alkali metal ions. Several intriguing questions about the energetics and structural aspects still remain unanswered. For instance, what causes Ca(2+) to permeate as well as block the selectivity filter (SF) of the NaK ion channel and act as a "permeating blocker"? How and at what energetic cost does another chemical congener, Sr(2+), as well as Ba(2+), a potent blocker of the K(+) ion channel, permeate through the SF of the NaK ion channel? Finally, how do their translocation energetics differ from those of monovalent ions such as K(+)? Here, in an attempt to address these outstanding issues, we elucidate the structure, binding and selectivity of divalent ions (Ca(2+), Sr(2+) and Ba(2+)) as they permeate through the SF of the NaK ion channel using all-atom molecular dynamics simulations and density functional theory based calculations. We unveil mechanistic insight into this translocation event using well-tempered metadynamics simulations in a polarizable environment using the mean-field model of water and incorporating electronic continuum corrections for ions via charge rescaling. The results show that, akin to K(+) coordination, Sr(2+) and Ba(2+) bind at the SF in a very similar fashion and remain octa-coordinated at all sites. Interestingly, differing from its local hydration structure, Ca(2+) interacts with eight carbonyls to remain at the middle of the S3 site. Furthermore, the binding of divalent metals at SF binding sites is more favorable than the binding of K(+). However, their permeation through the extracellular entrance faces a considerably higher energetic barrier compared to that for K(+), which eventually manifests their inherent blocking feature.

  13. Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts

    PubMed Central

    Li, Gui-Rong; Sun, Hai-Ying; Chen, Jing-Bo; Zhou, Yuan; Tse, Hung-Fat; Lau, Chu-Pak

    2009-01-01

    Background Although fibroblast-to-myocyte electrical coupling is experimentally suggested, electrophysiology of cardiac fibroblasts is not as well established as contractile cardiac myocytes. The present study was therefore designed to characterize ion channels in cultured human cardiac fibroblasts. Methods and Findings A whole-cell patch voltage clamp technique and RT-PCR were employed to determine ion channels expression and their molecular identities. We found that multiple ion channels were heterogeneously expressed in human cardiac fibroblasts. These include a big conductance Ca2+-activated K+ current (BKCa) in most (88%) human cardiac fibroblasts, a delayed rectifier K+ current (IKDR) and a transient outward K+ current (Ito) in a small population (15 and 14%, respectively) of cells, an inwardly-rectifying K+ current (IKir) in 24% of cells, and a chloride current (ICl) in 7% of cells under isotonic conditions. In addition, two types of voltage-gated Na+ currents (INa) with distinct properties were present in most (61%) human cardiac fibroblasts. One was a slowly inactivated current with a persistent component, sensitive to tetrodotoxin (TTX) inhibition (INa.TTX, IC50 = 7.8 nM), the other was a rapidly inactivated current, relatively resistant to TTX (INa.TTXR, IC50 = 1.8 µM). RT-PCR revealed the molecular identities (mRNAs) of these ion channels in human cardiac fibroblasts, including KCa.1.1 (responsible for BKCa), Kv1.5, Kv1.6 (responsible for IKDR), Kv4.2, Kv4.3 (responsible for Ito), Kir2.1, Kir2.3 (for IKir), Clnc3 (for ICl), NaV1.2, NaV1.3, NaV1.6, NaV1.7 (for INa.TTX), and NaV1.5 (for INa.TTXR). Conclusions These results provide the first information that multiple ion channels are present in cultured human cardiac fibroblasts, and suggest the potential contribution of these ion channels to fibroblast-myocytes electrical coupling. PMID:19806193

  14. Characterization of multiple ion channels in cultured human cardiac fibroblasts.

    PubMed

    Li, Gui-Rong; Sun, Hai-Ying; Chen, Jing-Bo; Zhou, Yuan; Tse, Hung-Fat; Lau, Chu-Pak

    2009-10-06

    Although fibroblast-to-myocyte electrical coupling is experimentally suggested, electrophysiology of cardiac fibroblasts is not as well established as contractile cardiac myocytes. The present study was therefore designed to characterize ion channels in cultured human cardiac fibroblasts. A whole-cell patch voltage clamp technique and RT-PCR were employed to determine ion channels expression and their molecular identities. We found that multiple ion channels were heterogeneously expressed in human cardiac fibroblasts. These include a big conductance Ca(2+)-activated K(+) current (BK(Ca)) in most (88%) human cardiac fibroblasts, a delayed rectifier K(+) current (IK(DR)) and a transient outward K(+) current (I(to)) in a small population (15 and 14%, respectively) of cells, an inwardly-rectifying K(+) current (I(Kir)) in 24% of cells, and a chloride current (I(Cl)) in 7% of cells under isotonic conditions. In addition, two types of voltage-gated Na(+) currents (I(Na)) with distinct properties were present in most (61%) human cardiac fibroblasts. One was a slowly inactivated current with a persistent component, sensitive to tetrodotoxin (TTX) inhibition (I(Na.TTX), IC(50) = 7.8 nM), the other was a rapidly inactivated current, relatively resistant to TTX (I(Na.TTXR), IC(50) = 1.8 microM). RT-PCR revealed the molecular identities (mRNAs) of these ion channels in human cardiac fibroblasts, including KCa.1.1 (responsible for BK(Ca)), Kv1.5, Kv1.6 (responsible for IK(DR)), Kv4.2, Kv4.3 (responsible for I(to)), Kir2.1, Kir2.3 (for I(Kir)), Clnc3 (for I(Cl)), Na(V)1.2, Na(V)1.3, Na(V)1.6, Na(V)1.7 (for I(Na.TTX)), and Na(V)1.5 (for I(Na.TTXR)). These results provide the first information that multiple ion channels are present in cultured human cardiac fibroblasts, and suggest the potential contribution of these ion channels to fibroblast-myocytes electrical coupling.

  15. Vacuolar ion channels: Roles in plant nutrition and signalling.

    PubMed

    Isayenkov, Stanislav; Isner, Jean Charles; Maathuis, Frans J M

    2010-05-17

    Vacuoles play various roles in many physiologically relevant processes in plants. Some of the more prominent are turgor provision, the storage of minerals and nutrients, and cellular signalling. To fulfil these functions a complement of membrane transporters is present at the tonoplast. Prolific patch clamp studies have shown that amongst these, both selective and non-selective ion channels participate in turgor regulation, nutrient storage and signalling. This article reviews the physiological roles, expression patterns and structure function properties of plant vacuolar anion and cation channels that are gated by voltage and ligands.

  16. Acid-sensing ion channels in pain and disease.

    PubMed

    Wemmie, John A; Taugher, Rebecca J; Kreple, Collin J

    2013-07-01

    Why do neurons sense extracellular acid? In large part, this question has driven increasing investigation on acid-sensing ion channels (ASICs) in the CNS and the peripheral nervous system for the past two decades. Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease. This Review highlights recent findings linking these channels to physiology and disease. In addition, it discusses some of the implications for therapy and points out questions that remain unanswered.

  17. Ion-channeling analysis of boron clusters in silicon

    NASA Astrophysics Data System (ADS)

    Selen, L. J. M.; Janssen, F. J. J.; van IJzendoorn, L. J.; de Voigt, M. J. A.; Theunissen, M. J. J.; Smulders, P. J. M.; Eijkemans, T. J.

    2001-11-01

    We have measured axially channeled Rutherford backscattering spectra of Si1-xGex nanofilms in silicon(001). A step in the yield of the host crystal was found for off-normal axes at the depth of the nanofilm. The step was measured as a function of the angle between the incoming beam and the [011] axis and shows two maxima. It is found that Monte Carlo simulations assuming tetragonal distortion reproduce the experimental results. A universal curve was derived which enables determination of the tetragonal distortion from ion-channeling experiments, for a given film thickness. The results are compared with XRD measurements.

  18. From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

    PubMed Central

    Nasiripourdori, Adak; Taly, Valérie; Grutter, Thomas; Taly, Antoine

    2011-01-01

    Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted. PMID:22069709

  19. Hydrogen ions control synaptic vesicle ion channel activity in Torpedo electromotor neurones.

    PubMed

    Ahdut-Hacohen, Ronit; Duridanova, Dessislava; Meiri, Halina; Rahamimoff, Rami

    2004-04-15

    During exocytosis the synaptic vesicle fuses with the surface membrane and undergoes a pH jump. When the synaptic vesicle is inside the presynaptic nerve terminal its internal pH is about 5.5 and after fusion, the inside of the vesicle comes in contact with the extracellular medium with a pH of about 7.25. We examined the effect of such pH jump on the opening of the non-specific ion channel in the synaptic vesicle membrane, in the context of the post-fusion hypothesis of transmitter release control. The vesicles were isolated from Torpedo ocellata electromotor neurones. The pH dependence of the opening of the non-specific ion channel was examined using the fused vesicle-attached configuration of the patch clamp technique. The rate of opening depends on both pH and voltage. Increasing the pH from 5.5 to 7.25 activated dramatically the non-specific ion channel of the vesicle membrane. The single channel conductance did not change significantly with the alteration in the pH, and neither did the mean channel open time. These results support the hypothesis that during partial fusion of the vesicle with the surface membrane, ion channels in the vesicle membrane open, admit ions and thus help in the ion exchange process mechanism, leading to the release of the transmitter from the intravesicular ion exchange matrix. This process may have also a pathophysiological significance in conditions of altered pH.

  20. Density of voltage-gated potassium channels is a bifurcation parameter in pyramidal neurons

    PubMed Central

    Robinson, Hugh P. C.; Århem, Peter

    2014-01-01

    Several types of intrinsic dynamics have been identified in brain neurons. Type 1 excitability is characterized by a continuous frequency-stimulus relationship and, thus, an arbitrarily low frequency at threshold current. Conversely, Type 2 excitability is characterized by a discontinuous frequency-stimulus relationship and a nonzero threshold frequency. In previous theoretical work we showed that the density of Kv channels is a bifurcation parameter, such that increasing the Kv channel density in a neuron model transforms Type 1 excitability into Type 2 excitability. Here we test this finding experimentally, using the dynamic clamp technique on Type 1 pyramidal cells in rat cortex. We found that increasing the density of slow Kv channels leads to a shift from Type 1 to Type 2 threshold dynamics, i.e., a distinct onset frequency, subthreshold oscillations, and reduced latency to first spike. In addition, the action potential was resculptured, with a narrower spike width and more pronounced afterhyperpolarization. All changes could be captured with a two-dimensional model. It may seem paradoxical that an increase in slow K channel density can lead to a higher threshold firing frequency; however, this can be explained in terms of bifurcation theory. In contrast to previous work, we argue that an increased outward current leads to a change in dynamics in these neurons without a rectification of the current-voltage curve. These results demonstrate that the behavior of neurons is determined by the global interactions of their dynamical elements and not necessarily simply by individual types of ion channels. PMID:25339708

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

    PubMed Central

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

    2011-01-01

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

  2. Electron and ion densities in interstellar clouds

    NASA Technical Reports Server (NTRS)

    Glassgold, A. E.; Langer, W. D.

    1974-01-01

    A quantitative theory of ionization in diffuse clouds is developed which includes H(+) charge exchange with O. Dissociative charge exchange of He(+) with H2 plays an important role in the densities of H(+) and He(+). The abundance of HD is also discussed.

  3. High current density beamlets from RF Argon source for heavy ion fusion applications

    SciTech Connect

    Kwan, J.W.; Grote, D.P.; Westenskow, G.

    2003-08-01

    In a new approach to develop high current beams for heavy ion fusion, beam current at about 0.5 ampere per channel can be obtained by merging an array of high current density beamlets of 5 mA each. We have done computer simulations to study the transport of high current density beamlets and the emittance growth due to this merging process. In our RF multicusp source experiment, we have produced a cluster of 61 beamlets using minimum gas flow. The current density from a 0.25 cm diameter aperture reached 100 mA/cm{sup 2}. The normalized emittance of 0.02 {pi}-mm-mrad corresponds to an equivalent ion temperature of 2.4 eV. These results showed that the RF argon plasma source is suitable for producing high current density beamlets that can be merged to form a high current high brightness beam for HIF application.

  4. High Current Density Beamlets from an RF Argon Source for Heavy Ion Fusion Applications

    SciTech Connect

    Kwan, J W; Grote, D P; Westenskow, G A

    2003-09-04

    In a new approach to develop high current beams for heavy ion fusion, beam current at about 0.5 ampere per channel can be obtained by merging an array of high current density beamlets of 5 mA each. We have done computer simulations to study the transport of high current density beamlets and the emittance growth due to this merging process. In our RF multicusp source experiment, we have produced a cluster of 61 beamlets using minimum gas flow. The current density from a 0.25 cm diameter aperture reached 100 mA/cm{sup 2}. The normalized emittance of 0.02 {pi}-mm-mrad corresponds to an equivalent ion temperature of 2.4 eV. These results showed that the RF argon plasma source is suitable for producing high current density beamlets that can be merged to form a high current high brightness beam for HIF application.

  5. Biomimetic Nanotubes Based on Cyclodextrins for Ion-Channel Applications.

    PubMed

    Mamad-Hemouch, Hajar; Ramoul, Hassen; Abou Taha, Mohammad; Bacri, Laurent; Huin, Cécile; Przybylski, Cédric; Oukhaled, Abdelghani; Thiébot, Bénédicte; Patriarche, Gilles; Jarroux, Nathalie; Pelta, Juan

    2015-11-11

    Biomimetic membrane channels offer a great potential for fundamental studies and applications. Here, we report the fabrication and characterization of short cyclodextrin nanotubes, their insertion into membranes, and cytotoxicity assay. Mass spectrometry and high-resolution transmission electron microscopy were used to confirm the synthesis pathway leading to the formation of short nanotubes and to describe their structural parameters in terms of length, diameter, and number of cyclodextrins. Our results show the control of the number of cyclodextrins threaded on the polyrotaxane leading to nanotube synthesis. Structural parameters obtained by electron microscopy are consistent with the distribution of the number of cyclodextrins evaluated by mass spectrometry from the initial polymer distribution. An electrophysiological study at single molecule level demonstrates the ion channel formation into lipid bilayers, and the energy penalty for the entry of ions into the confined nanotube. In the presence of nanotubes, the cell physiology is not altered.

  6. Microstructured apertures in planar glass substrates for ion channel research.

    PubMed

    Fertig, Niels; George, Michael; Klau, Michèle; Meyer, Christine; Tilke, Armin; Sobotta, Constanze; Blick, Robert H; Behrends, Jan C

    2003-01-01

    We have developed planar glass chip devices for patch clamp recording. Glass has several key advantages as a substrate for planar patch clamp devices. It is a good dielectric, is well-known to interact strongly with cell membranes and is also a relatively in-expensive material. In addition, it is optically neutral. However, microstructuring processes for glass are less well established than those for silicon-based substrates. We have used ion-track etching techniques to produce micron-sized apertures into borosilicate and quartz-glass coverslips. These apertures, which can be easily produced in arrays, have been used for high resolution recording of single ion channels as well as for whole-cell current recordings from mammalian cell lines. An additional attractive application that is greatly facilitated by the combination of planar geometry with the optical neutrality of the substrate is single-molecule fluorescence recording with simultaneous single-channel measurements.

  7. Ion channels and drug transporters as targets for anthelmintics

    PubMed Central

    Greenberg, Robert M.

    2014-01-01

    Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance. PMID:25554739

  8. The screw-helical voltage gating of ion channels.

    PubMed Central

    Keynes, R D; Elinder, F

    1999-01-01

    In the voltage-gated ion channels of every animal, whether they are selective for K+, Na+ or Ca2+, the voltage sensors are the S4 transmembrane segments carrying four to eight positive charges always separated by two uncharged residues. It is proposed that they move across the membrane in a screw-helical fashion in a series of three or more steps that each transfer a single electronic charge. The unit steps are stabilized by ion pairing between the mobile positive charges and fixed negative charges, of which there are invariably two located near the inner ends of segments S2 and S3 and a third near the outer end of either S2 or S3. Opening of the channel involves three such steps in each domain. PMID:10343407

  9. Ion channels and drug transporters as targets for anthelmintics.

    PubMed

    Greenberg, Robert M

    2014-12-01

    Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

  10. The role of synaptic ion channels in synaptic plasticity

    PubMed Central

    Voglis, Giannis; Tavernarakis, Nektarios

    2006-01-01

    The nervous system receives a large amount of information about the environment through elaborate sensory routes. Processing and integration of these wide-ranging inputs often results in long-term behavioural alterations as a result of past experiences. These relatively permanent changes in behaviour are manifestations of the capacity of the nervous system for learning and memory. At the cellular level, synaptic plasticity is one of the mechanisms underlying this process. Repeated neural activity generates physiological changes in the nervous system that ultimately modulate neuronal communication through synaptic transmission. Recent studies implicate both presynaptic and postsynaptic ion channels in the process of synapse strength modulation. Here, we review the role of synaptic ion channels in learning and memory, and discuss the implications and significance of these findings towards deciphering the molecular biology of learning and memory. PMID:17077866

  11. New roles for old holes: ion channel function in aquaporin-1.

    PubMed

    Yool, Andrea J; Weinstein, Alan M

    2002-04-01

    Mammalian aquaporins are part of the diverse major intrinsic protein family of water and solute channels. Intriguing links exist in structural and functional properties between aquaporins and ion channels. A novel role for aquaporin-1 as a gated ion channel reshapes our current views of this ancient family of transmembrane channel proteins.

  12. [Role of voltage-dependent ion channels in epileptogenesis].

    PubMed

    Ricard-Mousnier, B; Couraud, F

    1993-10-01

    The aim of this review is to gather information in favour of the involvement of voltage-dependent ion channels in epileptogenesis. Although, up to now, no study has shown that epilepsy is accompanied by a modification in the activity to these channels, the recently acquired knowledge of their physiology allows to presume would favor their involvement in epileptogenesis. The results from electrophysiological studies are as follows: a persistent sodium current increases neuronal excitability whereas potassium currents have an inhibitory role. In particular, calcium-dependent potassium current are involved in the post-hyperpolarization phases which follows PDS. Calcium currents are also involved in the genesis of the "bursting pacemaker" activity displayed by the neurons presumed to be inducers of the epileptic activity. Biochemical data has shown that as a consequence of epileptic activity, sodium and calcium channels are down regulated. This down-regulation could be a way to reduces neuronal hyperexcitability. Pharmacological data demonstrate the drugs which activate calcium channels or which inhibit potassium channels have a convusilvant effect. On the contrary, agents which block calcium or sodium channels or which properties. Among the latter ones, some antiepileptic drugs can be found. In summary situations which lead to increase in calcium and sodium currents and/or to an inhibition in potassium currents are potentially epileptogenic.

  13. Enhancement of laser-driven electron acceleration in an ion channel

    SciTech Connect

    Arefiev, Alexey V.; Khudik, Vladimir N.; Schollmeier, Marius

    2014-03-15

    A laser beam with duration longer than the period of plasma oscillations propagating through an underdense plasma produces a steady-state positively charged channel in the electron density. We consider a test electron in the two-dimensional plane channel under the combined action of the laser field and the transverse static electric field of the channel. At ultrarelativistic laser wave amplitude (a≫1), the electron is pushed primarily forward. As the electron gradually dephases from the wave, the field it samples and its relativistic γ-factor strongly oscillate. The natural frequency of electron oscillations across the channel (betatron frequency) depends on γ, which couples the betatron oscillations to the longitudinal motion induced by the wave. We show that the modulation of the natural frequency makes the oscillations unstable. The resulting amplification of the oscillations across the channel reduces the axial dephasing between the electron and the wave, leading to a considerable electron energy enhancement well above the ponderomotive energy. We find that there is a well-pronounced laser amplitude threshold a{sub *}, above which the enhancement takes place, that scales as a{sub *}∝1/√(n{sub 0}), where n{sub 0} is the ion density. The presented mechanism of energy enhancement is robust with respect to a longitudinal variation of the density, because it relies on a threshold phenomenon rather than on a narrow linear resonance.

  14. Ion density variation at upper ionosphere during thunderstorm

    NASA Astrophysics Data System (ADS)

    Mangla, Bindu; Sharma, D. K.; Rajput, Anupama

    2017-03-01

    Ionosphere is found to be affected by phenomenon taking place above and below it. Troposphere incidents of thunderstorm and lightning, influence ionospheric temperatures and ion density, from D region to a region of high altitude. Low latitude upper ionosphere in the altitude range of 425-625 km over Indian subcontinent is studied for ion density variation during the event of active thunderstorm. Study is done with the help of ionospheric data obtained from in situ measurements made by Indian satellite SROSS C2, and thunderstorm and other related data obtained from Indian Meteorological Department. Ion density in this region found to show a regular fall from 5 to 65% during the event of thunderstorm over normal day values but consistent heating of ions takes place. O+ being the main part of the composition of ionosphere at this altitude so total ion density variation show a similar trend as that of O+ ion, while other ions like O2+, He+ and H+ do not follow any regular trend with the activity of thunderstorm.

  15. 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.

  16. Amino acid-sensing ion channels in plants

    SciTech Connect

    Spalding, Edgar P.

    2014-08-12

    The title of our project is “Amino acid-sensing ion channels in plants”. Its goals are two-fold: to determine the molecular functions of glutamate receptor-like (GLR) proteins, and to elucidate their biological roles (physiological or developmental) in plants. Here is our final technical report. We were highly successful in two of the three aims, modestly successful in the third.

  17. Ion channel recordings on an injection-molded polymer chip.

    PubMed

    Tanzi, Simone; Matteucci, Marco; Christiansen, Thomas Lehrmann; Friis, Søren; Christensen, Mette Thylstrup; Garnaes, Joergen; Wilson, Sandra; Kutchinsky, Jonatan; Taboryski, Rafael

    2013-12-21

    In this paper, we demonstrate recordings of the ion channel activity across the cell membrane in a biological cell by employing the so-called patch clamping technique on an injection-molded polymer microfluidic device. The findings will allow direct recordings of ion channel activity to be made using the cheapest materials and production platform to date and with the potential for very high throughput. The employment of cornered apertures for cell capture allowed the fabrication of devices without through holes and via a scheme comprising master origination by dry etching in a silicon substrate, electroplating in nickel and injection molding of the final part. The most critical device parameters were identified as the length of the patching capillary and the very low surface roughness on the inside of the capillary. The cross-sectional shape of the orifice was found to be less critical, as both rectangular and semicircular profiles seemed to have almost the same ability to form tight seals with cells with negligible leak currents. The devices were functionally tested using human embryonic kidney cells expressing voltage-gated sodium channels (Nav1.7) and benchmarked against a commercial state-of-the-art system for automated ion channel recordings. These experiments considered current-voltage (IV) relationships for activation and inactivation of the Nav1.7 channels and their sensitivity to a local anesthetic, lidocaine. Both IVs and lidocaine dose-response curves obtained from the injection-molded polymer device were in good agreement with data obtained from the commercial system.

  18. Membranes with the Same Ion Channel Populations but Different Excitabilities

    PubMed Central

    Herrera-Valdez, Marco Arieli

    2012-01-01

    Electrical signaling allows communication within and between different tissues and is necessary for the survival of multicellular organisms. The ionic transport that underlies transmembrane currents in cells is mediated by transporters and channels. Fast ionic transport through channels is typically modeled with a conductance-based formulation that describes current in terms of electrical drift without diffusion. In contrast, currents written in terms of drift and diffusion are not as widely used in the literature in spite of being more realistic and capable of displaying experimentally observable phenomena that conductance-based models cannot reproduce (e.g. rectification). The two formulations are mathematically related: conductance-based currents are linear approximations of drift-diffusion currents. However, conductance-based models of membrane potential are not first-order approximations of drift-diffusion models. Bifurcation analysis and numerical simulations show that the two approaches predict qualitatively and quantitatively different behaviors in the dynamics of membrane potential. For instance, two neuronal membrane models with identical populations of ion channels, one written with conductance-based currents, the other with drift-diffusion currents, undergo transitions into and out of repetitive oscillations through different mechanisms and for different levels of stimulation. These differences in excitability are observed in response to excitatory synaptic input, and across different levels of ion channel expression. In general, the electrophysiological profiles of membranes modeled with drift-diffusion and conductance-based models having identical ion channel populations are different, potentially causing the input-output and computational properties of networks constructed with these models to be different as well. The drift-diffusion formulation is thus proposed as a theoretical improvement over conductance-based models that may lead to more

  19. Poisson-Nernst-Planck-Fermi theory for modeling biological ion channels.

    PubMed

    Liu, Jinn-Liang; Eisenberg, Bob

    2014-12-14

    A Poisson-Nernst-Planck-Fermi (PNPF) theory is developed for studying ionic transport through biological ion channels. Our goal is to deal with the finite size of particle using a Fermi like distribution without calculating the forces between the particles, because they are both expensive and tricky to compute. We include the steric effect of ions and water molecules with nonuniform sizes and interstitial voids, the correlation effect of crowded ions with different valences, and the screening effect of water molecules in an inhomogeneous aqueous electrolyte. Including the finite volume of water and the voids between particles is an important new part of the theory presented here. Fermi like distributions of all particle species are derived from the volume exclusion of classical particles. Volume exclusion and the resulting saturation phenomena are especially important to describe the binding and permeation mechanisms of ions in a narrow channel pore. The Gibbs free energy of the Fermi distribution reduces to that of a Boltzmann distribution when these effects are not considered. The classical Gibbs entropy is extended to a new entropy form - called Gibbs-Fermi entropy - that describes mixing configurations of all finite size particles and voids in a thermodynamic system where microstates do not have equal probabilities. The PNPF model describes the dynamic flow of ions, water molecules, as well as voids with electric fields and protein charges. The model also provides a quantitative mean-field description of the charge/space competition mechanism of particles within the highly charged and crowded channel pore. The PNPF results are in good accord with experimental currents recorded in a 10(8)-fold range of Ca(2+) concentrations. The results illustrate the anomalous mole fraction effect, a signature of L-type calcium channels. Moreover, numerical results concerning water density, dielectric permittivity, void volume, and steric energy provide useful details to study

  20. Poisson-Nernst-Planck-Fermi theory for modeling biological ion channels

    NASA Astrophysics Data System (ADS)

    Liu, Jinn-Liang; Eisenberg, Bob

    2014-12-01

    A Poisson-Nernst-Planck-Fermi (PNPF) theory is developed for studying ionic transport through biological ion channels. Our goal is to deal with the finite size of particle using a Fermi like distribution without calculating the forces between the particles, because they are both expensive and tricky to compute. We include the steric effect of ions and water molecules with nonuniform sizes and interstitial voids, the correlation effect of crowded ions with different valences, and the screening effect of water molecules in an inhomogeneous aqueous electrolyte. Including the finite volume of water and the voids between particles is an important new part of the theory presented here. Fermi like distributions of all particle species are derived from the volume exclusion of classical particles. Volume exclusion and the resulting saturation phenomena are especially important to describe the binding and permeation mechanisms of ions in a narrow channel pore. The Gibbs free energy of the Fermi distribution reduces to that of a Boltzmann distribution when these effects are not considered. The classical Gibbs entropy is extended to a new entropy form — called Gibbs-Fermi entropy — that describes mixing configurations of all finite size particles and voids in a thermodynamic system where microstates do not have equal probabilities. The PNPF model describes the dynamic flow of ions, water molecules, as well as voids with electric fields and protein charges. The model also provides a quantitative mean-field description of the charge/space competition mechanism of particles within the highly charged and crowded channel pore. The PNPF results are in good accord with experimental currents recorded in a 108-fold range of Ca2+ concentrations. The results illustrate the anomalous mole fraction effect, a signature of L-type calcium channels. Moreover, numerical results concerning water density, dielectric permittivity, void volume, and steric energy provide useful details to study

  1. Two-Channel Kondo Effect Emerging from Nd Ions

    NASA Astrophysics Data System (ADS)

    Hotta, Takashi

    2017-08-01

    We discuss Kondo phenomena in a seven-orbital impurity Anderson model hybridized with Γ8 conduction electrons by employing a numerical renormalization group method. In particular, we focus on the case with three local f electrons, corresponding to a Nd3+ ion. For realistic values of Coulomb interactions, spin-orbit coupling, cubic crystalline electric field potentials, and hybridization, we find a residual entropy of 0.5 log 2, a characteristic of two-channel Kondo phenomena, for the wide range of parameters of the local Γ6 ground state. This is considered to be the magnetic two-channel Kondo effect, consistent with the result from an extended s-d model constructed on the basis of the j-j coupling scheme. Finally, we briefly discuss candidates of Nd compounds to observe the two-channel Kondo effect.

  2. Regulation of lysosomal ion homeostasis by channels and transporters.

    PubMed

    Xiong, Jian; Zhu, Michael X

    2016-08-01

    Lysosomes are the major organelles that carry out degradation functions. They integrate and digest materials compartmentalized by endocytosis, phagocytosis or autophagy. In addition to more than 60 hydrolases residing in the lysosomes, there are also ion channels and transporters that mediate the flux or transport of H(+), Ca(2+), Na(+), K(+), and Cl(-) across the lysosomal membranes. Defects in ionic exchange can lead to abnormal lysosome morphology, defective vesicle trafficking, impaired autophagy, and diseases such as neurodegeneration and lysosomal storage disorders. The latter are characterized by incomplete lysosomal digestion and accumulation of toxic materials inside enlarged intracellular vacuoles. In addition to degradation, recent studies have revealed the roles of lysosomes in metabolic pathways through kinases such as mechanistic target of rapamycin (mTOR) and transcriptional regulation through calcium signaling molecules such as transcription factor EB (TFEB) and calcineurin. Owing to the development of new approaches including genetically encoded fluorescence probes and whole endolysosomal patch clamp recording techniques, studies on lysosomal ion channels have made remarkable progress in recent years. In this review, we will focus on the current knowledge of lysosome-resident ion channels and transporters, discuss their roles in maintaining lysosomal function, and evaluate how their dysfunction can result in disease.

  3. Automated ion channel screening: patch clamping made easy.

    PubMed

    Farre, Cecilia; Stoelzle, Sonja; Haarmann, Claudia; George, Michael; Brüggemann, Andrea; Fertig, Niels

    2007-04-01

    Efficient high resolution techniques are required for screening efforts and research targeting ion channels. The conventional patch clamp technique, a high resolution but low efficiency technique, has been established for 25 years. Recent advances have opened up new possibilities for automated patch clamping. This new technology meets the need of drug developers for higher throughput and facilitates new experimental approaches in ion channel research. Specifically, Nanion's electrophysiology workstations, the Port-a-Patch and the Patchliner, have been successfully introduced as high-quality automated patch clamp platforms for industry as well as academic users. Both platforms give high quality patch clamp recordings, capable of true giga-seals and stable recordings, accessible to the user without the need for years of practical training. They also offer sophisticated experimental possibilities, such as accurate and fast ligand application, temperature control and internal solution exchange. This article describes the chip-based patch clamp technology and its usefulness in ion channel drug screening and academic research.

  4. Regulation of lysosomal ion homeostasis by channels and transporters

    PubMed Central

    Xiong, Jian; Zhu, Michael X.

    2016-01-01

    Lysosomes are the major organelles that carry out degradation functions. They integrate and digest materials compartmentalized by endocytosis, phagocytosis or autophagy. In addition to more than 60 hydrolases residing in the lysosomes, there are also ion channels and transporters that mediate the flux or transport of H+, Ca2+, Na+, K+, and Cl− across the lysosomal membranes. Defects in ionic exchange can lead to abnormal lysosome morphology, defective vesicle trafficking, impaired autophagy, and diseases such as neurodegeneration and lysosomal storage disorders. The latter are characterized by incomplete lysosomal digestion and accumulation of toxic materials inside enlarged intracellular vacuoles. In addition to degradation, recent studies have revealed the roles of lysosomes in metabolic pathways through kinases such as mechanistic target of rapamycin (mTOR) and transcriptional regulation through calcium signaling molecules such as transcription factor EB (TFEB) and calcineurin. Owing to the development of new approaches including genetically encoded fluorescence probes and whole endolysosomal patch clamp recording techniques, studies on lysosomal ion channels have made remarkable progress in recent years. In this review, we will focus on the current knowledge of lysosome-resident ion channels and transporters, discuss their roles in maintaining lysosomal function, and evaluate how their dysfunction can result in disease. PMID:27430889

  5. Acid-sensing ion channels in postoperative pain.

    PubMed

    Deval, Emmanuel; Noël, Jacques; Gasull, Xavier; Delaunay, Anne; Alloui, Abdelkrim; Friend, Valérie; Eschalier, Alain; Lazdunski, Michel; Lingueglia, Eric

    2011-04-20

    Iatrogenic pain consecutive to a large number of surgical procedures has become a growing health concern. The etiology and pathophysiology of postoperative pain are still poorly understood, but hydrogen ions appear to be important in this process. We have investigated the role of peripheral acid-sensing ion channels (ASICs), which form depolarizing channels activated by extracellular protons, in a rat model of postoperative pain (i.e., hindpaw skin/muscle incision). We report high levels of ASIC-type currents (∼ 77%) in sensory neurons innervating the hindpaw muscles, with a prevalence of ASIC3-like currents. The ASIC3 protein is largely expressed in lumbar DRG neurons innervating the plantar muscle, and its mRNA and protein levels are increased by plantar incision 24 h after surgery. Pharmacological inhibition of ASIC3 channels with the specific toxin APETx2 or in vivo knockdown of ASIC3 subunit by small interfering RNA led to a significant reduction of postoperative spontaneous, thermal, and postural pain behaviors (spontaneous flinching, heat hyperalgesia, and weight bearing). ASIC3 appears to have an important role in deep tissue but also affects prolonged pain evoked by skin incision alone. The specific homomeric ASIC1a blocker PcTx1 has no effect on spontaneous flinching, when applied peripherally. Together, these data demonstrate a significant role for peripheral ASIC3-containing channels in postoperative pain.

  6. Peptidomimetic Star Polymers for Targeting Biological Ion Channels

    PubMed Central

    Chen, Rong; Lu, Derong; Xie, Zili; Feng, Jing; Jia, Zhongfan; Ho, Junming; Coote, Michelle L.; Wu, Yingliang; Monteiro, Michael J.; Chung, Shin-Ho

    2016-01-01

    Four end-functionalized star polymers that could attenuate the flow of ionic currents across biological ion channels were first de novo designed computationally, then synthesized and tested experimentally on mammalian K+ channels. The 4-arm ethylene glycol conjugate star polymers with lysine or a tripeptide attached to the end of each arm were specifically designed to mimic the action of scorpion toxins on K+ channels. Molecular dynamics simulations showed that the lysine side chain of the polymers physically occludes the pore of Kv1.3, a target for immuno-suppression therapy. Two of the compounds tested were potent inhibitors of Kv1.3. The dissociation constants of these two compounds were computed to be 0.1 μM and 0.7 μM, respectively, within 3-fold to the values derived from subsequent experiments. These results demonstrate the power of computational methods in molecular design and the potential of star polymers as a new infinitely modifiable platform for ion channel drug discovery. PMID:27007701

  7. The Concise Guide to Pharmacology 2013/14: Ion Channels

    PubMed Central

    Alexander, Stephen PH; Benson, Helen E; Faccenda, Elena; Pawson, Adam J; Sharman, Joanna L; Catterall, William A; Spedding, Michael; Peters, John A; Harmar, Anthony J

    2013-01-01

    The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full. Ion channels are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets. It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates. PMID:24528239

  8. Functional and structural properties of ion channels at the nerve terminal depends on compact myelin.

    PubMed

    Berret, Emmanuelle; Kim, Sei Eun; Lee, Seul Yi; Kushmerick, Christopher; Kim, Jun Hee

    2016-10-01

    In the present study, we document the role of compact myelin in regulating the structural and functional properties of ion channels at the nerve terminals, using electrophysiology, dynamic Na(+) imaging and immunohistochemistry. The subcellular segregation of Na(+) channel expression and intracellular Na(+) dynamics at the heminode and terminal was lost in the dysmyelinated axon from Long-Evans shaker rats, which lack compact myelin. In Long-Evans shaker rats, loss of the Nav β4 subunit specifically at the heminode reduced resurgent and persistent Na(+) currents, whereas K(+) channel expression and currents were increased. The results of the present study suggest that there is a specific role for compact myelin in dictating protein expression and function at the axon heminode and in regulating excitability of the nerve terminal. Axon myelination increases the conduction velocity and precision of action potential propagation. Although the negative effects of demyelination are generally attributed to conduction failure, accumulating evidence suggests that myelination also regulates the structural properties and molecular composition of the axonal membrane. In the present study, we investigated how myelination affects ion channel expression and function, particularly at the last axon heminode before the nerve terminal, which regulates the presynaptic excitability of the nerve terminal. We compared the structure and physiology of normal axons and those of the Long-Evans shaker (LES) rat, which lacks compact myelin. The normal segregation of Na(+) channel expression and dynamics at the heminode and terminal was lost in the LES rat. Specifically, NaV -α subunits were dispersed and NaV β4 subunit was absent, whereas the density of K(+) channels was increased at the heminode. Correspondingly, resurgent and persistent Na(+) currents were reduced and K(+) current was increased. Taken together, these data suggest a specific role for compact myelin in the orchestration of

  9. Functional and structural properties of ion channels at the nerve terminal depends on compact myelin

    PubMed Central

    Berret, Emmanuelle; Kim, Sei Eun; Lee, Seul Yi; Kushmerick, Christopher

    2016-01-01

    Key points In the present study, we document the role of compact myelin in regulating the structural and functional properties of ion channels at the nerve terminals, using electrophysiology, dynamic Na+ imaging and immunohistochemistry.The subcellular segregation of Na+ channel expression and intracellular Na+ dynamics at the heminode and terminal was lost in the dysmyelinated axon from Long–Evans shaker rats, which lack compact myelin.In Long–Evans shaker rats, loss of the Navβ4 subunit specifically at the heminode reduced resurgent and persistent Na+ currents, whereas K+ channel expression and currents were increased.The results of the present study suggest that there is a specific role for compact myelin in dictating protein expression and function at the axon heminode and in regulating excitability of the nerve terminal. Abstract Axon myelination increases the conduction velocity and precision of action potential propagation. Although the negative effects of demyelination are generally attributed to conduction failure, accumulating evidence suggests that myelination also regulates the structural properties and molecular composition of the axonal membrane. In the present study, we investigated how myelination affects ion channel expression and function, particularly at the last axon heminode before the nerve terminal, which regulates the presynaptic excitability of the nerve terminal. We compared the structure and physiology of normal axons and those of the Long–Evans shaker (LES) rat, which lacks compact myelin. The normal segregation of Na+ channel expression and dynamics at the heminode and terminal was lost in the LES rat. Specifically, NaV‐α subunits were dispersed and NaVβ4 subunit was absent, whereas the density of K+ channels was increased at the heminode. Correspondingly, resurgent and persistent Na+ currents were reduced and K+ current was increased. Taken together, these data suggest a specific role for compact myelin in the orchestration

  10. Stochastic dynamics of electrical membrane with voltage-dependent ion channel fluctuations

    NASA Astrophysics Data System (ADS)

    Qian, Hong; Zhang, Xue-Juan; Qian, Min

    2014-04-01

    A Brownian-ratchet-like stochastic theory for the electrochemical membrane system of Hodgkin-Huxley (HH) is developed. The system is characterized by a continuous variable Q_m(t) , representing mobile membrane charge density, and a discrete variable Kt representing ion channel conformational dynamics. A Nernst-Planck-Nyquist-Johnson-type equilibrium is obtained when multiple conducting ions have a common reversal potential. Detailed balance yields a previously unknown relation between the channel switching rates and membrane capacitance, bypassing an Eyring-type explicit treatment of gating charge kinetics. From a molecular structural standpoint, the membrane charge Qm is a more natural dynamic variable than the potential Vm; our formalism treats Qm-dependent conformational transition rates \\lambda_{ij} as intrinsic parameters. Therefore, in principle, \\lambda_{ij} vs. Vm is experimental-protocol-dependent, e.g., different from voltage or charge clamping measurements. For constant membrane capacitance per unit area Cm and neglecting the membrane potential induced by gating charges, V_m=Q_m/C_m , and HH's formalism is recovered. The presence of two types of ions, with different channels and reversal potentials, gives rise to a nonequilibrium steady state with positive entropy production ep. For rapidly fluctuating channels, an expression for ep is obtained.

  11. Laser-guided, intersecting discharge channels for the final beam transport in heavy-ion fusion

    NASA Astrophysics Data System (ADS)

    Niemann, C.; Neff, S.; Tauschwitz, A.; Penache, D.; Birkner, R.; Constantin, C.; Knobloch, R.; Presura, R.; Rosmej, F. B.; Hoffmann, D. H. H.; Yu, S. S.

    2003-06-01

    Ion-beam transport in space charge neutralizing discharge channels has been proposed for the final focus and chamber transport in a heavy-ion fusion reactor. A driver scenario with two-sided target illumination requires a system of two intersecting discharges to transport beams of the same charge from opposite sides towards the fusion target. In this article we report on experiments on the creation of free-standing, intersecting high-current discharge channels. The discharges are initiated in ammonia gas (NH3) in a metallic chamber by two perpendicular CO2-laser beams, which resonantly heat and subsequently rarefy the gas along the laser paths before the breakdown. These low density channels guide the discharges along the predefined paths and also around the 90° angles without any mechanical guiding structures. In this way stable X-, T-, and L-shaped discharges with currents in excess of 40 kA, at pressures of a few mbar were created with a total length of 110 cm. An 11.4 A MeV 58Ni+12 beam from the UNILAC (Universal Linear Accelerator) linear accelerator was used to probe the line-integrated ion-optical properties of the central channel in a T-shaped discharge.

  12. Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels

    PubMed Central

    Sauguet, Ludovic; Poitevin, Frédéric; Murail, Samuel; Van Renterghem, Catherine; Moraga-Cid, Gustavo; Malherbe, Laurie; Thompson, Andrew W; Koehl, Patrice; Corringer, Pierre-Jean; Baaden, Marc; Delarue, Marc

    2013-01-01

    To understand the molecular mechanism of ion permeation in pentameric ligand-gated ion channels (pLGIC), we solved the structure of an open form of GLIC, a prokaryotic pLGIC, at 2.4 Å. Anomalous diffraction data were used to place bound anions and cations. This reveals ordered water molecules at the level of two rings of hydroxylated residues (named Ser6′ and Thr2′) that contribute to the ion selectivity filter. Two water pentagons are observed, a self-stabilized ice-like water pentagon and a second wider water pentagon, with one sodium ion between them. Single-channel electrophysiology shows that the side-chain hydroxyl of Ser6′ is crucial for ion translocation. Simulations and electrostatics calculations complemented the description of hydration in the pore and suggest that the water pentagons observed in the crystal are important for the ion to cross hydrophobic constriction barriers. Simulations that pull a cation through the pore reveal that residue Ser6′ actively contributes to ion translocation by reorienting its side chain when the ion is going through the pore. Generalization of these findings to the pLGIC family is proposed. PMID:23403925

  13. Ion channels and transporters in tumour cell migration and invasion

    PubMed Central

    Schwab, Albrecht; Stock, Christian

    2014-01-01

    Cell migration is a central component of the metastatic cascade requiring a concerted action of ion channels and transporters (migration-associated transportome), cytoskeletal elements and signalling cascades. Ion transport proteins and aquaporins contribute to tumour cell migration and invasion among other things by inducing local volume changes and/or by modulating Ca2+ and H+ signalling. Targeting cell migration therapeutically bears great clinical potential, because it is a prerequisite for metastasis. Ion transport proteins appear to be attractive candidate target proteins for this purpose because they are easily accessible as membrane proteins and often overexpressed or activated in cancer. Importantly, a number of clinically widely used drugs are available whose anticipated efficacy as anti-tumour drugs, however, has now only begun to be evaluated. PMID:24493750

  14. Progress in Development of Improved Ion-Channel Biosensors

    NASA Technical Reports Server (NTRS)

    Nadeau, Jay L.; White, Victor E.; Maurer, Joshua A.; Dougherty, Dennis A.

    2008-01-01

    Further improvements have recently been made in the development of the devices described in Improved Ion-Channel Biosensors (NPO-30710), NASA Tech Briefs, Vol. 28, No. 10 (October 2004), page 30. As discussed in more detail in that article, these sensors offer advantages of greater stability, greater lifetime, and individual electrical addressability, relative to prior ion-channel biosensors. In order to give meaning to a brief description of the recent improvements, it is necessary to recapitulate a substantial portion of the text of the cited previous article. The figure depicts one sensor that incorporates the recent improvements, and can be helpful in understanding the recapitulated text, which follows: These sensors are microfabricated from silicon and other materials compatible with silicon. Typically, the sensors are fabricated in arrays in silicon wafers on glass plates. Each sensor in the array can be individually electrically addressed, without interference with its neighbors. Each sensor includes a well covered by a thin layer of silicon nitride, in which is made a pinhole for the formation of a lipid bilayer membrane. In one stage of fabrication, the lower half of the well is filled with agarose, which is allowed to harden. Then the upper half of the well is filled with a liquid electrolyte (which thereafter remains liquid) and a lipid bilayer is painted over the pinhole. The liquid contains a protein that forms an ion channel on top of the hardened agarose. The combination of enclosure in the well and support by the hardened agarose provides the stability needed to keep the membrane functional for times as long as days or even weeks. An electrode above the well, another electrode below the well, and all the materials between the electrodes together constitute a capacitor. What is measured is the capacitive transient current in response to an applied voltage pulse. One notable feature of this sensor, in comparison with prior such sensors, is a

  15. Ca2+ channel blockade inhibits gallbladder ion transport.

    PubMed

    Saunders, K D; Cates, J A; Abedin, M Z; Kleinman, R; Roslyn, J J

    1990-10-01

    Recent studies suggest that cholesterol gallstone (GS) formation is characterized by altered gallbladder epithelial ion transport and increased gallbladder (GB) luminal Ca2+. Moreover, intracellular Ca2+ has been reported to be an important modulator of intestinal ion transport. The aim of the present study was to determine the effects of Ca2+ channel inhibition on GB ion transport. Prairie dog GBs were mounted in a Ussing chamber and bathed in warm oxygenated Ringer's solution, and short-circuit current (Isc), transepithelial potential difference (Vms), and tissue resistance (Rt) were recorded. Following stabilization, the mucosal surfaces of the GBs were exposed to 1 or 0.1 mM verapamil (VER). Effects on Isc were apparent within 10 sec with nadir values reached in 5 +/- 1 min. Profound (76%) inhibition of Isc was seen with 1 mM verapamil exposure (26 +/- 6 microA.cm-2) as compared to baseline values (170 +/- 6 microA.cm-2) (P less than 0.001). Verapamil exposure (1 mM) also led to a marked inhibition of Vms (P less than 0.001, vs baseline) and a significant increase in Rt (P less than 0.05 vs baseline). Similar trends were seen using 0.1 mM verapamil (Isc nadir 133 +/- 13 microA.cm-2). Verapamil-induced effects on gallbladder electrophysiology were largely reversible (75-90% recovery of baseline Isc after tissue washing). These data suggest that (1) verapamil induces rapid but reversible inhibition of ion transport and (2) Ca2+ channel blockade inhibits ion transport in a dose-dependent fashion. We would propose that intracellular Ca2+ may be a regulator of GB ion transport.

  16. Mn ions pass through calcium channels. A possible explanation

    PubMed Central

    1983-01-01

    The divalent transition-metal cations Fe, Co, and Ni were used to test the hypothesis that Mn ions pass through calcium channels because Mn ions have a relatively low energy of hydration. The test ions were applied to the bath and comparisons were made of their effects on Ca or Mn spikes elicited from myoepithelial cells of the proventriculus of the polychaete worm Syllis spongiphila. Control experiments showed that (a) results obtained using deoxygenated solutions (required to stabilize Fe2+ ions) could be compared with those using solutions containing oxygen, and (b) the test cations did not measurably affect the electrical coupling between cells. Ca spikes were reversibly abolished by the test cations in the order of effectiveness: Fe (16.1 mM +/- 1.0, SE; n = 15) = Co (14.6 mM +/- 0.8; n = 27) less than Ni (8.3 mM +/- 0.7; n = 16). The test cations diminished Mn spikes by decreasing maximum rates of rise (Fe = Co less than Ni) and overshoot amplitudes (Fe less than Co less than Ni). The test cations also increased the current intensity required for Ca (Fe = Co less than Ni) or Mn spike initiation (Fe less than Co less than Ni). Since the energies of hydration of Fe, Co, and Ni increase stepwise from that of Mn, and the effectiveness of these ions in diminishing Ca and Mn spikes increased in the order Fe less than or equal to Co less than Ni, these data support the hypothesis that Mn ions pass through Ca channels because they shed waters of hydration relatively easily. An additional observation was that, at below-blocking concentrations, the test cations caused decreased duration of Mn spikes and increased duration of Ca spikes. PMID:6308126

  17. Cavity Ring-Down System for Density Measurement of Negative Hydrogen Ion on Negative Ion Source

    SciTech Connect

    Nakano, Haruhisa; Tsumori, Katsuyoshi; Nagaoka, Kenichi; Shibuya, Masayuki; Kisaki, Masashi; Ikeda, Katsunori; Osakabe, Masaki; Kaneko, Osamu; Asano, Eiji; Kondo, Tomoki; Sato, Mamoru; Komada, Seiji; Sekiguchi, Haruo; Takeiri, Yasuhiko; Fantz, Ursel

    2011-09-26

    A Cavity Ring-Down (CRD) system was applied to measure the density of negative hydrogen ion (H{sup -}) in vicinity of extraction surface in the H{sup -} source for the development of neutral beam injector on Large Helical Device (LHD). The density measurement with sampling time of 50 ms was carried out. The measured density with the CRD system is relatively good agreement with the density evaluated from extracted beam-current with applying a similar relation of positive ion sources. In cesium seeded into ion-source plasma, the linearity between an arc power of the discharge and the measured density with the CRD system was observed. Additionally, the measured density was proportional to the extracted beam current. These characteristics indicate the CRD system worked well for H{sup -} density measurement in the region of H{sup -} and extraction.

  18. Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins.

    PubMed

    Peralta, Francisco Andrés; Huidobro-Toro, Juan Pablo

    2016-07-02

    Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve as ligands for metal coordination are not necessarily the same in structural proteins compared to enzymes. While crystals of structural proteins that bind zinc reveal a higher preference for cysteine sulfhydryls rather than histidine imidazole rings, catalytic enzymes reveal the opposite, i.e., a greater preference for the histidines over cysteines for catalysis, plus the influence of carboxylic acids. Based on this paradigm, we reviewed the putative ligands of zinc in ionotropic receptors, where zinc has been described as an allosteric modulator of channel receptors. Although these receptors do not strictly qualify as metalloproteins since they do not normally bind zinc in structural domains, they do transitorily bind zinc at allosteric sites, modifying transiently the receptor channel's ion permeability. The present contribution summarizes current information showing that zinc allosteric modulation of receptor channels occurs by the preferential metal coordination to imidazole rings as well as to the sulfhydryl groups of cysteine in addition to the carboxyl group of acid residues, as with enzymes and catalysis. It is remarkable that most channels, either voltage-sensitive or transmitter-gated receptor channels, are susceptible to zinc modulation either as positive or negative regulators.

  19. Acid-sensing ion channels in pathological conditions

    PubMed Central

    Chu, Xiang-Ping; Xiong, Zhi-Gang

    2013-01-01

    Acid-sensing ion channels (ASICs), a novel family of proton-gated amiloride-sensitive cation channels, are expressed primarily in neurons of peripheral sensory and central nervous systems. Recent studies have shown that activation of ASICs, particularly the ASIC1a channels, plays a critical role in neuronal injury associated with neurological disorders such as brain ischemia, multiple sclerosis, and spinal cord injury, etc. In normal conditions in vitro, ASIC1a channels desensitize rapidly in the presence of a continuous acidosis or following a pre-exposure to minor pH drop, raising doubt for their contributions to the acidosis-mediated neuronal injury. It is now known that the properties of ASICs can be dramatically modulated by signaling molecules or biochemical changes associated with pathological conditions. Modulation of ASICs by these molecules can lead to dramatically enhanced and/or prolonged activities of these channels thus promoting their pathological functions. Understanding of how ASICs behave in pathological conditions may help define new strategies for the treatment and/or prevention of neuronal injury associated with various neurological disorders. PMID:23224900

  20. Estimation of ion channel kinetics from fluctuations of macroscopic currents.

    PubMed

    Moffatt, Luciano

    2007-07-01

    For single channel recordings, the maximum likelihood estimation (MLE) of kinetic rates and conductance is well established. A direct extrapolation of this method to macroscopic currents is computationally prohibitive: it scales as a power of the number of channels. An approximated MLE that ignored the local time correlation of the data has been shown to provide estimates of the kinetic parameters. In this article, an improved approximated MLE that takes into account the local time correlation is proposed. This method estimates the channel kinetics using both the time course and the random fluctuations of the macroscopic current generated by a homogeneous population of ion channels under white noise. It allows arbitrary kinetic models and stimulation protocols. The application of the proposed algorithm to simulated data from a simple three-state model on nonstationary conditions showed reliable estimates of all the kinetic constants, the conductance and the number of channels, and reliable values for the standard error of those estimates. Compared to the previous approximated MLE, it reduces by a factor of 10 the amount of data needed to secure a given accuracy and it can even determine the kinetic rates in macroscopic stationary conditions.

  1. Estimation of Ion Channel Kinetics from Fluctuations of Macroscopic Currents

    PubMed Central

    Moffatt, Luciano

    2007-01-01

    For single channel recordings, the maximum likelihood estimation (MLE) of kinetic rates and conductance is well established. A direct extrapolation of this method to macroscopic currents is computationally prohibitive: it scales as a power of the number of channels. An approximated MLE that ignored the local time correlation of the data has been shown to provide estimates of the kinetic parameters. In this article, an improved approximated MLE that takes into account the local time correlation is proposed. This method estimates the channel kinetics using both the time course and the random fluctuations of the macroscopic current generated by a homogeneous population of ion channels under white noise. It allows arbitrary kinetic models and stimulation protocols. The application of the proposed algorithm to simulated data from a simple three-state model on nonstationary conditions showed reliable estimates of all the kinetic constants, the conductance and the number of channels, and reliable values for the standard error of those estimates. Compared to the previous approximated MLE, it reduces by a factor of 10 the amount of data needed to secure a given accuracy and it can even determine the kinetic rates in macroscopic stationary conditions. PMID:17416622

  2. Neurosensory mechanotransduction through acid-sensing ion channels

    PubMed Central

    Chen, Chih-Cheng; Wong, Chia-Wen

    2013-01-01

    Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels responding to extracellular acidification. ASIC proteins have two transmembrane domains and a large extracellular domain. The molecular topology of ASICs is similar to that of the mechanosensory abnormality 4- or 10-proteins expressed in touch receptor neurons and involved in neurosensory mechanotransduction in nematodes. The ASIC proteins are involved in neurosensory mechanotransduction in mammals. The ASIC isoforms are expressed in Merkel cell–neurite complexes, periodontal Ruffini endings and specialized nerve terminals of skin and muscle spindles, so they might participate in mechanosensation. In knockout mouse models, lacking an ASIC isoform produces defects in neurosensory mechanotransduction of tissue such as skin, stomach, colon, aortic arch, venoatrial junction and cochlea. The ASICs are thus implicated in touch, pain, digestive function, baroreception, blood volume control and hearing. However, the role of ASICs in mechanotransduction is still controversial, because we lack evidence that the channels are mechanically sensitive when expressed in heterologous cells. Thus, ASIC channels alone are not sufficient to reconstruct the path of transducing molecules of mechanically activated channels. The mechanotransducers associated with ASICs need further elucidation. In this review, we discuss the expression of ASICs in sensory afferents of mechanoreceptors, findings of knockout studies, technical issues concerning studies of neurosensory mechanotransduction and possible missing links. Also we propose a molecular model and a new approach to disclose the molecular mechanism underlying the neurosensory mechanotransduction. PMID:23490035

  3. Molecular dynamics simulations of water within models of ion channels.

    PubMed

    Breed, J; Sankararamakrishnan, R; Kerr, I D; Sansom, M S

    1996-04-01

    The transbilayer pores formed by ion channel proteins contain extended columns of water molecules. The dynamic properties of such waters have been suggested to differ from those of water in its bulk state. Molecular dynamics simulations of ion channel models solvated within and at the mouths of their pores are used to investigate the dynamics and structure of intra-pore water. Three classes of channel model are investigated: a) parallel bundles of hydrophobic (Ala20) alpha-helices; b) eight-stranded hydrophobic (Ala10) antiparallel beta-barrels; and c) parallel bundles of amphipathic alpha-helices (namely, delta-toxin, alamethicin, and nicotinic acetylcholine receptor M2 helix). The self-diffusion coefficients of water molecules within the pores are reduced significantly relative to bulk water in all of the models. Water rotational reorientation rates are also reduced within the pores, particularly in those pores formed by alpha-helix bundles. In the narrowest pore (that of the Ala20 pentameric helix bundle) self-diffusion coefficients and reorientation rates of intra-pore waters are reduced by approximately an order of magnitude relative to bulk solvent. In Ala20 helix bundles the water dipoles orient antiparallel to the helix dipoles. Such dipole/dipole interaction between water and pore may explain how water-filled ion channels may be formed by hydrophobic helices. In the bundles of amphipathic helices the orientation of water dipoles is modulated by the presence of charged side chains. No preferential orientation of water dipoles relative to the pore axis is observed in the hydrophobic beta-barrel models.

  4. Characterization of the internal ion environment of biofilms based on charge density and shape of ion.

    PubMed

    Kurniawan, Andi; Tsuchiya, Yuki; Eda, Shima; Morisaki, Hisao

    2015-12-01

    Biofilm polymers contain both electrically positively and negatively charged sites. These charged sites enable the biofilm to trap and retain ions leading to an important role of biofilm such as nutrient recycling and pollutant purification. Much work has focused on the ion-exchange capacity of biofilms, and they are known to adsorb ions through an exchange mechanism between the ions in solution and the ions adsorbed to the charged sites on the biofilm polymer. However, recent studies suggest that the adsorption/desorption behavior of ions in a biofilm cannot be explained solely by this ion exchange mechanism. To examine the possibility that a substantial amount of ions are held in the interstitial region of the biofilm polymer by an electrostatic interaction, intact biofilms formed in a natural environment were immersed in distilled water and ion desorption was investigated. All of the detected ion species were released from the biofilms over a short period of time, and very few ions were subsequently released over more time, indicating that the interstitial region of biofilm polymers is another ion reserve. The extent of ion retention in the interstitial region of biofilms for each ion can be determined largely by charge density, |Z|/r, where |Z| is the ion valence as absolute value and r is the ion radius. The higher |Z|/r value an ion has, the stronger it is retained in the interstitial region of biofilms. Ion shape is also a key determinant of ion retention. Spherical and non-spherical ions have different correlations between the condensation ratio and |Z|/r. The generality of these findings were assured by various biofilm samples. Thus, the internal regions of biofilms exchange ions dynamically with the outside environment.

  5. Distributions of the ion temperature, ion pressure, and electron density over the current sheet surface

    SciTech Connect

    Kyrie, N. P. Markov, V. S. Frank, A. G.; Vasilkov, D. G.; Voronova, E. V.

    2016-06-15

    The distributions of the ion temperature, ion pressure, and electron density over the width (the major transverse dimension) of the current sheet have been studied for the first time. The current sheets were formed in discharges in argon and helium in 2D and 3D magnetic configurations. It is found that the temperature of argon ions in both 2D and 3D magnetic configurations is almost uniform over the sheet width and that argon ions are accelerated by the Ampère force. In contrast, the distributions of the electron density and the temperature of helium ions are found to be substantially nonuniform. As a result, in the 2D magnetic configuration, the ion pressure gradient across the sheet width makes a significant contribution (comparable with the Ampère force) to the acceleration of helium ions, whereas in the 3D magnetic configuration, the Ampère force is counterbalanced by the pressure gradient.

  6. Validation of an atomic absorption rubidium ion efflux assay for KCNQ/M-channels using the ion Channel Reader 8000.

    PubMed

    Wang, Kewei; McIlvain, Beal; Tseng, Eugene; Kowal, Dianne; Jow, Flora; Shen, Ru; Zhang, Howard; Shan, Qin Jennifer; He, Lan; Chen, Diana; Lu, Qiang; Dunlop, John

    2004-10-01

    M-channels (M-current), encoded by KCNQ2/3 K(+) channel genes, have emerged as novel drug targets for a number of neurological disorders. The lack of direct high throughput assays combined with the low throughput of conventional electrophysiology (EP) has impeded rapid screening and evaluation of K(+)-channel modulators. Development of a sensitive and efficient assay for the direct measurement of M-current activity is critical for identifying novel M-channel modulators and subsequent investigation of their therapeutic potential. Using a stable CHO cell line expressing rat KCNQ2/3 K(+) channels confirmed by EP, we have developed and validated a nonradioactive rubidium (Rb(+)) efflux assay in a 96-well plate format. The Rb(+) efflux assay directly measures the activity of functional channels by atomic absorption spectroscopy using the automated Ion Channel Reader (ICR) 8000. The stimulated Rb(+) efflux from KCNQ2/3-expressing cells was blocked by the channel blockers XE991 and linopirdine with IC(50) values of 0.15 microM and 1.3 microM, respectively. Twelve compounds identified as KCNQ2/3 openers were further assessed in this assay, and their EC(50) values were compared with those obtained with EP. A higher positive correlation coefficient between these two assays (r = 0.60) was observed than that between FlexStation membrane potential and EP assays (r = 0.23). To simplify the assay and increase the throughput, we demonstrate that EC(50) values obtained by measuring Rb(+) levels in the supernatant are as robust and consistent as those obtained from the ratio of Rb(+) in supernatant/lysate. By measuring the supernatant only, the throughput of ICR8000 in an eight-point titration is estimated to be 40 compounds per day, which is suitable for a secondary confirmation assay.

  7. Ion permeation of AQP6 water channel protein. Single channel recordings after Hg2+ activation.

    PubMed

    Hazama, Akihiro; Kozono, David; Guggino, William B; Agre, Peter; Yasui, Masato

    2002-08-09

    Aquaporin-6 (AQP6) has recently been identified as an intracellular vesicle water channel with anion permeability that is activated by low pH or HgCl2. Here we present direct evidence of AQP6 channel gating using patch clamp techniques. Cell-attached patch recordings of AQP6 expressed in Xenopus laevis oocytes indicated that AQP6 is a gated channel with intermediate conductance (49 picosiemens in 100 mm NaCl) induced by 10 microm HgCl2. Current-voltage relationships were linear, and open probability was fairly constant at any given voltage, indicating that Hg2+-induced AQP6 conductance is voltage-independent. The excised outside-out patch recording revealed rapid activation of AQP6 channels immediately after application of 10 microm HgCl2. Reduction of both Na+ and Cl- concentrations from 100 to 30 mm did not shift the reversal potential of the Hg2+-induced AQP6 current, suggesting that Na+ is as permeable as Cl-. The Na+ permeability of Hg2+-induced AQP6 current was further demonstrated by 22Na+ influx measurements. Site-directed mutagenesis identified Cys-155 and Cys-190 residues as the sites of Hg2+ activation both for water permeability and ion conductance. The Hill coefficient from the concentration-response curve for Hg2+-induced conductance was 1.1 +/- 0.3. These data provide the first evidence of AQP6 channel gating at a single-channel level and suggest that each monomer contains the pore region for ions based on the number of Hg2+-binding sites and the kinetics of Hg2+-activation of the channel.

  8. Developmental Profile of Ion Channel Specializations in the Avian Nucleus Magnocellularis

    PubMed Central

    Hong, Hui; Rollman, Lisia; Feinstein, Brooke; Sanchez, Jason Tait

    2016-01-01

    Ultrafast and temporally precise action potentials (APs) are biophysical specializations of auditory brainstem neurons; properties necessary for encoding sound localization and communication cues. Fundamental to these specializations are voltage dependent potassium (KV) and sodium (NaV) ion channels. Here, we characterized the functional development of these ion channels and quantified how they shape AP properties in the avian cochlear nucleus magnocellularis (NM). We report that late developing NM neurons (embryonic [E] days 19–21) generate fast APs that reliably phase lock to sinusoidal inputs at 75 Hz. In contrast, early developing neurons (channels were blocked, APs for all ages became significantly slower. This was most evident for early developing neurons where the ratio of K+HVA current accounted for ~85% of the total KV response. This ratio dropped to ~50% for late developing neurons, suggesting a developmental upregulation of low-voltage activated potassium (K+LVA) channels. Indeed, blockade of K+LVA eliminated remaining current and increased neural excitability for late developing neurons. We also report developmental changes in the amplitude, kinetics and voltage dependence of NaV currents. For early developing neurons, increase in NaV current amplitude was due to channel density while channel conductance dominated for late developing neurons. From E10 to E21, NaV channel currents became faster but differed in their voltage dependence; early developing neurons (channel inactivation voltages while late developing NM neurons (>E19) contained NaV channels that inactivate at more

  9. Identification and characterization of a bacterial hydrosulfide ion channel

    PubMed Central

    Czyzewski, Bryan K.; Wang, Da-Neng

    2013-01-01

    Believed to have been critical to the origin of life on Earth 1, the hydrosulfide ion (HS−) and its undissociated form, hydrogen sulfide (H2S), continue to play a prominent role in physiology and cellular signaling 2. As a major metabolite in anaerobic bacterial growth, hydrogen sulfide is a product of both assimilatory and dissimilatory sulfate reduction 2–4. These pathways can reduce various oxidized sulfur compounds including sulfate, sulfite and thiosulfate. The dissimilatory sulfate reduction pathway uses this molecule as the terminal electron acceptor for anaerobic respiration, where it produces excess amounts of H2S4. The reduction of sulfite is a key intermediate step in all sulfate reduction pathways. In Clostridium and Salmonella, an inducible sulfite reductase is directly linked to the regeneration of NAD+, which has been suggested to play a role in energy production and growth, as well as in the detoxification of sulfite 3. Above a certain concentration threshold, both H2S and HS− nhibit cell growth by binding the metal centers of enzymes and cytochrome oxidase5, necessitating a release mechanism for the export of this toxic metabolite from the cell 5–9. Through a combination of genetic, biochemical and functional approaches, we have identified a hydrosulfide ion channel (HSC) in the pathogen Clostridium difficile. The HS− channel is a member of the formate-nitrite-transport (FNT) family, in which ~50 HSC genes form a third subfamily alongside those for formate (FocA) 10,11 and for nitrite (NirC) 12. In addition to HS− ions, HSC is also permeable to formate and nitrite. Such polyspecificity can be explained by the conserved ion selectivity filter observed in the HSC crystal structure. The channel has a low open probability and is tightly regulated, to avoid decoupling of the membrane proton gradient. PMID:22407320

  10. Computer Simulation Studies of Ion Channels at High Temperatures

    NASA Astrophysics Data System (ADS)

    Song, Hyun Deok

    The gramicidin channel is the smallest known biological ion channel, and it exhibits cation selectivity. Recently, Dr. John Cuppoletti's group at the University of Cincinnati showed that the gramicidin channel can function at high temperatures (360 ˜ 380K) with significant currents. This finding may have significant implications for fuel cell technology. In this thesis, we have examined the gramicidin channel at 300K, 330K, and 360K by computer simulation. We have investigated how the temperature affects the current and differences in magnitude of free energy between the two gramicidin forms, the helical dimer (HD) and the double helix (DH). A slight decrease of the free energy barrier inside the gramicidin channel and increased diffusion at high temperatures result in an increase of current. An applied external field of 0.2V/nm along the membrane normal results in directly observable ion transport across the channels at high temperatures for both HD and DH forms. We found that higher temperatures also affect the probability distribution of hydrogen bonds, the bending angle, the distance between dimers, and the size of the pore radius for the helical dimer structure. These findings may be related to the gating of the gramicidin channel. Methanococcus jannaschii (MJ) is a methane-producing thermophile, which was discovered at a depth of 2600m in a Pacific Ocean vent in 1983. It has the ability to thrive at high temperatures and high pressures, which are unfavorable for most life forms. There have been some experiments to study its stability under extreme conditions, but still the origin of the stability of MJ is not exactly known. MJ0305 is the chloride channel protein from the thermophile MJ. After generating a structure of MJ0305 by homology modeling based on the Ecoli ClC templates, we examined the thermal stability, and the network stability from the change of network entropy calculated from the adjacency matrices of the protein. High temperatures increase the

  11. Molecular Architecture and Subunit Organization of TRPA1 Ion Channel Revealed by Electron Microscopy*

    PubMed Central

    Cvetkov, Teresa L.; Huynh, Kevin W.; Cohen, Matthew R.; Moiseenkova-Bell, Vera Y.

    2011-01-01

    Transient receptor potential ankyrin 1 (TRPA1) is a non-selective ion channel, which is expressed in nociceptor sensory neurons and transduces chemical, inflammatory, and neuropathic pain signals. Numerous non-reactive compounds and electrophilic compounds, such as endogenous inflammatory mediators and exogenous pungent chemicals, can activate TRPA1. Here we report a 16-Å resolution structure of purified, functional, amphipol-stabilized TRPA1 analyzed by single-particle EM. Molecular models of the N and C termini of the channel were generated using the I-TASSER protein structure prediction server and docked into the EM density to provide insight into the TRPA1 subunit organization. This structural analysis suggests a location for critical N-terminal cysteine residues involved in electrophilic activation at the interface between neighboring subunits. Our results indicate that covalent modifications within this pocket may alter interactions between subunits and promote conformational changes that lead to channel activation. PMID:21908607

  12. Distinct ion channel classes are expressed on the outer nuclear envelope of T- and B-lymphocyte cell lines.

    PubMed Central

    Franco-Obregón, A; Wang, H W; Clapham, D E

    2000-01-01

    The outer nuclear membrane, endoplasmic reticulum, and mitochondrial membrane ion channels are poorly understood, although they are important in the control of compartmental calcium levels, cell division, and apoptosis. Few direct recordings of these ion channels have been made because of the difficulty of accessing these intracellular membranes. Using patch-clamp techniques on isolated nuclei, we measured distinct ion channel classes on the outer nuclear envelope of T-cell (human Jurkat) and BFL5 cell (murine promyelocyte) lines. We first imaged the nuclear envelopes of both Jurkat and FL5 cells with atomic force microscopy to determine the density of pore proteins. The nuclear pore complex was intact at roughly similar densities in both cell types. In patch-clamp recordings of Jurkat nuclear membranes, Cl channels (105 +/- 5 pS) predominated and inactivated with negative pipette potentials. Nucleotides transiently inhibited the anion channel. In contrast, FL5 nuclear channels were cation selective (52 +/- 2 pS), were inactivated with positive membrane potentials, and were insensitive to GTPgammaS applied to the bath. We hypothesize that T- and B-cell nuclear membrane channels are distinct, and that this is perhaps related to their unique roles in the immune system. PMID:10866948

  13. Nicotinic acid is a common regulator of heat-sensing TRPV1-4 ion channels.

    PubMed

    Ma, Linlin; Lee, Bo Hyun; Clifton, Heather; Schaefer, Saul; Zheng, Jie

    2015-03-10

    Nicotinic acid (NA, a.k.a. vitamin B3 or niacin) can reduce blood cholesterol and low-density lipoproteins whereas increase high-density lipoproteins. However, when NA is used to treat dyslipidemias, it causes a strong side effect of cutaneous vasodilation, commonly called flushing. A recent study showed that NA may cause flushing by lowering activation threshold temperature of the heat-sensitive capsaicin receptor TRPV1 ion channel, leading to its activation at body temperature. The finding calls into question whether NA might also interact with the homologous heat-sensitive TRPV2-4 channels, particularly given that TRPV3 and TRPV4 are abundantly expressed in keratinocytes of the skin where much of the flushing response occurs. We found that NA indeed potentiated TRPV3 while inhibited TRPV2 and TRPV4. Consistent with these gating effects, NA lowered the heat-activation threshold of TRPV3 but elevated that of TRPV4. We further found that activity of TRPV1 was substantially prolonged by extracellular NA, which may further enhance the direct activation effect. Consistent with the broad gating effect on TRPV1-4 channels, evidence from the present study hints that NA may share the same activation pathway as 2-aminoethoxydiphenyl borate (2-APB), a common agonist for these TRPV channels. These findings shed new light on the molecular mechanism underlying NA regulation of TRPV channels.

  14. A parallel finite element simulator for ion transport through three-dimensional ion channel systems.

    PubMed

    Tu, Bin; Chen, Minxin; Xie, Yan; Zhang, Linbo; Eisenberg, Bob; Lu, Benzhuo

    2013-09-15

    A parallel finite element simulator, ichannel, is developed for ion transport through three-dimensional ion channel systems that consist of protein and membrane. The coordinates of heavy atoms of the protein are taken from the Protein Data Bank and the membrane is represented as a slab. The simulator contains two components: a parallel adaptive finite element solver for a set of Poisson-Nernst-Planck (PNP) equations that describe the electrodiffusion process of ion transport, and a mesh generation tool chain for ion channel systems, which is an essential component for the finite element computations. The finite element method has advantages in modeling irregular geometries and complex boundary conditions. We have built a tool chain to get the surface and volume mesh for ion channel systems, which consists of a set of mesh generation tools. The adaptive finite element solver in our simulator is implemented using the parallel adaptive finite element package Parallel Hierarchical Grid (PHG) developed by one of the authors, which provides the capability of doing large scale parallel computations with high parallel efficiency and the flexibility of choosing high order elements to achieve high order accuracy. The simulator is applied to a real transmembrane protein, the gramicidin A (gA) channel protein, to calculate the electrostatic potential, ion concentrations and I - V curve, with which both primitive and transformed PNP equations are studied and their numerical performances are compared. To further validate the method, we also apply the simulator to two other ion channel systems, the voltage dependent anion channel (VDAC) and α-Hemolysin (α-HL). The simulation results agree well with Brownian dynamics (BD) simulation results and experimental results. Moreover, because ionic finite size effects can be included in PNP model now, we also perform simulations using a size-modified PNP (SMPNP) model on VDAC and α-HL. It is shown that the size effects in SMPNP can

  15. Ion Channels in the Eye: Involvement in Ocular Pathologies.

    PubMed

    Giblin, Jonathan P; Comes, Nuria; Strauss, Olaf; Gasull, Xavier

    2016-01-01

    The eye is the sensory organ of vision. There, the retina transforms photons into electrical signals that are sent to higher brain areas to produce visual sensations. In the light path to the retina, different types of cells and tissues are involved in maintaining the transparency of avascular structures like the cornea or lens, while others, like the retinal pigment epithelium, have a critical role in the maintenance of photoreceptor function by regenerating the visual pigment. Here, we have reviewed the roles of different ion channels expressed in ocular tissues (cornea, conjunctiva and neurons innervating the ocular surface, lens, retina, retinal pigment epithelium, and the inflow and outflow systems of the aqueous humor) that are involved in ocular disease pathophysiologies and those whose deletion or pharmacological modulation leads to specific diseases of the eye. These include pathologies such as retinitis pigmentosa, macular degeneration, achromatopsia, glaucoma, cataracts, dry eye, or keratoconjunctivitis among others. Several disease-associated ion channels are potential targets for pharmacological intervention or other therapeutic approaches, thus highlighting the importance of these channels in ocular physiology and pathophysiology. © 2016 Elsevier Inc. All rights reserved.

  16. Amiloride Docking to Acid-sensing Ion Channel-1*

    PubMed Central

    Qadri, Yawar J.; Song, Yuhua; Fuller, Catherine M.; Benos, Dale J.

    2010-01-01

    Amiloride is a small molecule diuretic, which has been used to dissect sodium transport pathways in many different systems. This drug is known to interact with the epithelial sodium channel and acid-sensing ion channel proteins, as well as sodium/hydrogen antiporters and sodium/calcium exchangers. The exact structural basis for these interactions has not been elucidated as crystal structures of these proteins have been challenging to obtain, though some involved residues and domains have been mapped. This work examines the interaction of amiloride with acid-sensing ion channel-1, a protein whose structure is available using computational and experimental techniques. Using molecular docking software, amiloride and related molecules were docked to model structures of homomeric human ASIC-1 to generate potential interaction sites and predict which analogs would be more or less potent than amiloride. The predictions made were experimentally tested using whole-cell patch clamp. Drugs previously classified as NCX or NHE inhibitors are shown to also inhibit hASIC-1. Potential docking sites were re-examined against experimental data to remove spurious interaction sites. The voltage sensitivity of inhibitors was also examined. Using the aggregated data from these computational and experimental experiments, putative interaction sites for amiloride and hASIC-1 have been defined. Future work will experimentally verify these interaction sites, but at present this should allow for virtual screening of drug libraries at these putative interaction sites. PMID:20048170

  17. Modelling modal gating of ion channels with hierarchical Markov models

    PubMed Central

    Fackrell, Mark; Crampin, Edmund J.; Taylor, Peter

    2016-01-01

    Many ion channels spontaneously switch between different levels of activity. Although this behaviour known as modal gating has been observed for a long time it is currently not well understood. Despite the fact that appropriately representing activity changes is essential for accurately capturing time course data from ion channels, systematic approaches for modelling modal gating are currently not available. In this paper, we develop a modular approach for building such a model in an iterative process. First, stochastic switching between modes and stochastic opening and closing within modes are represented in separate aggregated Markov models. Second, the continuous-time hierarchical Markov model, a new modelling framework proposed here, then enables us to combine these components so that in the integrated model both mode switching as well as the kinetics within modes are appropriately represented. A mathematical analysis reveals that the behaviour of the hierarchical Markov model naturally depends on the properties of its components. We also demonstrate how a hierarchical Markov model can be parametrized using experimental data and show that it provides a better representation than a previous model of the same dataset. Because evidence is increasing that modal gating reflects underlying molecular properties of the channel protein, it is likely that biophysical processes are better captured by our new approach than in earlier models. PMID:27616917

  18. Acid-sensing ion channels: trafficking and synaptic function

    PubMed Central

    2013-01-01

    Extracellular acidification occurs in the brain with elevated neural activity, increased metabolism, and neuronal injury. This reduction in pH can have profound effects on brain function because pH regulates essentially every single biochemical reaction. Therefore, it is not surprising to see that Nature evolves a family of proteins, the acid-sensing ion channels (ASICs), to sense extracellular pH reduction. ASICs are proton-gated cation channels that are mainly expressed in the nervous system. In recent years, a growing body of literature has shown that acidosis, through activating ASICs, contributes to multiple diseases, including ischemia, multiple sclerosis, and seizures. In addition, ASICs play a key role in fear and anxiety related psychiatric disorders. Several recent reviews have summarized the importance and therapeutic potential of ASICs in neurological diseases, as well as the structure-function relationship of ASICs. However, there is little focused coverage on either the basic biology of ASICs or their contribution to neural plasticity. This review will center on these topics, with an emphasis on the synaptic role of ASICs and molecular mechanisms regulating the spatial distribution and function of these ion channels. PMID:23281934

  19. Crystal structures of a double-barrelled fluoride ion channel

    PubMed Central

    Stockbridge, Randy B.; Kolmakova-Partensky, Ludmila; Shane, Tania; Koide, Akiko; Koide, Shohei; Miller, Christopher; Newstead, Simon

    2016-01-01

    To contend with hazards posed by environmental fluoride, microorganisms export this anion through F--specific ion channels of the Fluc family1–4. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including extreme selectivity for F- over Cl- and dual-topology dimeric assembly5–6. To understand the chemical basis for F- permeation and how the antiparallel subunits convene to form a F--selective pore, we solved crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F- present, to a maximum resolution of 2.1 Å. The structures reveal a surprising “double-barrelled” channel architecture in which two F- ion pathways span the membrane and the dual-topology arrangement includes a centrally coordinated cation, most likely Na+. F- selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings. PMID:26344196

  20. Stoichiometry of the KCNQ1 - KCNE1 ion channel complex.

    PubMed

    Nakajo, Koichi; Ulbrich, Maximilian H; Kubo, Yoshihiro; Isacoff, Ehud Y

    2010-11-02

    The KCNQ1 voltage-gated potassium channel and its auxiliary subunit KCNE1 play a crucial role in the regulation of the heartbeat. The stoichiometry of KCNQ1 and KCNE1 complex has been debated, with some results suggesting that the four KCNQ1 subunits that form the channel associate with two KCNE1 subunits (a 42 stoichiometry), while others have suggested that the stoichiometry may not be fixed. We applied a single molecule fluorescence bleaching method to count subunits in many individual complexes and found that the stoichiometry of the KCNQ1 - KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits of the channel (a 44 stoichiometry). The proportion of the various stoichiometries was found to depend on the relative expression densities of KCNQ1 and KCNE1. Strikingly, both the voltage-dependence and kinetics of gating were found to depend on the relative densities of KCNQ1 and KCNE1, suggesting the heart rhythm may be regulated by the relative expression of the auxiliary subunit and the resulting stoichiometry of the channel complex.

  1. Ion transport in a model gramicidin channel. Structure and thermodynamics.

    PubMed Central

    Roux, B; Karplus, M

    1991-01-01

    The potential of mean force for Na+ and K+ ions as a function of position in the interior of a periodic poly(L,D)-alanine model for the gramicidin beta-helix is calculated with a detailed atomic model and realistic interactions. The calculated free energy barriers are 4.5 kcal/mol for Na+ and 1.0 kcal/mol for K+. A decomposition of the free energy demonstrates that the water molecules make a significant contribution to the free energy of activation. There is an increase in entropy at the transition state associated with greater fluctuations. Analysis reveals that the free energy profile of ions in the periodic channel is controlled not by the large interaction energy involving the ion but rather by the weaker water-water, water-peptide and peptide-peptide hydrogen bond interactions. The interior of the channel retains much of the solvation properties of a liquid in its interactions with the cations. Of particular importance is the flexibility of the helix, which permits it to respond to the presence of an ion in a fluidlike manner. The distortion of the helix is local (limited to a few carbonyls) because the structure is too flexible to transmit a perturbation to large distances. The plasticity of the structure (i.e., the property to deform without generating a large energy stress) appears to be an essential factor in the transport of ions, suggesting that a rigid helix model would be inappropriate. Images FIGURE 1 FIGURE 10 PMID:1714305

  2. Current Density Measurements of an Annular-Geometry Ion Engine

    NASA Technical Reports Server (NTRS)

    Shastry, Rohit; Patterson, Michael J.; Herman, Daniel A.; Foster, John E.

    2012-01-01

    The concept of the annular-geometry ion engine, or AGI-Engine, has been shown to have many potential benefits when scaling electric propulsion technologies to higher power. However, the necessary asymmetric location of the discharge cathode away from thruster centerline could potentially lead to non-uniformities in the discharge not present in conventional geometry ion thrusters. In an effort to characterize the degree of this potential nonuniformity, a number of current density measurements were taken on a breadboard AGI-Engine. Fourteen button probes were used to measure the ion current density of the discharge along a perforated electrode that replaced the ion optics during conditions of simulated beam extraction. Three Faraday probes spaced apart in the vertical direction were also used in a separate test to interrogate the plume of the AGI-Engine during true beam extraction. It was determined that both the discharge and the plume of the AGI-Engine are highly uniform, with variations under most conditions limited to 10% of the average current density in the discharge and 5% of the average current density in the plume. Beam flatness parameter measured 30 mm from the ion optics ranged from 0.85 0.95, and overall uniformity was shown to generally increase with increasing discharge and beam currents. These measurements indicate that the plasma is highly uniform despite the asymmetric location of the discharge cathode.

  3. Current Density Measurements of an Annular-Geometry Ion Engine

    NASA Technical Reports Server (NTRS)

    Shastry, Rohit; Patterson, Michael J.; Herman, Daniel A.; Foster, John E.

    2012-01-01

    The concept of the annular-geometry ion engine, or AGI-Engine, has been shown to have many potential benefits when scaling electric propulsion technologies to higher power. However, the necessary asymmetric location of the discharge cathode away from thruster centerline could potentially lead to non-uniformities in the discharge not present in conventional geometry ion thrusters. In an effort to characterize the degree of this potential non-uniformity, a number of current density measurements were taken on a breadboard AGI-Engine. Fourteen button probes were used to measure the ion current density of the discharge along a perforated electrode that replaced the ion optics during conditions of simulated beam extraction. Three Faraday probes spaced apart in the vertical direction were also used in a separate test to interrogate the plume of the AGI-Engine during true beam extraction. It was determined that both the discharge and the plume of the AGI-Engine are highly uniform, with variations under most conditions limited to +/-10% of the average current density in the discharge and +/-5% of the average current density in the plume. Beam flatness parameter measured 30 mm from the ion optics ranged from 0.85 - 0.95, and overall uniformity was shown to generally increase with increasing discharge and beam currents. These measurements indicate that the plasma is highly uniform despite the asymmetric location of the discharge cathode.

  4. Asymmetrical distribution of ion channels in canine and human left-ventricular wall: epicardium versus midmyocardium.

    PubMed

    Szabó, Gergely; Szentandrássy, Norbert; Bíró, Tamás; Tóth, Balázs I; Czifra, Gabriella; Magyar, János; Bányász, Tamás; Varró, András; Kovács, László; Nánási, Péter P

    2005-08-01

    The aim of the present study was to compare the distribution of ion currents and the major underlying ion channel proteins in canine and human subepicardial (EPI) and midmyocardial (MID) left-ventricular muscle. Ion currents and action potentials were recorded from canine cardiomyocytes derived from the very superficial EPI and central MID regions of the left ventricle. Amplitude, duration and the maximum velocity of depolarization of the action potential were significantly greater in MID than EPI myocytes, whereas phase-1 repolarization was more pronounced in the EPI cells. Amplitudes of the transient outwards K+ current (29.5+/-1.5 vs. 19.0+/-2.3 pA/pF at +50 mV) and the slow component of the delayed rectifier K+ current (10.3+/-2.3 vs. 6.5+/-1.0 pA/pF at +50 mV) were significantly larger in EPI than in MID myocytes under whole-cell voltage-clamp conditions. The densities of the inwards rectifier K+ current, rapid delayed rectifier K+ current and L-type Ca2+ current were similar in both cell types. Expression of channel proteins in both canine and human ventricular myocardium was determined by Western blotting. In the canine heart, the expression of Kv4.3, Kv1.4, KChIP2 and KvLQT1 was significantly higher, and that of Nav1.5 and MinK much lower, in EPI than in MID. No significant EPI-MID differences were observed in the expression of the other channel proteins studied (Kir2.1, alpha1C, HERG and MiRP1). Similar results were obtained in human hearts, although the HERG was more abundant in the EPI than in the MID layer. In the canine heart, the EPI-MID differences in ion current densities were proportional to differences in channel protein expression. Except for the density of HERG, the pattern of EPI-MID distribution of ion-channel proteins was identical in canine and human ventricles.

  5. Identification of the Energetic Plume Ion Escape Channel at Mars

    NASA Astrophysics Data System (ADS)

    Johnson, B. C.; Liemohn, M. W.; Fraenz, M.; Barabash, S.

    2013-12-01

    Mars lacks a global dipole magnetic field. The resulting induced magnetosphere arising from Mars' atmosphere's direct interaction with the solar wind differs significantly from that of Venus. The weak gravitational field of Mars creates scale heights so large that the exosphere extends out beyond the Induced Magnetosphere Boundary (IMB), where newly ionized exospheric oxygen is exposed to high speed shocked solar wind flow and the associated strong convective electric field (E). The weaker Interplanetary Magnetic Field (IMF) at Mars, combined with this strong electric field, should be expected to result in heavy pickup ions with gyroradii much larger than the radius of Mars. Test particle models and hybrid models have predicted that these pickup ions create an energetic plume of escaping planetary ions that may have a flux on the same order of magnitude as the flow of planetary ions down the central tail loss channel. This study presents an analysis of data from the Ion Mass Analyzer aboard European Space Agency's Mars Express (MEX) to identify the presence of this energetic ion plume. We searched through the time period when Mars Global Surveyor (MGS) was operating simultaneously with MEX, and selected hundreds of time intervals when IMF proxies from MGS show the convective electric field to be aligned with the orbit of MEX. We then examined plots of the MEX orbit during these intervals and selected times when MEX was positioned on the +E side of Mars and outside the nominal IMB. Finally, from these intervals we identified the cases in which oxygen ions were detected with energies above 2 keV. The result is a set of several direct measurements of the energetic plume.

  6. Note: High density pulsed molecular beam for cold ion chemistry

    SciTech Connect

    Kokish, M. G.; Rajagopal, V.; Marler, J. P.; Odom, B. C.

    2014-08-15

    A recent expansion of cold and ultracold molecule applications has led to renewed focus on molecular species preparation under ultrahigh vacuum conditions. Meanwhile, molecular beams have been used to study gas phase chemical reactions for decades. In this paper, we describe an apparatus that uses pulsed molecular beam technology to achieve high local gas densities, leading to faster reaction rates with cold trapped ions. We characterize the beam's spatial profile using the trapped ions themselves. This apparatus could be used for preparation of molecular species by reactions requiring excitation of trapped ion precursors to states with short lifetimes or for obtaining a high reaction rate with minimal increase of background chamber pressure.

  7. 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

  8. Ion Upflow Dependence on Ionospheric Density and Solar Photoionization

    NASA Astrophysics Data System (ADS)

    Cohen, I. J.; Lessard, M.; Varney, R. H.; Oksavik, K.; Zettergren, M. D.; Lynch, K. A.

    2015-12-01

    Wahlund et al. [1992] first categorized the upflow of ionospheric ions into two types: that driven by ion frictional heating and that caused by auroral precipitation. Motivated by rocket observations showing a variety of different ionospheric responses to precipitation, this paper explores the influence of the background ionospheric density on upflow resulting from auroral precipitation. Simulations of upflow driven by auroral precipitation were conducted using a version of the Varney et al. [2014] model driven by precipitation characterized by observations made during the 2012 Magnetosphere-Ionosphere Coupling in the Alfvén resonator (MICA) rocket mission and using a variety of different initial electron density profiles. The simulation results show that increased initial density before the onset of precipitation leads to smaller electron temperature increases, longer ionospheric heating timescales, weaker ambipolar electric fields, lower upflow speeds, longer upflow timescales, but larger upflow fluxes. The upflow flux can increase even when the ambipolar electric field strength decreases due to the larger number of ions that are accelerated. Long-term observations from the European Incoherent Scatter (EISCAT) Svalbard radar taken during the International Polar Year (IPY) support the effects seen in the simulations. This correlation between ionospheric density and ion upflows emphasizes the important role of photoionization from solar ultraviolet radiation, which the EISCAT observations show can increase ionospheric density by as much as an order of magnitude during the summer months.

  9. Pipeline for the identification and classification of ion channels in parasitic flatworms.

    PubMed

    Nor, Bahiyah; Young, Neil D; Korhonen, Pasi K; Hall, Ross S; Tan, Patrick; Lonie, Andrew; Gasser, Robin B

    2016-03-16

    Ion channels are well characterised in model organisms, principally because of the availability of functional genomic tools and datasets for these species. This contrasts the situation, for example, for parasites of humans and animals, whose genomic and biological uniqueness means that many genes and their products cannot be annotated. As ion channels are recognised as important drug targets in mammals, the accurate identification and classification of parasite channels could provide major prospects for defining unique targets for designing novel and specific anti-parasite therapies. Here, we established a reliable bioinformatic pipeline for the identification and classification of ion channels encoded in the genome of the cancer-causing liver fluke Opisthorchis viverrini, and extended its application to related flatworms affecting humans. We built an ion channel identification + classification pipeline (called MuSICC), employing an optimised support vector machine (SVM) model and using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) classification system. Ion channel proteins were first identified and grouped according to amino acid sequence similarity to classified ion channels and the presence and number of ion channel-like conserved and transmembrane domains. Predicted ion channels were then classified to sub-family using a SVM model, trained using ion channel features. Following an evaluation of this pipeline (MuSICC), which demonstrated a classification sensitivity of 95.2 % and accuracy of 70.5 % for known ion channels, we applied it to effectively identify and classify ion channels in selected parasitic flatworms. MuSICC provides a practical and effective tool for the identification and classification of ion channels of parasitic flatworms, and should be applicable to a broad range of organisms that are evolutionarily distant from taxa whose ion channels are functionally characterised.

  10. Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins

    PubMed Central

    Peralta, Francisco Andrés; Huidobro-Toro, Juan Pablo

    2016-01-01

    Zinc is an essential metal to life. This transition metal is a structural component of many proteins and is actively involved in the catalytic activity of cell enzymes. In either case, these zinc-containing proteins are metalloproteins. However, the amino acid residues that serve as ligands for metal coordination are not necessarily the same in structural proteins compared to enzymes. While crystals of structural proteins that bind zinc reveal a higher preference for cysteine sulfhydryls rather than histidine imidazole rings, catalytic enzymes reveal the opposite, i.e., a greater preference for the histidines over cysteines for catalysis, plus the influence of carboxylic acids. Based on this paradigm, we reviewed the putative ligands of zinc in ionotropic receptors, where zinc has been described as an allosteric modulator of channel receptors. Although these receptors do not strictly qualify as metalloproteins since they do not normally bind zinc in structural domains, they do transitorily bind zinc at allosteric sites, modifying transiently the receptor channel’s ion permeability. The present contribution summarizes current information showing that zinc allosteric modulation of receptor channels occurs by the preferential metal coordination to imidazole rings as well as to the sulfhydryl groups of cysteine in addition to the carboxyl group of acid residues, as with enzymes and catalysis. It is remarkable that most channels, either voltage-sensitive or transmitter-gated receptor channels, are susceptible to zinc modulation either as positive or negative regulators. PMID:27384555

  11. Strain tensors in layer systems by precision ion channeling measurements

    SciTech Connect

    Trinkaus, H.; Buca, D.; Hollaender, B.; Minamisawa, R. A.; Mantl, S.; Hartmann, J. M.

    2010-06-15

    A powerful method for analyzing general strain states in layer systems is the measurement of changes in the ion channeling directions. We present a systematic derivation and compilation of the required relations between the strain induced angle changes and the components of the strain tensor for general crystalline layer systems of reduced symmetry compared to the basic (cubic) crystal. It is shown that, for the evaluation of channeling measurements, virtually all layers of interest may be described as being 'pseudo-orthorhombic'. The commonly assumed boundary conditions and the effects of surface misorientations on them are discussed. Asymmetric strain relaxation in layers of reduced symmetry is attributed to a restriction in the slip system of the dislocations inducing it. The results are applied to {l_brace}110{r_brace}SiGe/Si layer systems.

  12. Acid-sensing ion channels: trafficking and pathophysiology.

    PubMed

    Zeng, Wei-Zheng; Liu, Di-Shi; Xu, Tian-Le

    2014-01-01

    Acid-sensing ion channels (ASICs) are proton-gated cation channels that are widely expressed in both the peripheral and central nervous systems. ASICs contribute to a variety of pathophysiological conditions that involve tissue acidosis, such as ischemic stroke, epileptic seizures and multiple sclerosis. Although much progress has been made in researching the structure-function relationship and pharmacology of ASICs, little is known about the trafficking of ASICs and its contribution to ASIC function. The recent identification of the mechanism of membrane insertion and endocytosis of ASIC1a highlights the emerging role of ASIC trafficking in regulating its pathophysiological functions. In this review, we summarize the recent advances and discuss future directions on this topic.

  13. Patch electrode glass composition affects ion channel currents.

    PubMed

    Furman, R E; Tanaka, J C

    1988-02-01

    The influence of patch electrode glass composition on macroscopic IV relations in inside-out patches of the cGMP-activated ion channel from rod photoreceptors was examined for a soda lime glass, a Kovar sealing glass, a borosilicate glass, and several soft lead glasses. In several glasses the shape or magnitude of the currents changed as the concentration of EGTA or EDTA was increased from 200 microM to 10 mM. The changes in IV response suggest that, at low concentrations of chelator, divalent cations are released from the electrode glass and interact with the cGMP-activated channel. Possible mechanisms are discussed to explain the observations, and several comments are made concerning the choice of a glass for patching.

  14. Copper ion-exchanged channel waveguides optimization for optical trapping.

    PubMed

    Reshak, A H; Khor, K N; Shahimin, M M; Murad, S A Z

    2013-08-01

    Optical trapping of particles has become a powerful non-mechanical and non-destructive technique for precise particle positioning. The manipulation of particles in the evanescent field of a channel waveguide potentially allows for sorting and trapping of several particles and cells simultaneously. Channel waveguide designs can be further optimized to increase evanescent field prior to the fabrication process. This is crucial in order to make sure that the surface intensity is sufficient for optical trapping. Simulation configurations are explained in detail with specific simulation flow. Discussion on parameters optimization; physical geometry, optical polarization and wavelength is included in this paper. The effect of physical, optical parameters and beam spot size on evanescent field has been thoroughly discussed. These studies will continue toward the development of a novel copper ion-exchanged waveguide as a method of particle sorting, with biological cell propulsion studies presently underway. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Acid-sensing ion channels in gastrointestinal function.

    PubMed

    Holzer, Peter

    2015-07-01

    Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  16. Electrical injury alters ion channel expression levels and electrophysiological properties in rabbit dorsal root ganglia neurons.

    PubMed

    Chen, Rui; Li, Yue-Jun; Li, Jin-Qing; Lv, Xiao-Xing; Chen, Shao-Zong; Li, Wang-Zhou; Feng, Jian; Li, Xue-Yong

    2011-03-01

    The electrophysiological and morphological changes of nerve fibers induced by electrical injury have been widely addressed. However, the changes of ion channels in neurons after electrical shocks have not been systematically investigated yet. In this study, the sciatic nerves of rabbit were injured by 50 V 50 Hz, 110 V 50 Hz, and 220 V 50 Hz alternating current, respectively. One week later, the expression levels and electrophysiological changes of voltage-gated potassium (Kv) and sodium (Nav) channels in dorsal root ganglia (DRG) neurons were evaluated by RT-PCR, immunofluorescence staining and patch clamp technique. The Nav1.1 expression was decreased by 50V injury. The Kv1.2, Kv1.4, Nav1.1 and Nav1.7 expression levels and Kv current densities were reduced after 110 V injury. Under the 220 V injury circumstance, Kv1.2, Nav1.1, Nav1.7 expression levels, Kv current densities and TTX-R Na(+) current densities were significantly decreased, while TTX-S Na(+) current densities increased. These findings suggest that the expression levels, subunit compositions, and electrophysiological properties of Kv and Nav channels are altered after electrical injury, and the severity of injury gets worse as injury voltage increases. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

  17. Transition from heating to cooling of channeled ion beams

    SciTech Connect

    Toepffer, Christian

    2006-06-15

    Experiments showing a transverse heating or cooling of channeled ion beams are explained in terms of electron capture and loss processes between the projectile ions and the target. Such processes violate reversibility as the projectile captures electrons from occupied bound states and loses them to unoccupied weakly bound or continuum states. The transition probabilities for the transfer of electrons are calculated in the impact parameter Born approximation. Their dependence on the distance from the crystal strings is determined by scale factors which depend in turn on the relative velocity and the binding energies of the transferred electrons in the projectile and in the crystal, respectively. The appearance of transverse heating and cooling depends on the relative size of the scale factors for capture and loss. The transition from heating to cooling as function of velocity is described in good agreement with the experiments.

  18. Parameterization of ion channeling half-angles and minimum yields

    NASA Astrophysics Data System (ADS)

    Doyle, Barney L.

    2016-03-01

    A MS Excel program has been written that calculates ion channeling half-angles and minimum yields in cubic bcc, fcc and diamond lattice crystals. All of the tables and graphs in the three Ion Beam Analysis Handbooks that previously had to be manually looked up and read from were programed into Excel in handy lookup tables, or parameterized, for the case of the graphs, using rather simple exponential functions with different power functions of the arguments. The program then offers an extremely convenient way to calculate axial and planar half-angles, minimum yields, effects on half-angles and minimum yields of amorphous overlayers. The program can calculate these half-angles and minimum yields for axes and [h k l] planes up to (5 5 5). The program is open source and available at

  19. Noise analysis of an ion channel in the cardiac myocyte--study based on a Markov model.

    PubMed

    Sato, Shunsuke

    2007-06-01

    Mechanical contraction of a cardiac muscle cell is related to the electric activation of the plasma membrane. As in the neuron cell, inflow of the Na(+) ions across the cell membrane causes electric activation with amplitude of about 100 mV. However, differently from the nerve cell, the action potential lasts a few hundred milliseconds before repolarization. Moreover, several types of K(+) channel such as the classical inward rectifier K(+) channel, the voltage dependent channel and others are responsible for the formation of the action potential. The mechanism of opening and closing the K(+) channels is not thoroughly elucidated. In the present paper, a four state Markov model with one open and three closed states is studied to obtain open and close probabilities of the gates constituting a specific ionic channel. The probability density functions of durations of opening and closing of the channel are also discussed.

  20. Signal transduction and ion channels in guard cells.

    PubMed Central

    MacRobbie, E A

    1998-01-01

    Our understanding of the signalling mechanisms involved in the process of stomatal closure is reviewed. Work has concentrated on the mechanisms by which abscisic acid (ABA) induces changes in specific ion channels at both the plasmalemma and the tonoplast, leading to efflux of both K+ and anions at both membranes, requiring four essential changes. For each we need to identify the specific channels concerned, and the detailed signalling chains by which each is linked through signalling intermediates to ABA. There are two global changes that are identified following ABA treatment: an increase in cytoplasmic pH and an increase in cytoplasmic Ca2+, although stomata can close without any measurable global increase in cytoplasmic Ca2+. There is also evidence for the importance of several protein phosphatases and protein kinases in the regulation of channel activity. At the plasmalemma, loss of K+ requires depolarization of the membrane potential into the range at which the outward K+ channel is open. ABA-induced activation of a non-specific cation channel, permeable to Ca2+, may contribute to the necessary depolarization, together with ABA-induced activation of S-type anion channels in the plasmalemma, which are then responsible for the necessary anion efflux. The anion channels are activated by Ca2+ and by phosphorylation, but the precise mechanism of their activation by ABA is not yet clear. ABA also up-regulates the outward K+ current at any given membrane potential; this activation is Ca(2+)-independent and is attributed to the increase in cytoplasmic pH, perhaps through the marked pH-sensitivity of protein phosphatase type 2C. Our understanding of mechanisms at the tonoplast is much less complete. A total of two channels, both Ca(2+)-activated, have been identified which are capable of K+ efflux; these are the voltage-independent VK channel specific to K+, and the slow vacuolar (SV) channel which opens only at non-physiological tonoplast potentials (cytoplasm

  1. What Ion Flow along Ion Channels Can Tell us about Their Functional Activity

    PubMed Central

    Becucci, Lucia; Guidelli, Rolando

    2016-01-01

    The functional activity of channel-forming peptides and proteins is most directly verified by monitoring the flow of physiologically relevant inorganic ions, such as Na+, K+ and Cl−, along the ion channels. Electrical current measurements across bilayer lipid membranes (BLMs) interposed between two aqueous solutions have been widely employed to this end and are still extensively used. However, a major drawback of BLMs is their fragility, high sensitivity toward vibrations and mechanical shocks, and low resistance to electric fields. To overcome this problem, metal-supported tethered BLMs (tBLMs) have been devised, where the BLM is anchored to the metal via a hydrophilic spacer that replaces and mimics the water phase on the metal side. However, only mercury-supported tBLMs can measure and regulate the flow of the above inorganic ions, thanks to mercury liquid state and high hydrogen overpotential. This review summarizes the main results achieved by BLMs incorporating voltage-gated channel-forming peptides, interpreting them on the basis of a kinetic mechanism of nucleation and growth. Hg-supported tBLMs are then described, and their potential for the investigation of voltage-gated and ohmic channels is illustrated by the use of different electrochemical techniques. PMID:27983579

  2. 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.

  3. 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

  4. Light-controlled ion channels formed by amphiphilic small molecules regulate ion conduction via cis-trans photoisomerization.

    PubMed

    Liu, Tao; Bao, Chunyan; Wang, Haiyan; Lin, Yao; Jia, Huijuan; Zhu, Linyong

    2013-11-11

    Light-regulated ion channel-transport across lipid bilayers was realized using structurally simple azobenzene-based amphiphilic small molecules. UV or visible irradiation triggers molecular photoisomerization, which induces structural and membrane affinity changes in self-assembled channels, thus resulting in light-regulated ion transmembrane transport.

  5. Controlled fabrication of ion track nanowires and channels

    NASA Astrophysics Data System (ADS)

    Spohr, Reimar; Zet, Cristian; Eberhard Fischer, Bernd; Kiesewetter, Helge; Apel, Pavel; Gunko, Igor; Ohgai, Takeshi; Westerberg, Lars

    2010-03-01

    We describe a system for fabricating prescribed numbers of ion track nanochannels and nanowires from a few hundred down to one. It consists of two parts: first, a mobile tape transport system, which, in connection with an ion beam from a heavy-ion accelerator (nuclear charge Z above 18 and specific energy between 1 and 10 MeV/nucleon) tuned down to low flux density by means of defocusing and a set of sensitive fluorescence screens, can fabricate a series of equidistant irradiation spots on a tape, whereby each spot corresponds to a preset number of ion tracks. The tape transport system uses films of 36 mm width and thicknesses between 5 and 100 μm. The aiming precision of the system depends on the diameter of the installed beam-defining aperture, which is between 50 and 500 μm. The distance between neighboring irradiation spots on the tape is variable and typically set to 25 mm. After reaching the preset number of ion counts the irradiation is terminated, the tape is marked and moved to the next position. The irradiated frames are punched out to circular membranes with the irradiation spot in the center. The second part of the setup is a compact conductometric system with 10 picoampere resolution consisting of a computer controlled conductometric cell, sealing the membrane hermetically between two chemically inert half-chambers containing electrodes and filling/flushing openings, and is encased by an electrical shield and a thermal insulation. The ion tracks can be etched to a preset diameter and the system can be programmed to electroreplicate nanochannels in a prescribed sequence of magnetic/nonmagnetic metals, alloys or semiconductors. The goal of our article is to make the scientific community aware of the special features of single-ion fabrication and to demonstrate convincingly the significance of controlled etching and electro-replication.

  6. Target current density effects in al-cluster ion emission

    NASA Astrophysics Data System (ADS)

    Ray, N.; Rajasekar, P.; Chakraborty, P.; Dey, S. D.

    1994-04-01

    Target current density effects in secondary emission of positively-charged sputtered clusters from an ion-bombarded polycrystalline aluminium surface have been investigated for various primary Cd+ ion energies. For each cluster type, at medium target current densities (Jp : 0?350 ?A/cm2), apart from the presence of the expected linear term in the I+ s α Jp curves, there is a square law term, depicting that some fraction of the pre-emitted neutral clusters gets ionized in vacuum above the target surface. Thus, a sum of these two terms constitutes the total cluster ion current which shows a non-linear dependence on the target current density. At higher target current densities (350 ?A cm?2?1.05 mA cm?2), in addition to the parabolic effect, a higher order non-linearity comes into play and the net cluster ion current I + s , measured as a function of target current density within the Ip range concerned, can be expressed in terms of our previously proposed semi-empirical formula I+ s = C.Ip + D.I2 p + F.In p , which was earlier found to be applicable in case of single and double charged secondary monomers. A higher power (n > 2) dependence has been observed here for the first time in case of cluster ion emission, suggesting chemical enhancement of secondary clusters. Our present observations seem to support ?direct emission model? even for small metal clusters?a proposition which is in apparent contradiction to the current notion in this field, i.e. vacuum recombination of individual atoms in small cluster formation.

  7. Interaction of a polar molecule with an ion channel

    SciTech Connect

    Levadny, V.; Aguilella, V.M.; Aguilella-Arzo, M.; Belaya, M.

    2004-10-01

    The binding of a polar macromolecule to a large ion channel is studied theoretically, paying special attention to the influence of external conditions (applied voltage and ion strength of solution). The molecule behavior in bound state is considered as random thermal fluctuations within a limited fraction of its phase space. The mean duration of molecule binding (residence time {tau}{sub r}) is represented as the mean first passage time to reach the boundary of that restricted domain. By invoking the adiabatic approximation we reduce the problem to one dimension with the angle between macromolecule dipole and channel axes being the key variable of the problem. The model accounts for experimental measurements of {tau}{sub r} for the antibiotic Ampicillin within the bacterial porin OmpF of Escherichia coli. By assuming that the electrical interaction between Ampicillin dipole and OmpF ionizable groups affects the fluctuations, we find that the biased residence time-voltage dependence observed in experiments is the result of the strong transversal electric field in OmpF constriction with a tilt {approx}30 deg. aside the cis side.

  8. Ion channels induced by the prion protein: mediators of neurotoxicity.

    PubMed

    Solomon, Isaac H; Biasini, Emiliano; Harris, David A

    2012-01-01

    Prion diseases comprise a group of rapidly progressive and invariably fatal neurodegenerative disorders for which there are no effective treatments. While conversion of the cellular prion protein (PrP(C)) to a β-sheet rich isoform (PrP(Sc) ) is known to be a critical event in propagation of infectious prions, the identity of the neurotoxic form of PrP and its mechanism of action remain unclear. Insights into this mechanism have been provided by studying PrP molecules harboring deletions and point mutations in the conserved central region, encompassing residues 105-125. When expressed in transgenic mice, PrP deleted for these residues (Δ105-125) causes a spontaneous neurodegenerative illness that is reversed by co-expression of wild-type PrP. In cultured cells, Δ105-125 PrP confers hypersensitivity to certain cationic antibiotics and induces spontaneous ion channel activity that can be recorded by electrophysiological techniques. We have utilized these drug-hypersensitization and current-inducing activities to identify which PrP domains and subcellular locations are required for toxicity. We present an ion channel model for the toxicity of Δ105-125 PrP and related mutants and speculate how a similar mechanism could mediate PrP(Sc)-associated toxicity. Therapeutic regimens designed to inhibit prion-induced toxicity, as well as formation of PrP(Sc) , may prove to be the most clinically beneficial.

  9. Computational studies of transport in ion channels using metadynamics.

    PubMed

    Furini, Simone; Domene, Carmen

    2016-07-01

    Molecular dynamics simulations have played a fundamental role in numerous fields of science by providing insights into the structure and dynamics of complex systems at the atomistic level. However, exhaustive sampling by standard molecular dynamics is in most cases computationally prohibitive, and the time scales accessible remain significantly shorter than many biological processes of interest. In particular, in the study of ion channels, realistic models to describe permeation and gating require accounting for large numbers of particles and accurate interaction potentials, which severely limits the length of the simulations. To overcome such limitations, several advanced methods have been proposed among which is metadynamics. In this algorithm, an external bias potential to accelerate sampling along selected collective variables is introduced. This bias potential discourages visiting regions of the configurational space already explored. In addition, the bias potential provides an estimate of the free energy as a function of the collective variables chosen once the simulation has converged. In this review, recent contributions of metadynamics to the field of ion channels are discussed, including how metadynamics has been used to search for transition states, predict permeation pathways, treat conformational flexibility that underlies the coupling between gating and permeation, or compute free energy of permeation profiles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

  10. Interaction of a polar molecule with an ion channel

    NASA Astrophysics Data System (ADS)

    Levadny, V.; Aguilella, V. M.; Aguilella-Arzo, M.; Belaya, M.

    2004-10-01

    The binding of a polar macromolecule to a large ion channel is studied theoretically, paying special attention to the influence of external conditions (applied voltage and ion strength of solution). The molecule behavior in bound state is considered as random thermal fluctuations within a limited fraction of its phase space. The mean duration of molecule binding (residence time τr ) is represented as the mean first passage time to reach the boundary of that restricted domain. By invoking the adiabatic approximation we reduce the problem to one dimension with the angle between macromolecule dipole and channel axes being the key variable of the problem. The model accounts for experimental measurements of τr for the antibiotic Ampicillin within the bacterial porin OmpF of Escherichia coli. By assuming that the electrical interaction between Ampicillin dipole and OmpF ionizable groups affects the fluctuations, we find that the biased residence time-voltage dependence observed in experiments is the result of the strong transversal electric field in OmpF constriction with a tilt ˜30° aside the cis side.

  11. Stoichiometry for drug potentiation of a pentameric ion channel

    PubMed Central

    daCosta, Corrie J. B.; Sine, Steven M.

    2013-01-01

    Drug modulation of ion channels is a powerful means to alter physiological responses for therapeutic benefit, yet the structural bases of modulation remain poorly understood. Here we study potentiation of nicotinic α7 acetylcholine receptors, which are emerging drug targets in several neurological disorders. α7 receptors are ligand-gated ion channels composed of five identical subunits, each bearing a site for the potentiating drug PNU-120596 (PNU). How the individual subunits contribute to PNU potentiation is not known. Taking advantage of a PNU-resistant mutant, we generated receptors composed of normal and PNU-resistant subunits and tagged one of the subunits with conductance mutations to report subunit stoichiometry. We then used patch clamp recording to monitor PNU potentiation of single α7 receptors with defined stoichiometry in real time. We find that potentiation depends steeply on the number of PNU-resistant subunits and that four, and possibly five, subunits must be sensitive to PNU for potentiation to occur. Thus, by monitoring the activity of every possible subunit combination, our findings predict that at the macroscopic level, PNU potentiation is highly cooperative. PMID:23576748

  12. Glutamate Receptor Ion Channels: Structure, Regulation, and Function

    PubMed Central

    Wollmuth, Lonnie P.; McBain, Chris J.; Menniti, Frank S.; Vance, Katie M.; Ogden, Kevin K.; Hansen, Kasper B.; Yuan, Hongjie; Myers, Scott J.; Dingledine, Ray

    2010-01-01

    The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors. PMID:20716669

  13. Emerging models of glutamate receptor ion channel structure and function.

    PubMed

    Mayer, Mark L

    2011-10-12

    Excitatory synaptic transmission in the brain is mediated by ligand-gated ion channels (iGluRs) activated by glutamate. Distinct from other neurotransmitter receptors, the extracellular domains of iGluRs are loosely packed assemblies with two clearly distinct layers, each of which has both local and global 2-fold axes of symmetry. By contrast, the iGluR transmembrane segments have 4-fold symmetry and share a conserved pore loop architecture found in tetrameric voltage-gated ion channels. The striking layered architecture of iGluRs revealed by the 3.6 Å resolution structure of an AMPA receptor homotetramer likely arose from gene fusion events that occurred early in evolution. Although this modular design has greatly facilitated biophysical and structural studies on individual iGluR domains, and suggested conserved mechanisms for iGluR gating, recent work is beginning to reveal unanticipated diversity in the structure, allosteric regulation, and assembly of iGluR subtypes.

  14. Acid-Sensing Ion Channels in Gastrointestinal Function

    PubMed Central

    Holzer, Peter

    2015-01-01

    Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders. PMID:25582294

  15. A role for ion channels in perivascular glioma invasion

    PubMed Central

    Thompson, Emily G.

    2017-01-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuro-peptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials. PMID:27424110

  16. Coarse Architecture of the Transient Receptor Potential Vanilloid 1 (TRPV1) Ion Channel Determined by Fluorescence Resonance Energy Transfer*

    PubMed Central

    De-la-Rosa, Víctor; Rangel-Yescas, Gisela E.; Ladrón-de-Guevara, Ernesto; Rosenbaum, Tamara; Islas, León D.

    2013-01-01

    The transient receptor potential vanilloid 1 ion channel is responsible for the perception of high temperatures and low extracellular pH, and it is also involved in the response to some pungent compounds. Importantly, it is also associated with the perception of pain and noxious stimuli. Here, we attempt to discern the molecular organization and location of the N and C termini of the transient receptor potential vanilloid 1 ion channel by measuring FRET between genetically attached enhanced yellow and cyan fluorescent protein to the N or C terminus of the channel protein, expressed in transfected HEK 293 cells or Xenopus laevis oocytes. The static measurements of the domain organization were mapped into an available cryo-electron microscopy density of the channel with good agreement. These measurements also provide novel insights into the organization of terminal domains and their proximity to the plasma membrane. PMID:23965996

  17. Ultralow energy ion beam surface modification of low density polyethylene.

    PubMed

    Shenton, Martyn J; Bradley, James W; van den Berg, Jaap A; Armour, David G; Stevens, Gary C

    2005-12-01

    Ultralow energy Ar+ and O+ ion beam irradiation of low density polyethylene has been carried out under controlled dose and monoenergetic conditions. XPS of Ar+-treated surfaces exposed to ambient atmosphere show that the bombardment of 50 eV Ar+ ions at a total dose of 10(16) cm(-2) gives rise to very reactive surfaces with oxygen incorporation at about 50% of the species present in the upper surface layer. Using pure O+ beam irradiation, comparatively low O incorporation is achieved without exposure to atmosphere (approximately 13% O in the upper surface). However, if the surface is activated by Ar+ pretreatment, then large oxygen contents can be achieved under subsequent O+ irradiation (up to 48% O). The results show that for very low energy (20 eV) oxygen ions there is a dose threshold of about 5 x 10(15) cm(-2) before surface oxygen incorporation is observed. It appears that, for both Ar+ and O+ ions in this regime, the degree of surface modification is only very weakly dependent on the ion energy. The results suggest that in the nonequilibrium plasma treatment of polymers, where the ion flux is typically 10(18) m(-2) s(-1), low energy ions (<50 eV) may be responsible for surface chemical modification.

  18. Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury

    PubMed Central

    Radulovic, Miroslav; Anand, Preeti; Korsten, Mark A; Gong, Bing

    2015-01-01

    Gastrointestinal (GI) dysmotility is a severe, and common complication in patients with spinal cord injury (SCI). Current therapeutic methods using acetylcholine analogs or laxative agents have unwanted side effects, besides often fail to have desired effect. Various ion channels such as ATP-sensitive potassium (KATP) channel, calcium ions (Ca2+)-activated potassium ions (K+) channels, voltage-sensitive Ca2+ channels and chloride ion (Cl−) channels are abundantly expressed in GI tissues, and play an important role in regulating GI motility. The release of neurotransmitters from the enteric nerve terminal, innervating GI interstitial cells of Cajal (ICC), and smooth muscle cells (SMC), causes inactivation of K+ and Cl− channels, increasing Ca2+ influx into cytoplasm, resulting in membrane depolarization and smooth muscle contraction. Thus, agents directly regulating ion channels activity either in ICC or in SMC may affect GI peristalsis and would be potential therapeutic target for the treatment of GI dysmotility with SCI. PMID:26424038

  19. Computational Tools for Interpreting Ion Channel pH-Dependence.

    PubMed

    Sazanavets, Ivan; Warwicker, Jim

    2015-01-01

    Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) - Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone.

  20. Computational Tools for Interpreting Ion Channel pH-Dependence

    PubMed Central

    Sazanavets, Ivan; Warwicker, Jim

    2015-01-01

    Activity in many biological systems is mediated by pH, involving proton titratable groups with pKas in the relevant pH range. Experimental analysis of pH-dependence in proteins focusses on particular sidechains, often with mutagenesis of histidine, due to its pKa near to neutral pH. The key question for algorithms that predict pKas is whether they are sufficiently accurate to effectively narrow the search for molecular determinants of pH-dependence. Through analysis of inwardly rectifying potassium (Kir) channels and acid-sensing ion channels (ASICs), mutational effects on pH-dependence are probed, distinguishing between groups described as pH-coupled or pH-sensor. Whereas mutation can lead to a shift in transition pH between open and closed forms for either type of group, only for pH-sensor groups does mutation modulate the amplitude of the transition. It is shown that a hybrid Finite Difference Poisson-Boltzmann (FDPB) – Debye-Hückel continuum electrostatic model can filter mutation candidates, providing enrichment for key pH-coupled and pH-sensor residues in both ASICs and Kir channels, in comparison with application of FDPB alone. PMID:25915903

  1. Receptor for protons: First observations on Acid Sensing Ion Channels.

    PubMed

    Krishtal, Oleg

    2015-07-01

    The history of ASICs began in 1980 with unexpected observation. The concept of highly selective Na(+) current gated by specific receptors for protons was not easily accepted. It took 16 years to get these receptor/channels cloned and start a new stage in their investigation. "The receptor for protons" became ASIC comprising under this name a family of receptor/channels ubiquitous for mammalian nervous system, both peripheral and central. The role of ASICs as putative nociceptors was suggested almost immediately after their discovery. This role subsequently was proven in many forms of pain-related phenomena. Many other functions of ASICs have been also found or primed for speculations both in physiology and in disease. Despite the width of field and strength of efforts, numerous basic questions are to be answered before we understand how the local changes in pH in the nervous tissue transform into electric and messenger signaling via ASICs as transducers. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'. Copyright © 2015. Published by Elsevier Ltd.

  2. Viral dependence on cellular ion channels - an emerging anti-viral target?

    PubMed

    Hover, Samantha; Foster, Becky; Barr, John; Mankouri, Jamel

    2017-01-22

    The broad range of cellular functions governed by ion channels represents an attractive target for viral manipulation. Indeed, modulation of host cell ion channel activity by viral proteins is being increasingly identified as an important virus-host interaction. Recent examples have demonstrated that virion entry, virus-egress and the maintenance of a cellular environment conducive to virus persistence are in part, dependent on virus manipulation of ion channel activity. Most excitingly, evidence has emerged that targeting ion channels pharmacologically can impede virus lifecycles. Here we discuss current examples of virus-ion channel interactions and the potential of targeting ion channel function as a new, pharmacologically safe and broad ranging anti-viral therapeutic strategy.

  3. Mapping the function of neuronal ion channels in model and experiment

    PubMed Central

    Podlaski, William F; Seeholzer, Alexander; Groschner, Lukas N; Miesenböck, Gero; Ranjan, Rajnish; Vogels, Tim P

    2017-01-01

    Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretation of simulations. However, the number of published models, and the lack of standardization, make the comparison of ion channel models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy (ICGenealogy) web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling. DOI: http://dx.doi.org/10.7554/eLife.22152.001 PMID:28267430

  4. Ankyrin-based Cellular Pathways for Cardiac Ion Channel and Transporter Targeting and Regulation

    PubMed Central

    Cunha, Shane R.; Mohler, Peter J.

    2010-01-01

    The coordinate activities of ion channels and transporters regulate myocyte membrane excitability and normal cardiac function. Dysfunction in cardiac ion channel and transporter function may result in cardiac arrhythmias and sudden cardiac death. While the past fifteen years have linked defects in ion channel biophysical properties with human disease, more recent findings illustrate that ion channel and transporter localization within cardiomyocytes is equally critical for normal membrane excitability and tissue function. Ankyrins are a family of multifunctional adapter proteins required for the expression, membrane localization, and regulation of select cardiac ion channels and transporters. Notably, loss of ankyrin expression in mice, and ankyrin loss-of-function in humans is now associated with defects in myocyte excitability and cardiac physiology. Here, we provide an overview of the roles of ankyrin polypeptides in cardiac physiology, as well as review other recently identified pathways required for the membrane expression and regulation of key cardiac ion channels and transporters. PMID:20934528

  5. Mapping the function of neuronal ion channels in model and experiment.

    PubMed

    Podlaski, William F; Seeholzer, Alexander; Groschner, Lukas N; Miesenböck, Gero; Ranjan, Rajnish; Vogels, Tim P

    2017-03-06

    Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretation of simulations. However, the number of published models, and the lack of standardization, make the comparison of ion channel models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy (ICGenealogy) web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling.

  6. Voyager observations of Saturnian ion and electron phase space densities

    SciTech Connect

    Armstrong, T.P.; Paonessa, M.T.; Bell, E.V. II; Krimigis, S.M.

    1983-11-01

    Voyager 1 and 2 low-energy charged particle (LECP) observations of 30-keV to 2-MeV electron and ion energy spectra and angular distributions have been used to calculate phase space densities at constant first and second adiabatic invariant in the Saturnian magnetosphere. The results are generally consistent with inward radial diffusion from a external source. The data obtained also indicate a source of ions located within the orbital distance of enceladus capable of producing 10-to 40-MeV/Gauss ions as well as a source of electrons at about 3.5 R/sub S/ which produces particles at 100 to 200 MeV/Gauss. Higher magnetic moment (200--400 MeV/Gauss) ions extend from the sunward boundary between a plasma mantle and the region of durable trapping at R/sub S/: the behavior of the phase space density suggests inward diffusion of these particles from a source at the boundary. The identification of sources of low (10 to 200 MeV/Gauss) magnetic moment particles deep in the Saturnian magnetosphere is a new result of this work. Several analyses of the observed phase space densities in terms of time-independent radial diffusion are presented.

  7. Ion energy distributions and densities in the plume of Enceladus

    NASA Astrophysics Data System (ADS)

    Sakai, Shotaro; Cravens, Thomas E.; Omidi, Nojan; Perry, Mark E.; Waite, J. Hunter

    2016-10-01

    Enceladus has a dynamic plume that is emitting gas, including water vapor, and dust. The gas is ionized by solar EUV radiation, charge exchange, and electron impact and extends throughout the inner magnetosphere of Saturn. The charge exchange collisions alter the plasma composition. Ice grains (dust) escape from the vicinity of Enceladus and form the E ring, including a portion that is negatively charged by the local plasma. The inner magnetosphere within 10 RS (Saturn radii) contains a complex mixture of plasma, neutral gas, and dust that links back to Enceladus. In this paper we investigate the energy distributions, ion species and densities of water group ions in the plume of Enceladus using test particle and Monte Carlo methods that include collisional processes such as charge exchange and ion-neutral chemical reactions. Ion observations from the Cassini Ion and Neutral Mass Spectrometer (INMS) for E07 are presented for the first time. We use the modeling results to interpret observations made by the Cassini Plasma Spectrometer (CAPS) and the INMS. The low energy ions, as observed by CAPS, appear to be affected by a vertical electric field (EZ=-10 μV/m) in the plume. The EZ field may be associated with the charged dust and/or the pressure gradient of plasma. The model results, along with the results of earlier models, show that H3O+ ions created by chemistry are predominant in the plume, which agrees with INMS and CAPS data, but the INMS count rate in the plume for the model is several times greater than the data, which we do not fully understand. This composition and the total ion count found in the plume agree with INMS and CAPS data. On the other hand, the Cassini Langmuir Probe measured a maximum plume ion density more than 30,000 cm-3, which is far larger than the maximum ion density from our model, 900 cm-3. The model results also demonstrate that most of the ions in the plume are from the external magnetospheric flow and are not generated by local

  8. Highly Compressed Ion Beam for High Energy Density Science

    SciTech Connect

    Friedman, A.; Barnard, J.J.; Briggs, R.J.; Callahan, D.A.; Caporaso, G.J.; Celata, C.M.; Davidson, R.C.; Faltens, A.; Grisham, L.; Grote, D.P.; Henestroza, E.; Kaganovich I.; Lee, E.P.; Lee, R.W.; Leitner, M.; Logan, B.G.; Nelson, S.D.; Olson, C.L.; Penn, G.; Reginato,L.R.; Renk, T.; Rose, D.; Seessler, A.; Staples, J.W.; Tabak, M.; Thoma,C.; Waldron, W.; Welch, D.R.; Wurtele, J.; Yu, S.S.

    2005-05-16

    The Heavy Ion Fusion Virtual National Laboratory is developing the intense ion beams needed to drive matter to the High Energy Density regimes required for Inertial Fusion Energy and other applications. An interim goal is a facility for Warm Dense Matter studies, wherein a target is heated volumetrically without being shocked, so that well-defined states of matter at 1 to 10 eV are generated within a diagnosable region. In the approach they are pursuing, low to medium mass ions with energies just above the Bragg peak are directed onto thin target ''foils,'' which may in fact be foams with mean densities 1% to 10% of solid. This approach complements that being pursued at GSI Darmstadt, wherein high-energy ion beams deposit a small fraction of their energy in a cylindrically target. They present the beam requirements for Warm Dense Matter experiments. The authors discuss neutralized drift compression and final focus experiments and modeling. They describe suitable accelerator architectures based on Drift-Tube Linac, RF, single-gap, Ionization-Front Accelerator, and Pulse-Line Ion Accelerator concepts. The last of these is being pursued experimentally. Finally, they discuss plans toward a user facility for target experiments.

  9. Asymmetric ion transport through ion-channel-mimetic solid-state nanopores.

    PubMed

    Guo, Wei; Tian, Ye; Jiang, Lei

    2013-12-17

    Both scientists and engineers are interested in the design and fabrication of synthetic nanofluidic architectures that mimic the gating functions of biological ion channels. The effort to build such structures requires interdisciplinary efforts at the intersection of chemistry, materials science, and nanotechnology. Biological ion channels and synthetic nanofluidic devices have some structural and chemical similarities, and therefore, they share some common features in regulating the traverse ionic flow. In the past decade, researchers have identified two asymmetric ion transport phenomena in synthetic nanofluidic structures, the rectified ionic current and the net diffusion current. The rectified ionic current is a diode-like current-voltage response that occurs when switching the voltage bias. This phenomenon indicates a preferential direction of transport in the nanofluidic system. The net diffusion current occurs as a direct product of charge selectivity and is generated from the asymmetric diffusion through charged nanofluidic channels. These new ion transport phenomena and the elaborate structures that occur in biology have inspired us to build functional nanofluidic devices for both fundamental research and practical applications. In this Account, we review our recent progress in the design and fabrication of biomimetic solid-state nanofluidic devices with asymmetric ion transport behavior. We demonstrate the origin of the rectified ionic current and the net diffusion current. We also identify several influential factors and discuss how to build these asymmetric features into nanofluidic systems by controlling (1) nanopore geometry, (2) surface charge distribution, (3) chemical composition, (4) channel wall wettability, (5) environmental pH, (6) electrolyte concentration gradient, and (7) ion mobility. In the case of the first four features, we build these asymmetric features directly into the nanofluidic structures. With the final three, we construct

  10. The Monte-Carlo Simulation of the Permeability of K Ion Channels

    NASA Astrophysics Data System (ADS)

    An, Hai-Long; Zhan, Yong; Liu, Jin-Wei; Zhang, Su-Hua; Zhao, Tong-Jun

    In this paper, by introducing the collision model of the K ion channel, the maximum value of ions inward the channel per second, the average velocity of ions in the channels and the average time of every ion passing through the channel are obtained. Moreover they are reconciled with the experimental data. Base on the experimental data, the empiristic potential function is deduced. With the Monte-Carlo simulation, the curve of average velocity versus time and average displacement versus time are calculated by resolving the over-damping Langevin equation with Gaussian-white noise. They are according with the experimental dada well.

  11. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy

    PubMed Central

    Pollak, Julia; Rai, Karan G.; Funk, Cory C.; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D.; Paddison, Patrick J.; Ramirez, Jan-Marino; Rostomily, Robert C.

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance. PMID:28264064

  12. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    PubMed

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  13. ModFossa: A library for modeling ion channels using Python.

    PubMed

    Ferneyhough, Gareth B; Thibealut, Corey M; Dascalu, Sergiu M; Harris, Frederick C

    2016-06-01

    The creation and simulation of ion channel models using continuous-time Markov processes is a powerful and well-used tool in the field of electrophysiology and ion channel research. While several software packages exist for the purpose of ion channel modeling, most are GUI based, and none are available as a Python library. In an attempt to provide an easy-to-use, yet powerful Markov model-based ion channel simulator, we have developed ModFossa, a Python library supporting easy model creation and stimulus definition, complete with a fast numerical solver, and attractive vector graphics plotting.

  14. The distribution and targeting of neuronal voltage-gated ion channels.

    PubMed

    Lai, Helen C; Jan, Lily Y

    2006-07-01

    Voltage-gated ion channels have to be at the right place in the right number to endow individual neurons with their specific character. Their biophysical properties together with their spatial distribution define the signalling characteristics of a neuron. Improper channel localization could cause communication defects in a neuronal network. This review covers recent studies of mechanisms for targeting voltage-gated ion channels to axons and dendrites, including trafficking, retention and endocytosis pathways for the preferential localization of particular ion channels. We also discuss how the spatial localization of these channels might contribute to the electrical excitability of neurons, and consider the need for future work in this emerging field.

  15. A New Poisson-Nernst-Planck Model with Ion-Water Interactions for Charge Transport in Ion Channels.

    PubMed

    Chen, Duan

    2016-08-01

    In this work, we propose a new Poisson-Nernst-Planck (PNP) model with ion-water interactions for biological charge transport in ion channels. Due to narrow geometries of these membrane proteins, ion-water interaction is critical for both dielectric property of water molecules in channel pore and transport dynamics of mobile ions. We model the ion-water interaction energy based on realistic experimental observations in an efficient mean-field approach. Variation of a total energy functional of the biological system yields a new PNP-type continuum model. Numerical simulations show that the proposed model with ion-water interaction energy has the new features that quantitatively describe dielectric properties of water molecules in narrow pores and are possible to model the selectivity of some ion channels.

  16. Two-photon scanning photochemical microscopy: mapping ligand-gated ion channel distributions.

    PubMed Central

    Denk, W

    1994-01-01

    The locations and densities of ionotropic membrane receptors, which are responsible for receiving synaptic transmission throughout the nervous system, are of prime importance in understanding the function of neural circuits. It is shown that the highly localized liberation of "caged" neurotransmitters by two-photon absorption-mediated photoactivation can be used in conjunction with recording the induced whole-cell current to determine the distribution of ligand-gated ion channels. The technique is potentially sensitive enough to detect individual channels with diffraction-limited spatial resolution. Images of the distribution of nicotinic acetylcholine receptors on cultured BC3H1 cells were obtained using a photoactivatable precursor of the nicotinic agonist carbamoylcholine. Images PMID:7517555

  17. Fe(2+) substrate transport through ferritin protein cage ion channels influences enzyme activity and biomineralization.

    PubMed

    Behera, Rabindra K; Torres, Rodrigo; Tosha, Takehiko; Bradley, Justin M; Goulding, Celia W; Theil, Elizabeth C

    2015-09-01

    Ferritins, complex protein nanocages, form internal iron-oxy minerals (Fe2O3·H2O), by moving cytoplasmic Fe(2+) through intracage ion channels to cage-embedded enzyme (2Fe(2+)/O2 oxidoreductase) sites where ferritin biomineralization is initiated. The products of ferritin enzyme activity are diferric oxy complexes that are mineral precursors. Conserved, carboxylate amino acid side chains of D127 from each of three cage subunits project into ferritin ion channels near the interior ion channel exits and, thus, could direct Fe(2+) movement to the internal enzyme sites. Ferritin D127E was designed and analyzed to probe properties of ion channel size and carboxylate crowding near the internal ion channel opening. Glu side chains are chemically equivalent to, but longer by one -CH2 than Asp, side chains. Ferritin D127E assembled into normal protein cages, but diferric peroxo formation (enzyme activity) was not observed, when measured at 650 nm (DFP λ max). The caged biomineral formation, measured at 350 nm in the middle of the broad, nonspecific Fe(3+)-O absorption band, was slower. Structural differences (protein X-ray crystallography), between ion channels in wild type and ferritin D127E, which correlate with the inhibition of ferritin D127E enzyme activity include: (1) narrower interior ion channel openings/pores; (2) increased numbers of ion channel protein-metal binding sites, and (3) a change in ion channel electrostatics due to carboxylate crowding. The contributions of ion channel size and structure to ferritin activity reflect metal ion transport in ion channels are precisely regulated both in ferritin protein nanocages and membranes of living cells.

  18. An efficient approach for the prediction of ion channels and their subfamilies.

    PubMed

    Tiwari, Arvind Kumar; Srivastava, Rajeev

    2015-10-01

    Ion channels are integral membrane proteins that are responsible for controlling the flow of ions across the cell. There are various biological functions that are performed by different types of ion channels. Therefore for new drug discovery it is necessary to develop a novel computational intelligence techniques based approach for the reliable prediction of ion channels families and their subfamilies. In this paper random forest based approach is proposed to predict ion channels families and their subfamilies by using sequence derived features. Here, seven feature vectors are used to represent the protein sample, including amino acid composition, dipeptide composition, correlation features, composition, transition and distribution and pseudo amino acid composition. The minimum redundancy and maximum relevance feature selection is used to find the optimal number of features for improving the prediction performance. The proposed method achieved an overall accuracy of 100%, 98.01%, 91.5%, 93.0%, 92.2%, 78.6%, 95.5%, 84.9%, MCC values of 1.00, 0.92, 0.88, 0.88, 0.90, 0.79, 0.91, 0.81 and ROC area values of 1.00, 0.99, 0.99, 0.99, 0.99, 0.95, 0.99 and 0.96 using 10-fold cross validation to predict the ion channels and non-ion channels, voltage gated ion channels and ligand gated ion channels, four subfamilies (calcium, potassium, sodium and chloride) of voltage gated ion channels, and four subfamilies of ligand gated ion channels and predict subfamilies of voltage gated calcium, potassium, sodium and chloride ion channels respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. New expression profiles of voltage-gated ion channels in arteries exposed to high blood pressure.

    PubMed

    Cox, Robert H; Rusch, Nancy J

    2002-01-01

    The diameters of small arteries and arterioles are tightly regulated by the dynamic interaction between Ca(2+) and K(+) channels in the vascular smooth muscle cells. Calcium influx through voltage-gated Ca(2+) channels induces vasoconstriction, whereas the opening of K(+) channels mediates hyperpolarization, inactivation of voltage-gated Ca(2+) channels, and vasodilation. Three types of voltage-sensitive ion channels have been highly implicated in the regulation of resting vascular tone. These include the L-type Ca(2+) (Ca(L)) channels, voltage-gated K(+) (K(V)) channels, and high-conductance voltage- and Ca(2+)-sensitive K(+) (BK(Ca)) channels. Recently, abnormal expression profiles of these ion channels have been identified as part of the pathogenesis of arterial hypertension and other vasospastic diseases. An increasing number of studies suggest that high blood pressure may trigger cellular signaling cascades that dynamically alter the expression profile of arterial ion channels to further modify vascular tone. This article will briefly review the properties of Ca(L), K(V), and BK(Ca) channels, present evidence that their expression profile is altered during systemic hypertension, and suggest potential mechanisms by which the signal of elevated blood pressure may result in altered ion channel expression. A final section will discuss emerging concepts and opportunities for the development of new vasoactive drugs, which may rely on targeting disease-specific changes in ion channel expression as a mechanism to lower vascular tone during hypertensive diseases.

  20. Ion upflow dependence on ionospheric density and solar photoionization

    NASA Astrophysics Data System (ADS)

    Cohen, I. J.; Lessard, M. R.; Varney, R. H.; Oksavik, K.; Zettergren, M.; Lynch, K. A.

    2015-11-01

    Motivated by rocket observations showing a variety of different ionospheric responses to precipitation, this paper explores the influence of the background ionospheric density on upflow resulting from auroral precipitation. Simulations of upflow driven by auroral precipitation were conducted using a version of the Varney et al. (2014) model driven by precipitation characterized by observations made during the 2012 Magnetosphere-Ionosphere Coupling in the Alfvén resonator rocket mission and using a variety of different initial electron density profiles. The simulation results show that increased initial density before the onset of precipitation leads to smaller electron temperature increases, longer ionospheric heating timescales, weaker ambipolar electric fields, lower upflow speeds, and longer upflow timescales but larger upflow fluxes. The upflow flux can increase even when the ambipolar electric field strength decreases due to the larger number of ions that are accelerated. Long-term observations from the European Incoherent Scatter (EISCAT) Svalbard radar taken during the International Polar Year support the effects seen in the simulations. This correlation between ionospheric density and ion upflows emphasizes the important role of photoionization from solar ultraviolet radiation, which the EISCAT observations show can increase ionospheric density by as much as an order of magnitude during the summer months.

  1. Investigation of Semiconductor Surface Structure by Transmission Ion Channeling.

    NASA Astrophysics Data System (ADS)

    Lyman, Paul Francis

    The primary thrust of this dissertation is the investigation of the composition and structure of two important surface systems on Si, and the study of how this structure evolves under the influence of ion bombardment or film growth. I have studied the initial stages of oxidation of Si immediately following removal of a surface oxide by an HF etch. I have also studied the structure of Ge deposited on clean Si(100) at low temperatures. These systems are of considerable technological interest, but were chosen because they naturally pose fundamental questions regarding physical and chemical processes at surfaces. In the study of the oxidation of Si, I have focused on the influence of the bombarding ion beam in altering the structure and composition of the surface layer. Thus, the system then provides a natural vehicle to study ion-induced chemistry. In the study of low-temperature growth of Ge, I have focused on the structure of the Ge layer and the evolution of that structure upon further deposition or upon heating. This simple system is a model one for observing strained semiconductor heteroepitaxial growth. The primary probe for these studies was transmission channeling of MeV ions. The sensitivity of this technique to correlations between the substrate and an overlayer allowed us to make the following observations. The O, Si and H bound in the thin oxide formed after an HF etch and H_2O rinse occupy preferred positions with respect to the Si matrix. Upon ion bombardment, the O further reacts with the Si (the reaction proceeds linearly with the ion fluence) and the portion of the H that is uncorrelated to the substrate is preferentially desorbed. For the case of Ge growth on Si(100)-(2 x 1) at room temperature, a substantial fraction of the Ge films is strained to occupy sites having the lattice constant of the Si substrate (pseudomorphic growth). A model for film growth is proposed in which pseudomorphic domains constitute roughly half of the Ge films up to a

  2. Electrostatic lens to focus an ion beam to uniform density

    DOEpatents

    Johnson, Cleland H.

    1977-01-11

    A focusing lens for an ion beam having a gaussian or similar density profile is provided. The lens is constructed to provide an inner zero electrostatic field, and an outer electrostatic field such that ions entering this outer field are deflected by an amount that is a function of their distance from the edge of the inner field. The result is a beam that focuses to a uniform density in a manner analogous to that of an optical ring lens. In one embodiment, a conically-shaped network of fine wires is enclosed within a cylindrical anode. The wire net together with the anode produces a voltage field that re-directs the outer particles of the beam while the axial particles pass undeflected through a zero field inside the wire net. The result is a focused beam having a uniform intensity over a given target area and at a given distance from the lens.

  3. Diagnostics for ion beam driven high energy density physics experiments.

    PubMed

    Bieniosek, F M; Henestroza, E; Lidia, S; Ni, P A

    2010-10-01

    Intense beams of heavy ions are capable of heating volumetric samples of matter to high energy density. Experiments are performed on the resulting warm dense matter (WDM) at the NDCX-I ion beam accelerator. The 0.3 MeV, 30 mA K(+) beam from NDCX-I heats foil targets by combined longitudinal and transverse neutralized drift compression of the ion beam. Both the compressed and uncompressed parts of the NDCX-I beam heat targets. The exotic state of matter (WDM) in these experiments requires specialized diagnostic techniques. We have developed a target chamber and fielded target diagnostics including a fast multichannel optical pyrometer, optical streak camera, laser Doppler-shift interferometer (Velocity Interferometer System for Any Reflector), beam transmission diagnostics, and high-speed gated cameras. We also present plans and opportunities for diagnostic development and a new target chamber for NDCX-II.

  4. Diagnostics for ion beam driven high energy density physics experimentsa)

    NASA Astrophysics Data System (ADS)

    Bieniosek, F. M.; Henestroza, E.; Lidia, S.; Ni, P. A.

    2010-10-01

    Intense beams of heavy ions are capable of heating volumetric samples of matter to high energy density. Experiments are performed on the resulting warm dense matter (WDM) at the NDCX-I ion beam accelerator. The 0.3 MeV, 30 mA K+ beam from NDCX-I heats foil targets by combined longitudinal and transverse neutralized drift compression of the ion beam. Both the compressed and uncompressed parts of the NDCX-I beam heat targets. The exotic state of matter (WDM) in these experiments requires specialized diagnostic techniques. We have developed a target chamber and fielded target diagnostics including a fast multichannel optical pyrometer, optical streak camera, laser Doppler-shift interferometer (Velocity Interferometer System for Any Reflector), beam transmission diagnostics, and high-speed gated cameras. We also present plans and opportunities for diagnostic development and a new target chamber for NDCX-II.

  5. Poisson-Nernst-Planck-Fermi theory for modeling biological ion channels

    SciTech Connect

    Liu, Jinn-Liang; Eisenberg, Bob

    2014-12-14

    A Poisson-Nernst-Planck-Fermi (PNPF) theory is developed for studying ionic transport through biological ion channels. Our goal is to deal with the finite size of particle using a Fermi like distribution without calculating the forces between the particles, because they are both expensive and tricky to compute. We include the steric effect of ions and water molecules with nonuniform sizes and interstitial voids, the correlation effect of crowded ions with different valences, and the screening effect of water molecules in an inhomogeneous aqueous electrolyte. Including the finite volume of water and the voids between particles is an important new part of the theory presented here. Fermi like distributions of all particle species are derived from the volume exclusion of classical particles. Volume exclusion and the resulting saturation phenomena are especially important to describe the binding and permeation mechanisms of ions in a narrow channel pore. The Gibbs free energy of the Fermi distribution reduces to that of a Boltzmann distribution when these effects are not considered. The classical Gibbs entropy is extended to a new entropy form — called Gibbs-Fermi entropy — that describes mixing configurations of all finite size particles and voids in a thermodynamic system where microstates do not have equal probabilities. The PNPF model describes the dynamic flow of ions, water molecules, as well as voids with electric fields and protein charges. The model also provides a quantitative mean-field description of the charge/space competition mechanism of particles within the highly charged and crowded channel pore. The PNPF results are in good accord with experimental currents recorded in a 10{sup 8}-fold range of Ca{sup 2+} concentrations. The results illustrate the anomalous mole fraction effect, a signature of L-type calcium channels. Moreover, numerical results concerning water density, dielectric permittivity, void volume, and steric energy provide useful

  6. Macroscopic kinetics of pentameric ligand gated ion channels: comparisons between two prokaryotic channels and one eukaryotic channel.

    PubMed

    Laha, Kurt T; Ghosh, Borna; Czajkowski, Cynthia

    2013-01-01

    Electrochemical signaling in the brain depends on pentameric ligand-gated ion channels (pLGICs). Recently, crystal structures of prokaryotic pLGIC homologues from Erwinia chrysanthemi (ELIC) and Gloeobacter violaceus (GLIC) in presumed closed and open channel states have been solved, which provide insight into the structural mechanisms underlying channel activation. Although structural studies involving both ELIC and GLIC have become numerous, thorough functional characterizations of these channels are still needed to establish a reliable foundation for comparing kinetic properties. Here, we examined the kinetics of ELIC and GLIC current activation, desensitization, and deactivation and compared them to the GABAA receptor, a prototypic eukaryotic pLGIC. Outside-out patch-clamp recordings were performed with HEK-293T cells expressing ELIC, GLIC, or α1β2γ2L GABAA receptors, and ultra-fast ligand application was used. In response to saturating agonist concentrations, we found both ELIC and GLIC current activation were two to three orders of magnitude slower than GABAA receptor current activation. The prokaryotic channels also had slower current desensitization on a timescale of seconds. ELIC and GLIC current deactivation following 25 s pulses of agonist (cysteamine and pH 4.0 buffer, respectively) were relatively fast with time constants of 24.9 ± 5.1 ms and 1.2 ± 0.2 ms, respectively. Surprisingly, ELIC currents evoked by GABA activated very slowly with a time constant of 1.3 ± 0.3 s and deactivated even slower with a time constant of 4.6 ± 1.2 s. We conclude that the prokaryotic pLGICs undergo similar agonist-mediated gating transitions to open and desensitized states as eukaryotic pLGICs, supporting their use as experimental models. Their uncharacteristic slow activation, slow desensitization and rapid deactivation time courses are likely due to differences in specific structural elements, whose future identification may help uncover mechanisms underlying p

  7. Universal scalings for laser acceleration of electrons in ion channels

    NASA Astrophysics Data System (ADS)

    Khudik, Vladimir; Arefiev, Alexey; Zhang, Xi; Shvets, Gennady

    2016-10-01

    We analytically investigate the acceleration of electrons undergoing betatron oscillations in an ion channel, driven by a laser beam propagating with superluminal (or luminal) phase velocity. The universal scalings for the maximum attainable electron energy are found for arbitrary laser and plasma parameters by deriving a set of dimensionless equations for paraxial ultra-relativistic electron motion. One of our analytic predictions is the emergence of forbidden zones in the electrons' phase space. For an individual electron, these give rise to a threshold-type dependence of the final energy gain on the laser intensity. The universal scalings are also generalized to the resonant laser interaction with the third harmonic of betatron motion and to the case when the laser beam is circularly polarized.

  8. TRPV4 ion channel as important cell sensors.

    PubMed

    Shibasaki, Koji

    2016-12-01

    This review provides a summary of the physiological significance of the TRPV4 ion channel. Although TRPV4 was initially characterized as an osmosensor, we found that TRPV4 can also act as a thermosensor or a mechanosensor in brain neurons or epithelial cells in the urinary bladder. Here, we summarize the newly characterized functions of TRPV4, including the research progress that has been made toward our understanding of TRPV4 physiology, and discuss other recent data pertaining to TRPV4. It is thought that TRPV4 may be an important drug target based on its broad expression patterns and important physiological functions. Possible associations between diseases and TRPV4 are also discussed.

  9. Bayesian restoration of ion channel records using hidden Markov models.

    PubMed

    Rosales, R; Stark, J A; Fitzgerald, W J; Hladky, S B

    2001-03-01

    Hidden Markov models have been used to restore recorded signals of single ion channels buried in background noise. Parameter estimation and signal restoration are usually carried out through likelihood maximization by using variants of the Baum-Welch forward-backward procedures. This paper presents an alternative approach for dealing with this inferential task. The inferences are made by using a combination of the framework provided by Bayesian statistics and numerical methods based on Markov chain Monte Carlo stochastic simulation. The reliability of this approach is tested by using synthetic signals of known characteristics. The expectations of the model parameters estimated here are close to those calculated using the Baum-Welch algorithm, but the present methods also yield estimates of their errors. Comparisons of the results of the Bayesian Markov Chain Monte Carlo approach with those obtained by filtering and thresholding demonstrate clearly the superiority of the new methods.

  10. The Ion Channel TRPA1 Is Required for Chronic Itch

    PubMed Central

    Wilson, Sarah R.; Nelson, Aislyn M.; Batia, Lyn; Morita, Takeshi; Estandian, Daniel; Owens, David M.; Lumpkin, Ellen A.; Bautista, Diana M.

    2013-01-01

    Chronic itch is a debilitating condition that affects one in 10 people. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. We demonstrate that the ion channel TRPA1 is required for chronic itch. Using a mouse model of chronic itch, we show that scratching evoked by impaired skin barrier is abolished in TRPA1-deficient animals. This model recapitulates many of the pathophysiological hallmarks of chronic itch that are observed in prevalent human diseases such as atopic dermatitis and psoriasis, including robust scratching, extensive epidermal hyperplasia, and dramatic changes in gene expression in sensory neurons and skin. Remarkably, TRPA1 is required for both transduction of chronic itch signals to the CNS and for the dramatic skin changes triggered by dry-skin-evoked itch and scratching. These data suggest that TRPA1 regulates both itch transduction and pathophysiological changes in the skin that promote chronic itch. PMID:23719797

  11. Cytoskeletal Basis of Ion Channel Function in Cardiac Muscle

    PubMed Central

    Vatta, Matteo; Faulkner, Georgine

    2009-01-01

    Summary The heart is a force-generating organ that responds to self-generated electrical stimuli from specialized cardiomyocytes. This function is modulated by sympathetic and parasympathetic activity. In order to contract and accommodate the repetitive morphological changes induced by the cardiac cycle, cardiomyocytes depend on their highly evolved and specialized cytoskeletal apparatus. Defects in components of the cytoskeleton, in the long term, affect the ability of the cell to compensate at both functional and structural levels. In addition to the structural remodeling, the myocardium becomes increasingly susceptible to altered electrical activity leading to arrhythmogenesis. The development of arrhythmias secondary to structural remodeling defects has been noted, although the detailed molecular mechanisms are still elusive. Here I will review the current knowledge of the molecular and functional relationships between the cytoskeleton and ion channels and, I will discuss the future impact of new data on molecular cardiology research and clinical practice. PMID:19774097

  12. On the estimation of cooperativity in ion channel kinetics: activation free energy and kinetic mechanism of Shaker K+ channel.

    PubMed

    Banerjee, Kinshuk; Das, Biswajit; Gangopadhyay, Gautam

    2013-04-28

    In this paper, we have explored generic criteria of cooperative behavior in ion channel kinetics treating it on the same footing with multistate receptor-ligand binding in a compact theoretical framework. We have shown that the characterization of cooperativity of ion channels in terms of the Hill coefficient violates the standard Hill criteria defined for allosteric cooperativity of ligand binding. To resolve the issue, an alternative measure of cooperativity is proposed here in terms of the cooperativity index that sets a unified criteria for both the systems. More importantly, for ion channel this index can be very useful to describe the cooperative kinetics as it can be readily determined from the experimentally measured ionic current combined with theoretical modelling. We have analyzed the correlation between the voltage value and slope of the voltage-activation curve at the half-activation point and consequently determined the standard free energy of activation of the ion channel using two well-established mechanisms of cooperativity, namely, Koshland-Nemethy-Filmer (KNF) and Monod-Wyman-Changeux (MWC) models. Comparison of the theoretical results for both the models with appropriate experimental data of mutational perturbation of Shaker K(+) channel supports the experimental fact that the KNF model is more suitable to describe the cooperative behavior of this class of ion channels, whereas the performance of the MWC model is unsatisfactory. We have also estimated the mechanistic performance through standard free energy of channel activation for both the models and proposed a possible functional disadvantage in the MWC scheme.

  13. Light-Activated Ion Channels for Remote Control of Neural Activity

    PubMed Central

    Chambers, James J.; Kramer, Richard H.

    2009-01-01

    Light-activated ion channels provide a new opportunity to precisely and remotely control neuronal activity for experimental applications in neurobiology. In the past few years, several strategies have arisen that allow light to control ion channels and therefore neuronal function. Light-based triggers for ion channel control include caged compounds, which release active neurotransmitters when photolyzed with light, and natural photoreceptive proteins, which can be expressed exogenously in neurons. More recently, a third type of light trigger has been introduced: a photoisomerizable tethered ligand that directly controls ion channel activity in a light-dependent manner. Beyond the experimental applications for light-gated ion channels, there may be clinical applications in which these light-sensitive ion channels could prove advantageous over traditional methods. Electrodes for neural stimulation to control disease symptoms are invasive and often difficult to reposition between cells in tissue. Stimulation by chemical agents is difficult to constrain to individual cells and has limited temporal accuracy in tissue due to diffusional limitations. In contrast, ion channels that can be directly activated with light allow control with unparalleled spatial and temporal precision. The goal of this chapter is to describe light-regulated ion channels and how they have been tailored to control different aspects of neural activity, and how to use these channels to manipulate and better understand development, function, and plasticity of neurons and neural circuits. PMID:19195553

  14. Structure, function and translational relevance of aquaporin dual water and ion channels

    PubMed Central

    Yool, Andrea J; Campbell, Ewan M

    2012-01-01

    Aquaporins have been assumed to be selective for water alone, and aquaglyceroporins are accepted as carrying water and small uncharged solutes including glycerol. This review presents an expanded view of aquaporins as channels with more complex mechanisms of regulation and diverse repertoires of substrate permeabilities than were originally appreciated in the early establishment of the field. The role of aquaporins as dual water and gated ion channels is likely to have physiological and potentially translational relevance, and can be evaluated with newly developed molecular and pharmacological tools. Ion channel activity has been shown for Aquaporins -0, -1, and -6, Drosphila Big Brain, and plant Nodulin-26. Although the concept of ion channel function in aquaporins remains controversial, research advances are beginning to define not only the ion channel function but also the detailed molecular mechanisms that govern and mediate the multifunctional capabilities. With regard to physiological relevance, the adaptive benefit of expression of ion channel activity in aquaporins, implied by amino acid sequence conservation of the ion channel gating domains, suggests they provide more than water or glycerol and solute transport. Dual ion and water channels are of interest for understanding the modulation of transmembrane fluid gradients, volume regulation, and possible signal transduction in tissues expressing classes of aquaporins that have the dual function capability. Other aquaporin classes might be found in future work to have ion channel activities, pending identification of the possible signaling pathways that could govern activation. PMID:22342689

  15. Lipid agonism: The PIP2 paradigm of ligand-gated ion channels.

    PubMed

    Hansen, Scott B

    2015-05-01

    The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid-ligand bind to a membrane protein in the plasma membrane, and what does it mean for a lipid to activate or regulate an ion channel? How does lipid binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular, ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.

  16. Molecular biology and biophysical properties of ion channel gating pores.

    PubMed

    Moreau, Adrien; Gosselin-Badaroudine, Pascal; Chahine, Mohamed

    2014-11-01

    The voltage sensitive domain (VSD) is a pivotal structure of voltage-gated ion channels (VGICs) and plays an essential role in the generation of electrochemical signals by neurons, striated muscle cells, and endocrine cells. The VSD is not unique to VGICs. Recent studies have shown that a VSD regulates a phosphatase. Similarly, Hv1, a voltage-sensitive protein that lacks an apparent pore domain, is a self-contained voltage sensor that operates as an H⁺ channel. VSDs are formed by four transmembrane helices (S1-S4). The S4 helix is positively charged due to the presence of arginine and lysine residues. It is surrounded by two water crevices that extend into the membrane from both the extracellular and intracellular milieus. A hydrophobic septum disrupts communication between these water crevices thus preventing the permeation of ions. The septum is maintained by interactions between the charged residues of the S4 segment and the gating charge transfer center. Mutating the charged residue of the S4 segment allows the water crevices to communicate and generate gating pore or omega pore. Gating pore currents have been reported to underlie several neuronal and striated muscle channelopathies. Depending on which charged residue on the S4 segment is mutated, gating pores are permeant either at depolarized or hyperpolarized voltages. Gating pores are cation selective and seem to converge toward Eisenmann's first or second selectivity sequences. Most gating pores are blocked by guanidine derivatives as well as trivalent and quadrivalent cations. Gating pores can be used to study the movement of the voltage sensor and could serve as targets for novel small therapeutic molecules.

  17. Cardiac ion channel gene mutations in sudden infant death syndrome.

    PubMed

    Otagiri, Tesshu; Kijima, Kazuki; Osawa, Motoki; Ishii, Kuniaki; Makita, Naomasa; Matoba, Ryoji; Umetsu, Kazuo; Hayasaka, Kiyoshi

    2008-11-01

    Sudden infant death syndrome (SIDS) is multifactorial and may result from the interaction of a number of environmental, genetic, and developmental factors. We studied three major genes causing long QT syndrome in 42 Japanese SIDS victims and found five mutations, KCNQ1-K598R, KCNH2-T895M, SCN5A-F532C, SCN5A-G1084S, and SCN5A-F1705S, in four cases; one case had both KCNH2-T895M and SCN5A-G1084S. All mutations were novel except for SCN5A-F532C, which was previously detected in an arrhythmic patient. Heterologous expression study revealed significant changes in channel properties of KCNH2-T895M, SCN5A-G1084S, and SCN5A-F1705S, but did not in KCNQ1-K598R and SCN5A-F532C. Our data suggests that nearly 10% of SIDS victims in Japan have mutations of the cardiac ion channel genes similar to in other countries.

  18. Biophysics, pathophysiology, and pharmacology of ion channel gating pores

    PubMed Central

    Moreau, Adrien; Gosselin-Badaroudine, Pascal; Chahine, Mohamed

    2014-01-01

    Voltage sensor domains (VSDs) are a feature of voltage gated ion channels (VGICs) and voltage sensitive proteins. They are composed of four transmembrane (TM) segments (S1–S4). Currents leaking through VSDs are called omega or gating pore currents. Gating pores are caused by mutations of the highly conserved positively charged amino acids in the S4 segment that disrupt interactions between the S4 segment and the gating charge transfer center (GCTC). The GCTC separates the intracellular and extracellular water crevices. The disruption of S4–GCTC interactions allows these crevices to communicate and create a fast activating and non-inactivating alternative cation-selective permeation pathway of low conductance, or a gating pore. Gating pore currents have recently been shown to cause periodic paralysis phenotypes. There is also increasing evidence that gating pores are linked to several other familial diseases. For example, gating pores in Nav1.5 and Kv7.2 channels may underlie mixed arrhythmias associated with dilated cardiomyopathy (DCM) phenotypes and peripheral nerve hyperexcitability (PNH), respectively. There is little evidence for the existence of gating pore blockers. Moreover, it is known that a number of toxins bind to the VSD of a specific domain of Na+ channels. These toxins may thus modulate gating pore currents. This focus on the VSD motif opens up a new area of research centered on developing molecules to treat a number of cell excitability disorders such as epilepsy, cardiac arrhythmias, and pain. The purpose of the present review is to summarize existing knowledge of the pathophysiology, biophysics, and pharmacology of gating pore currents and to serve as a guide for future studies aimed at improving our understanding of gating pores and their pathophysiological roles. PMID:24772081

  19. The nature of ion and water barrier crossings in a simulated ion channel.

    PubMed Central

    Chiu, S. W.; Novotny, J. A.; Jakobsson, E.

    1993-01-01

    state of matter" characteristic of the channel contents appears to have some properties typical of the solid and some typical of the liquid state. The magnitude of the local friction and nature of the ion solvation are similar to the liquid state, but the periodicities of structure, free energy, and dynamics are somewhat solid-like. The alignment of water dipoles in the channel bears some resemblance to the orientational ordering of a nematic liquid crystal, but unlike a nematic liquid crystal, the waters have a degree of translational order as well. Thus, the "channel state" is not adequately described by analogy to either the solid or liquid states or to liquid crystals but must be dealt with as its own characteristic type of condensed matter. PMID:7679301

  20. A Floating Potential Method for Determining Ion Density

    NASA Astrophysics Data System (ADS)

    Evans, John D.; Chen, Francis F.

    2001-10-01

    The density n in partially ionized discharges is often found from the saturation ion current Ii of a cylindrical Langmuir probe. Collisionless probe theories, however, disagree with measured I - V curves probably because of collisions^1. We use a heuristic method that yields n from probe data agreeing with microwave interferometry. Probe current I is raised to the 4/3 power and fitted to a straight line on an I^4/3-V plot. The line is extrapolated to the floating potential V_f, thus approximating I_i(V_f). The sheath thickness d_sh for V = Vf is calculated from the Child-Langmuir (CL) law, and applying the Bohm sheath criterion to the surface at r_sh = Rp + d_sh yields n when Ii = I_i(V_f). This method works, but it cannot be justified by theory. Neglected are (a) cylindrical convergence of the ion charge, (b) finite ion energy at r = r_sh, (c) ions orbiting the probe, and (d) escape of ions axially. The Allen-Boyd-Reynolds theory, which treats (a) and (b) and neglects (c) and (d), gives too low n's. Apparently the errors self-cancel, and the simple Vf method gives the right result. ^1 F.F. Chen, Phys. Plasmas 8, 3029 (2001).

  1. Properties of cytotoxic peptide-formed ion channels.

    PubMed

    Kourie, J I; Shorthouse, A A

    2000-06-01

    Cytotoxic peptides are relatively small cationic molecules such as those found 1) in venoms, e.g., melittin in bee, scorpion toxins in scorpion, pilosulin 1 in jumper ant, and lycotoxin I and II in wolf spider; 2) in skin secretions (e.g., magainin I and II from Xenopus laevis, dermaseptin from frog, antimicrobials from carp) and cells of the immune system (e.g., insect, scorpion, and mammalian defensins and cryptdins); 3) as autocytotoxicity peptides, e.g., amylin cytotoxic to pancreatic beta-cells, prion peptide fragment 106-126 [PrP-(106-126)], and amyloid beta-protein (AbetaP) cytotoxic to neurons; and 4) as designed synthetic peptides based on the sequences and properties of naturally occurring cytotoxic peptides. The small cytotoxic peptides are composed of beta-sheets, e.g., mammalian defensins, AbetaP, amylin, and PrP-(106-126), whereas the larger cytotoxic peptides have several domains composed of both alpha-helices and beta-sheets stabilized by cysteine bonds, e.g., scorpion toxins, scorpion, and insect defensins. Electrophysiological and molecular biology techniques indicate that these structures modify cell membranes via 1) interaction with intrinsic ion transport proteins and/or 2) formation of ion channels. These two nonexclusive mechanisms of action lead to changes in second messenger systems that further augment the abnormal electrical activity and distortion of the signal transduction causing cell death.

  2. Temporal evolution of helix hydration in a light-gated ion channel correlates with ion conductance.

    PubMed

    Lórenz-Fonfría, Víctor A; Bamann, Christian; Resler, Tom; Schlesinger, Ramona; Bamberg, Ernst; Heberle, Joachim

    2015-10-27

    The discovery of channelrhodopsins introduced a new class of light-gated ion channels, which when genetically encoded in host cells resulted in the development of optogenetics. Channelrhodopsin-2 from Chlamydomonas reinhardtii, CrChR2, is the most widely used optogenetic tool in neuroscience. To explore the connection between the gating mechanism and the influx and efflux of water molecules in CrChR2, we have integrated light-induced time-resolved infrared spectroscopy and electrophysiology. Cross-correlation analysis revealed that ion conductance tallies with peptide backbone amide I vibrational changes at 1,665(-) and 1,648(+) cm(-1). These two bands report on the hydration of transmembrane α-helices as concluded from vibrational coupling experiments. Lifetime distribution analysis shows that water influx proceeded in two temporally separated steps with time constants of 10 μs (30%) and 200 μs (70%), the latter phase concurrent with the start of ion conductance. Water efflux and the cessation of the ion conductance are synchronized as well, with a time constant of 10 ms. The temporal correlation between ion conductance and hydration of helices holds for fast (E123T) and slow (D156E) variants of CrChR2, strengthening its functional significance.

  3. Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

    PubMed Central

    Ge, Lisheng; Hoa, Neil T.; Wilson, Zechariah; Arismendi-Morillo, Gabriel; Kong, Xia-Tang; Tajhya, Rajeev B.; Beeton, Christine; Jadus, Martin R.

    2017-01-01

    The Big Potassium (BK) ion channel is commonly known by a variety of names (Maxi-K, KCNMA1, slo, Stretch-activated potassium channels, KCa1.1). Each name reflects a different physical property displayed by this single ion channel. This transmembrane channel is found on nearly every cell type of the body and has its own distinctive roles for that tissue type. The BKα channel contains the pore that releases potassium ions from intracellular stores. This ion channel is found on the cell membrane, endoplasmic reticulum, Golgi and mitochondria. Complex splicing pathways produce different isoforms. The BKα channels can be phosphorylated, palmitoylated and myristylated. BK is composed of a homo-tetramer that interacts with β and γ chains. These accessory proteins provide a further modulating effect on the functions of BKα channels. BK channels play important roles in cell division and migration. In this review, we will focus on the biology of BK channels, especially its role, and that it has in the immune response towards cancer. Recent proteomic studies have linked BK channels with various proteins. Some of these interactions offer further insight into the role that BK channels have with cancers, especially with brain tumors. This review shows that BK channels have a complex interplay with intracellular components of cancer cells and still have plenty of secrets to be discovered. PMID:25027630

  4. Robust ion current oscillations under a steady electric field: An ion channel analog

    NASA Astrophysics Data System (ADS)

    Yan, Yu; Wang, Yunshan; Senapati, Satyajyoti; Schiffbauer, Jarrod; Yossifon, Gilad; Chang, Hsueh-Chia

    2016-08-01

    We demonstrate a nonlinear, nonequilibrium field-driven ion flux phenomenon, which unlike Teorell's nonlinear multiple field theory, requires only the application of one field: robust autonomous current-mass flux oscillations across a porous monolith coupled to a capillary with a long air bubble, which mimics a hydrophobic protein in an ion channel. The oscillations are driven by the hysteretic wetting dynamics of the meniscus when electro-osmotic flow and pressure driven backflow, due to bubble expansion, compete to approach zero mass flux within the monolith. Delayed rupture of the film around the advancing bubble cuts off the electric field and switches the monolith mass flow from the former to the latter. The meniscus then recedes and repairs the rupture to sustain an oscillation for a range of applied fields. This generic mechanism shares many analogs with current oscillations in cell membrane ion channel. At sufficiently high voltage, the system undergoes a state transition characterized by appearance of the ubiquitous 1 /f power spectrum.

  5. 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.

  6. Comparative analysis of stable ultrahigh power-density 248 nm channels formed in Kr and Xe cluster targets

    NASA Astrophysics Data System (ADS)

    Borisov, Alex B.; McCorkindale, John C.; Poopalasingam, Sankar; Longworth, James W.; Rhodes, Charles K.

    2013-09-01

    Comparative single-pulse studies of self-trapped plasma channel formation in Xe and Kr cluster targets produced with 1-2 TW femtosecond 248 nm pulses reveal energy efficient channel formation (>90%) and highly robust stability for the channeled propagation in both materials. Images of the channel morphology produced by Thomson scattering from the electron density and direct visualization of the Xe(M) and Kr(L) x-ray emission from radiating ions illustrate the (1) channel formation, (2) the narrow region of confined trapped propagation, (3) the abrupt termination of the channel that occurs at the point the power falls below the critical power Pcr, and, in the case of Xe channels, (4) the presence of saturated absorption of Xe(M) radiation that generates an extended peripheral zone of ionization. The measured rates for energy deposition per unit length are ˜ 1.46 J cm-1 and ˜ 0.82 J cm-1 for Xe and Kr targets, respectively, and the single pulse Xe(M) energy yield is estimated to be > 50 mJ, a value indicating an efficiency >20% for ˜ 1 keV x-ray production from the incident 248 nm pulse.

  7. Screen-based identification and validation of four new ion channels as regulators of renal ciliogenesis

    PubMed Central

    Slaats, Gisela G.; Wheway, Gabrielle; Foletto, Veronica; Szymanska, Katarzyna; van Balkom, Bas W. M.; Logister, Ive; Den Ouden, Krista; Keijzer-Veen, Mandy G.; Lilien, Marc R.; Knoers, Nine V.; Johnson, Colin A.; Giles, Rachel H.

    2015-01-01

    ABSTRACT To investigate the contribution of ion channels to ciliogenesis, we carried out a small interfering RNA (siRNA)-based reverse genetics screen of all ion channels in the mouse genome in murine inner medullary collecting duct kidney cells. This screen revealed four candidate ion channel genes: Kcnq1, Kcnj10, Kcnf1 and Clcn4. We show that these four ion channels localize to renal tubules, specifically to the base of primary cilia. We report that human KCNQ1 Long QT syndrome disease alleles regulate renal ciliogenesis; KCNQ1-p.R518X, -p.A178T and -p.K362R could not rescue ciliogenesis after Kcnq1-siRNA-mediated depletion in contrast to wild-type KCNQ1 and benign KCNQ1-p.R518Q, suggesting that the ion channel function of KCNQ1 regulates ciliogenesis. In contrast, we demonstrate that the ion channel function of KCNJ10 is independent of its effect on ciliogenesis. Our data suggest that these four ion channels regulate renal ciliogenesis through the periciliary diffusion barrier or the ciliary pocket, with potential implication as genetic contributors to ciliopathy pathophysiology. The new functional roles of a subset of ion channels provide new insights into the disease pathogenesis of channelopathies, which might suggest future therapeutic approaches. PMID:26546361

  8. Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels.

    PubMed

    Redaelli, Elisa; Cassulini, Rita Restano; Silva, Deyanira Fuentes; Clement, Herlinda; Schiavon, Emanuele; Zamudio, Fernando Z; Odell, George; Arcangeli, Annarosa; Clare, Jeffrey J; Alagón, Alejandro; de la Vega, Ricardo C Rodríguez; Possani, Lourival D; Wanke, Enzo

    2010-02-05

    Venom-derived peptide modulators of ion channel gating are regarded as essential tools for understanding the molecular motions that occur during the opening and closing of ion channels. In this study, we present the characterization of five spider toxins on 12 human voltage-gated ion channels, following observations about the target promiscuity of some spider toxins and the ongoing revision of their "canonical" gating-modifying mode of action. The peptides were purified de novo from the venom of Grammostola rosea tarantulas, and their sequences were confirmed by Edman degradation and mass spectrometry analysis. Their effects on seven tetrodotoxin-sensitive Na(+) channels, the three human ether-à-go-go (hERG)-related K(+) channels, and two human Shaker-related K(+) channels were extensively characterized by electrophysiological techniques. All the peptides inhibited ion conduction through all the Na(+) channels tested, although with distinctive patterns. The peptides also affected the three pharmaceutically relevant hERG isoforms differently. At higher concentrations, all peptides also modified the gating of the Na(+) channels by shifting the activation to more positive potentials, whereas more complex effects were recorded on hERG channels. No effects were evident on the two Shaker-related K(+) channels at concentrations well above the IC(50) value for the affected channels. Given the sequence diversity of the tested peptides, we propose that tarantula toxins should be considered both as multimode and target-promiscuous ion channel modulators; both features should not be ignored when extracting mechanistic interpretations about ion channel gating. Our observations could also aid in future structure-function studies and might help the development of novel ion channel-specific drugs.

  9. Target Promiscuity and Heterogeneous Effects of Tarantula Venom Peptides Affecting Na+ and K+ Ion Channels*

    PubMed Central

    Redaelli, Elisa; Cassulini, Rita Restano; Silva, Deyanira Fuentes; Clement, Herlinda; Schiavon, Emanuele; Zamudio, Fernando Z.; Odell, George; Arcangeli, Annarosa; Clare, Jeffrey J.; Alagón, Alejandro; de la Vega, Ricardo C. Rodríguez; Possani, Lourival D.; Wanke, Enzo

    2010-01-01

    Venom-derived peptide modulators of ion channel gating are regarded as essential tools for understanding the molecular motions that occur during the opening and closing of ion channels. In this study, we present the characterization of five spider toxins on 12 human voltage-gated ion channels, following observations about the target promiscuity of some spider toxins and the ongoing revision of their “canonical” gating-modifying mode of action. The peptides were purified de novo from the venom of Grammostola rosea tarantulas, and their sequences were confirmed by Edman degradation and mass spectrometry analysis. Their effects on seven tetrodotoxin-sensitive Na+ channels, the three human ether-à-go-go (hERG)-related K+ channels, and two human Shaker-related K+ channels were extensively characterized by electrophysiological techniques. All the peptides inhibited ion conduction through all the Na+ channels tested, although with distinctive patterns. The peptides also affected the three pharmaceutically relevant hERG isoforms differently. At higher concentrations, all peptides also modified the gating of the Na+ channels by shifting the activation to more positive potentials, whereas more complex effects were recorded on hERG channels. No effects were evident on the two Shaker-related K+ channels at concentrations well above the IC50 value for the affected channels. Given the sequence diversity of the tested peptides, we propose that tarantula toxins should be considered both as multimode and target-promiscuous ion channel modulators; both features should not be ignored when extracting mechanistic interpretations about ion channel gating. Our observations could also aid in future structure-function studies and might help the development of novel ion channel-specific drugs. PMID:19955179

  10. Effects of a dielectric material in an ion source on the ion beam current density and ion beam energy

    SciTech Connect

    Fujiwara, Y. Sakakita, H.; Nakamiya, A.; Hirano, Y.; Kiyama, S.

    2016-02-15

    To understand a strong focusing phenomenon that occurs in a low-energy hydrogen ion beam, the electron temperature, the electron density, and the space potential in an ion source with cusped magnetic fields are measured before and after the transition to the focusing state using an electrostatic probe. The experimental results show that no significant changes are observed before or after the transition. However, we found unique phenomena that are characterized by the position of the electrostatic probe in the ion source chamber. Specifically, the extracted ion beam current density and energy are obviously enhanced in the case where the electrostatic probe, which is covered by a dielectric material, is placed close to an acceleration electrode.

  11. From foe to friend: using animal toxins to investigate ion channel function

    PubMed Central

    Salvatierra, Juan; Wagner, Jordan; Klint, Julie K; King, Glenn F; Olivera, Baldomero M; Bosmans, Frank

    2014-01-01

    Ion channels are vital contributors to cellular communication in a wide range of organisms, a distinct feature that renders this ubiquitous family of membrane-spanning proteins a prime target for toxins found in animal venom. For many years, the unique properties of these naturally-occurring molecules have enabled researchers to probe the structural and functional features of ion channels and to define their physiological roles in normal and diseased tissues. To illustrate their considerable impact on the ion channel field, this review will highlight fundamental insights into toxin-channel interactions as well as recently developed toxin screening methods and practical applications of engineered toxins. PMID:25088688

  12. Shielding analysis for a heavy ion beam chamber with plasma channels for ion transport

    SciTech Connect

    Sawan, M.E.; Peterson, R.R.; Yu, S.

    2000-06-28

    Neutronics analysis has been performed to assess the shielding requirements for the insulators and final focusing magnets in a modified HYLIFE-II target chamber that utilizes pre-formed plasma channels for heavy ion beam transport. Using 65 cm thick Flibe jet assemblies provides adequate shielding for the electrical insulator units. Additional shielding is needed in front of the final focusing superconducting quadrupole magnets. A shield with a thickness varying between 45 and 90 cm needs to be provided in front of the quadrupole unit. The final laser mirrors located along the channel axis are in the direct line-of-sight of source neutrons. Neutronics calculations were performed to determine the constraints on the placement of these mirrors to be lifetime components.

  13. Brownian dynamics study of ion transport in the vestibule of membrane channels.

    PubMed

    Li, S C; Hoyles, M; Kuyucak, S; Chung, S H

    1998-01-01

    Brownian dynamics simulations have been carried out to study the transport of ions in a vestibular geometry, which offers a more realistic shape for membrane channels than cylindrical tubes. Specifically, we consider a torus-shaped channel, for which the analytical solution of Poisson's equation is possible. The system is composed of the toroidal channel, with length and radius of the constricted region of 80 A and 4 A, respectively, and two reservoirs containing 50 sodium ions and 50 chloride ions. The positions of each of these ions executing Brownian motion under the influence of a stochastic force and a systematic electric force are determined at discrete time steps of 50 fs for up to 2.5 ns. All of the systematic forces acting on an ion due to the other ions, an external electric field, fixed charges in the channel protein, and the image charges induced at the water-protein boundary are explicitly included in the calculations. We find that the repulsive dielectric force arising from the induced surface charges plays a dominant role in channel dynamics. It expels an ion from the vestibule when it is deliberately put in it. Even in the presence of an applied electric potential of 100 mV, an ion cannot overcome this repulsive force and permeate the channel. Only when dipoles of a favorable orientation are placed along the sides of the transmembrane segment can an ion traverse the channel under the influence of a membrane potential. When the strength of the dipoles is further increased, an ion becomes detained in a potential well, and the driving force provided by the applied field is not sufficient to drive the ion out of the well. The trajectory of an ion navigating across the channel mostly remains close to the central axis of the pore lumen. Finally, we discuss the implications of these findings for the transport of ions across the membrane.

  14. Mechanistic Insights into the Modulation of Voltage-Gated Ion Channels by Inhalational Anesthetics.

    PubMed

    Covarrubias, Manuel; Barber, Annika F; Carnevale, Vincenzo; Treptow, Werner; Eckenhoff, Roderic G

    2015-11-17

    General anesthesia is a relatively safe medical procedure, which for nearly 170 years has allowed life saving surgical interventions in animals and people. However, the molecular mechanism of general anesthesia continues to be a matter of importance and debate. A favored hypothesis proposes that general anesthesia results from direct multisite interactions with multiple and diverse ion channels in the brain. Neurotransmitter-gated ion channels and two-pore K+ channels are key players in the mechanism of anesthesia; however, new studies have also implicated voltage-gated ion channels. Recent biophysical and structural studies of Na+ and K+ channels strongly suggest that halogenated inhalational general anesthetics interact with gates and pore regions of these ion channels to modulate function. Here, we review these studies and provide a perspective to stimulate further advances.

  15. Mechanistic Insights into the Modulation of Voltage-Gated Ion Channels by Inhalational Anesthetics

    PubMed Central

    Covarrubias, Manuel; Barber, Annika F.; Carnevale, Vincenzo; Treptow, Werner; Eckenhoff, Roderic G.

    2015-01-01

    General anesthesia is a relatively safe medical procedure, which for nearly 170 years has allowed life saving surgical interventions in animals and people. However, the molecular mechanism of general anesthesia continues to be a matter of importance and debate. A favored hypothesis proposes that general anesthesia results from direct multisite interactions with multiple and diverse ion channels in the brain. Neurotransmitter-gated ion channels and two-pore K+ channels are key players in the mechanism of anesthesia; however, new studies have also implicated voltage-gated ion channels. Recent biophysical and structural studies of Na+ and K+ channels strongly suggest that halogenated inhalational general anesthetics interact with gates and pore regions of these ion channels to modulate function. Here, we review these studies and provide a perspective to stimulate further advances. PMID:26588560

  16. A Grand Canonical Monte Carlo-Brownian dynamics algorithm for simulating ion channels.

    PubMed Central

    Im, W; Seefeld, S; Roux, B

    2000-01-01

    A computational algorithm based on Grand Canonical Monte Carlo (GCMC) and Brownian Dynamics (BD) is described to simulate the movement of ions in membrane channels. The proposed algorithm, GCMC/BD, allows the simulation of ion channels with a realistic implementation of boundary conditions of concentration and transmembrane potential. The method is consistent with a statistical mechanical formulation of the equilibrium properties of ion channels (; Biophys. J. 77:139-153). The GCMC/BD algorithm is illustrated with simulations of simple test systems and of the OmpF porin of Escherichia coli. The approach provides a framework for simulating ion permeation in the context of detailed microscopic models. PMID:10920012

  17. High density, optically corrected, micro-channel cooled, v-groove monolithic laser diode array

    DOEpatents

    Freitas, Barry L.

    1998-01-01

    An optically corrected, micro-channel cooled, high density laser diode array achieves stacking pitches to 33 bars/cm by mounting laser diodes into V-shaped grooves. This design will deliver>4kW/cm2 of directional pulsed laser power. This optically corrected, micro-channel cooled, high density laser is usable in all solid state laser systems which require efficient, directional, narrow bandwidth, high optical power density pump sources.

  18. High density, optically corrected, micro-channel cooled, v-groove monolithic laser diode array

    DOEpatents

    Freitas, B.L.

    1998-10-27

    An optically corrected, micro-channel cooled, high density laser diode array achieves stacking pitches to 33 bars/cm by mounting laser diodes into V-shaped grooves. This design will deliver > 4kW/cm{sup 2} of directional pulsed laser power. This optically corrected, micro-channel cooled, high density laser is usable in all solid state laser systems which require efficient, directional, narrow bandwidth, high optical power density pump sources. 13 figs.

  19. Evaluation of ion current density distribution on an extraction electrode of a radio frequency ion thruster

    NASA Astrophysics Data System (ADS)

    Masherov, P.; Riaby, V.; Abgaryan, V.

    2017-01-01

    The radial distributions of ion current density on an ion extracting electrode of a radio frequency (RF) ion thruster (RIT) with an inductive plasma source were obtained using probe diagnostics of the RF xenon plasma. Measurements were carried out using a plane wall probe simulator and the VGPS-12 Probe System of Plasma Sensors Co. At xenon flow rate q  =  2 sccm plasma pressure was 2 · 10-3 Torr, incident RF generator power varied in the range P g  =  50-250 W with RF power absorbed by plasma up to P p  =  220 W. Ion current densities were determined using semi- and double-logarithmic probe characteristics by linear extrapolations of their ion branches to probe floating potentials. The same parameters were also measured in undisturbed plasma by a classic cylindrical probe. They exceeded plane probe data by more than two times, showing the effectiveness of plasma sheath reproduction of the RIT ion extracting electrode by the plane wall probe simulator. Slight non-uniformity of the resulting plasma distributions and simplified RIT model design showed that the studied device with flat antenna coil and ferrite core could be considered as a promising prospect for RITs of new generation.

  20. Stable formation of ultrahigh power-density 248 nm channels in Xe cluster targets

    SciTech Connect

    Borisov, Alex B.; Racz, Ervin; Khan, Shahab F.; Poopalasingam, Sankar; McCorkindale, John C.; Boguta, John; Longworth, James W.; Rhodes, Charles K.

    2012-07-11

    The optimization of relativistic and ponderomotive self-channeling of ultra-powerful 248 nm laser pulses launched in underdense plasmas with an appropriate longitudinal gradient in the electron density profile located at the initial stage of the self-channeling leads to (1) stable channel formation and (2) highly efficient power compression producing power densities in the 10{sup 19}-10{sup 20} W/cm{sup 3} range. The comparison of theoretical studies with experimental results involving the correlation of (a) Thomson images of the electron density with (b) x-ray images of the channel morphology demonstrates that more than 90% of the incident 248 nm power can be trapped in stable channels and that this stable propagation can be extended to power levels significantly exceeding the critical power of the self-channeling process.

  1. Langmuir Probe Ion density and spacecraft potential analysis for low velocity ions at comet 67P

    NASA Astrophysics Data System (ADS)

    Leffe Johansson, Fredrik; Vigren, Erik; Eriksson, Anders; Henri, Pierre; Vallières, Xavier

    2017-04-01

    The RPC-LAP Langmuir Probe instrument on-board Rosetta monitored the evolution of the plasma around comet 67P/Churyumov-Gerasimenko for more than two years. As the neutral gas density was too low to support efficient electron cooling, the electron temperature remained around 10 eV which drove the spacecraft to negative potential of the same order, complicating the interpretation of the LAP data. To support data interpretation, spacecraft-plasma interaction simulations including simulated I-V curves were carried out using the SPIS code package and we find that the often highly negatively charged (-20V) Rosetta spacecraft accelerate ions towards the spacecraft. If not taken into account, this could lead to an overestimate of the ion speed in the I-V curves. The spacecraft-plasma interaction result is then applied to interpret and constrain cometary ion velocities and densities at perihelion in August 2015.

  2. Ion Channel Gene Expression in Lung Adenocarcinoma: Potential Role in Prognosis and Diagnosis

    PubMed Central

    Ko, Jae-Hong; Gu, Wanjun; Lim, Inja; Bang, Hyoweon; Ko, Eun A.; Zhou, Tong

    2014-01-01

    Ion channels are known to regulate cancer processes at all stages. The roles of ion channels in cancer pathology are extremely diverse. We systematically analyzed the expression patterns of ion channel genes in lung adenocarcinoma. First, we compared the expression of ion channel genes between normal and tumor tissues in patients with lung adenocarcinoma. Thirty-seven ion channel genes were identified as being differentially expressed between the two groups. Next, we investigated the prognostic power of ion channel genes in lung adenocarcinoma. We assigned a risk score to each lung adenocarcinoma patient based on the expression of the differentially expressed ion channel genes. We demonstrated that the risk score effectively predicted overall survival and recurrence-free survival in lung adenocarcinoma. We also found that the risk scores for ever-smokers were higher than those for never-smokers. Multivariate analysis indicated that the risk score was a significant prognostic factor for survival, which is independent of patient age, gender, stage, smoking history, Myc level, and EGFR/KRAS/ALK gene mutation status. Finally, we investigated the difference in ion channel gene expression between the two major subtypes of non-small cell lung cancer: adenocarcinoma and squamous-cell carcinoma. Thirty ion channel genes were identified as being differentially expressed between the two groups. We suggest that ion channel gene expression can be used to improve the subtype classification in non-small cell lung cancer at the molecular level. The findings in this study have been validated in several independent lung cancer cohorts. PMID:24466154

  3. Ion channel gene expression in lung adenocarcinoma: potential role in prognosis and diagnosis.

    PubMed

    Ko, Jae-Hong; Gu, Wanjun; Lim, Inja; Bang, Hyoweon; Ko, Eun A; Zhou, Tong

    2014-01-01

    Ion channels are known to regulate cancer processes at all stages. The roles of ion channels in cancer pathology are extremely diverse. We systematically analyzed the expression patterns of ion channel genes in lung adenocarcinoma. First, we compared the expression of ion channel genes between normal and tumor tissues in patients with lung adenocarcinoma. Thirty-seven ion channel genes were identified as being differentially expressed between the two groups. Next, we investigated the prognostic power of ion channel genes in lung adenocarcinoma. We assigned a risk score to each lung adenocarcinoma patient based on the expression of the differentially expressed ion channel genes. We demonstrated that the risk score effectively predicted overall survival and recurrence-free survival in lung adenocarcinoma. We also found that the risk scores for ever-smokers were higher than those for never-smokers. Multivariate analysis indicated that the risk score was a significant prognostic factor for survival, which is independent of patient age, gender, stage, smoking history, Myc level, and EGFR/KRAS/ALK gene mutation status. Finally, we investigated the difference in ion channel gene expression between the two major subtypes of non-small cell lung cancer: adenocarcinoma and squamous-cell carcinoma. Thirty ion channel genes were identified as being differentially expressed between the two groups. We suggest that ion channel gene expression can be used to improve the subtype classification in non-small cell lung cancer at the molecular level. The findings in this study have been validated in several independent lung cancer cohorts.

  4. Evolution of voltage-gated ion channels at the emergence of Metazoa.

    PubMed

    Moran, Yehu; Barzilai, Maya Gur; Liebeskind, Benjamin J; Zakon, Harold H

    2015-02-15

    Voltage-gated ion channels are large transmembrane proteins that enable the passage of ions through their pore across the cell membrane. These channels belong to one superfamily and carry pivotal roles such as the propagation of neuronal and muscular action potentials and the promotion of neurotransmitter secretion in synapses. In this review, we describe in detail the current state of knowledge regarding the evolution of these channels with a special emphasis on the metazoan lineage. We highlight the contribution of the genomic revolution to the understanding of ion channel evolution and for revealing that these channels appeared long before the appearance of the first animal. We also explain how the elucidation of channel selectivity properties and function in non-bilaterian animals such as cnidarians (sea anemones, corals, jellyfish and hydroids) can contribute to the study of channel evolution. Finally, we point to open questions and future directions in this field of research. © 2015. Published by The Company of Biologists Ltd.

  5. Decoupling ion conductivity and fluid permeation through optimizing hydrophilic channel morphology

    SciTech Connect

    Chu, Peter Po-Jen Fang, Yu-Shin; Tseng, Yu-Chen

    2016-05-18

    Approaches to improve membrane ion conductivity usually leads to higher degree of swelling, more serious fuel cross-over and often sacrificed membrane mechanical strength. Preserving all three main membrane properties is a tough challenge in searching high ion conducting fuel cell membrane. The long standing dilemma is resolved by decoupling ion conduction and fluid permeation property by creating optimized channel morphology using external electric field poling. Success of this approach is demonstrated in the proton conducting membrane composed of poly(ether sulfones) (PES) and sulfonated poly(ether ether ketone) (sPEEK, degree of sulfonation=50%) composites prepared under electric field poling condition. The external field enhanced the aromatic chain ordering from both sPEEK and PES and improved the miscibility. This induced interaction is conducive to the formation of more densely packed amorphous domains that eventually leads to preferentially ordered hydrophilic proton conducting channels having a average dimension (3 nm) smaller than that in generic sPEEK or Nafion. The narrower but more ordered channel displayed much lower methanol permeability (3.17×10{sup −7} cm{sup 2}/s), and lower swelling ratio (31.20%), while the conductivity (~10{sup −1} S/cm) is higher than that of Nafion, or sPEEK at higher (64%) degree of sulfonation. The composite is chemically stable and highly durable with improved membrane mechanical strength. Nearly 50% increase of DMFC power output is observed using this membrane, and the best power density is recorded at 155 mA/cm{sup 2} (80 °C, 1M Methanol).

  6. Radial acceleration of ions by a laser pulse in a plasma channel

    NASA Astrophysics Data System (ADS)

    Kovalev, V. F.; Bychenkov, V. Yu.

    2015-07-01

    The approximate analytic solution of the Cauchy problem is constructed for a system of kinetic equations of an electron-ion plasma that describe the acceleration of ions and the collisionless heating of electrons caused by the radial ponderomotive force of a laser beam that propagates in the transparent plasma of a gas or other low-density target. Under conditions where the Debye radius, r De , of the electrons is considerably smaller than the characteristic localization scale, L, of the laser beam along the radius, ɛ = r De / L ≪ 1, this solution is found by a group transformation that is specified by the operator of approximate renormalization-group symmetries over small parameters, , of the initial distribution functions of particles. For an axially symmetric geometry of the laser beam, the temporal and spatial dependences of the distribution functions of particles are obtained and their integral characteristics, such as the density, mean velocity, temperature, and energy spectrum, are found. The formation of a cylindrical density cusp and the localized heating of electrons at the laser-channel boundary are analytically described.

  7. Studies in High Current Density Ion Sources for Heavy Ion Fusion Applications

    SciTech Connect

    Chacon-Golcher, Edwin

    2002-06-01

    This dissertation develops diverse research on small (diameter ~ few mm), high current density (J ~ several tens of mA/cm2) heavy ion sources. The research has been developed in the context of a programmatic interest within the Heavy Ion Fusion (HIF) Program to explore alternative architectures in the beam injection systems that use the merging of small, bright beams. An ion gun was designed and built for these experiments. Results of average current density yield () at different operating conditions are presented for K+ and Cs+ contact ionization sources and potassium aluminum silicate sources. Maximum values for a K+ beam of ~90 mA/cm2 were observed in 2.3 μs pulses. Measurements of beam intensity profiles and emittances are included. Measurements of neutral particle desorption are presented at different operating conditions which lead to a better understanding of the underlying atomic diffusion processes that determine the lifetime of the emitter. Estimates of diffusion times consistent with measurements are presented, as well as estimates of maximum repetition rates achievable. Diverse studies performed on the composition and preparation of alkali aluminosilicate ion sources are also presented. In addition, this work includes preliminary work carried out exploring the viability of an argon plasma ion source and a bismuth metal vapor vacuum arc (MEVVA) ion source. For the former ion source, fast rise-times (~ 1 μs), high current densities (~ 100 mA/cm+) and low operating pressures (< 2 mtorr) were verified. For the latter, high but acceptable levels of beam emittance were measured (εn ≤ 0.006 π· mm · mrad) although measured currents differed from the desired ones (I ~ 5mA) by about a factor of 10.

  8. Entropy driven insulator-metal crossover in ion channels and water filled nanopores

    NASA Astrophysics Data System (ADS)

    Zhang, Jingshan; Kamenev, Alex; Shklovskii, Boris; Larkin, Anatony

    2006-03-01

    We consider ion transport of an ion channel in a lipid membrane or a water filled nanopore in silicon films [1]. It is known that due to the large ratio of dielectric constants of water (80) and lipid (2), the electric lines of an ion in the channel are squeezed. This should lead to a large electrostatic self-energy barrier for Ohmic resistance [2]. Nevertheless biological channels are well transparent at least for some selected ions. To address this paradox, we study reduction of the electrostatic barrier by a finite concentration of salt in water and/or by immobile charges on the internal channel walls. We show that both types of charges reduce the barrier, leading to insulator-metal crossover resembling metal-insulator transition in excited gas or in doped semiconductors. But here entropy plays the role of quantum mechanics. Evolution of ion channels took into account biological concentration of monovalent salt, and more importantly, made some channels charged from inside to reduce electrostatic barrier for a given sign of ions (cation/anion selectivity). We also show that in the channel with negative wall charges fractionalization of divalent Ca ions into monovalent excitations leads to good Ca-Vs.-Na selectivity of Ca channels. [1] A. Kamenev, J. Zhang, A. I. Larkin, B. I. Shklovskii, Physica A 359, 129 (2006); J. Zhang, A. Kamenev, B. I. Shklovskii, Phys. Rev. Lett. 95, 148101 (2005); cond-mat/0510327. [2] A. Parsegian, Nature 221, 844 (1969).

  9. Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

    PubMed Central

    Ryu, Shin-Young; Jhun, Bong Sook; Hurst, Stephen

    2014-01-01

    Abstract Significance: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently. Recent Advances: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K+ channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling. Critical Issues: Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation. Future Directions: Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters. Antioxid. Redox Signal. 21, 987–1006. PMID:24180309

  10. Hypoxia-Dependent Reactive Oxygen Species Signaling in the Pulmonary Circulation: Focus on Ion Channels

    PubMed Central

    Veit, Florian; Pak, Oleg; Brandes, Ralf P.

    2015-01-01

    Abstract Significance: An acute lack of oxygen in the lung causes hypoxic pulmonary vasoconstriction, which optimizes gas exchange. In contrast, chronic hypoxia triggers a pathological vascular remodeling causing pulmonary hypertension, and ischemia can cause vascular damage culminating in lung edema. Recent Advances: Regulation of ion channel expression and gating by cellular redox state is a widely accepted mechanism; however, it remains a matter of debate whether an increase or a decrease in reactive oxygen species (ROS) occurs under hypoxic conditions. Ion channel redox regulation has been described in detail for some ion channels, such as Kv channels or TRPC6. However, in general, information on ion channel redox regulation remains scant. Critical Issues and Future Directions: In addition to the debate of increased versus decreased ROS production during hypoxia, we aim here at describing and deciphering why different oxidants, under different conditions, can cause both activation and inhibition of channel activity. While the upstream pathways affecting channel gating are often well described, we need a better understanding of redox protein modifications to be able to determine the complexity of ion channel redox regulation. Against this background, we summarize the current knowledge on hypoxia-induced ROS-mediated ion channel signaling in the pulmonary circulation. Antioxid. Redox Signal. 22, 537–552 PMID:25545236

  11. Ion channels or aquaporins as novel molecular targets in gastric cancer.

    PubMed

    Xia, Jianling; Wang, Hongqiang; Li, Shi; Wu, Qinghui; Sun, Li; Huang, Hongxiang; Zeng, Ming

    2017-03-06

    Gastric cancer (GC) is a common disease with few effective treatment choices and poor prognosis, and has the second-highest mortality rates among all cancers worldwide. Dysregulation and/or malfunction of ion channels or aquaporins (AQPs) are common in various human cancers. Furthermore, ion channels are involved in numerous important aspects of the tumor aggressive phonotype, such as proliferation, cell cycle, apoptosis, motility, migration, and invasion. Indeed, by localizing in the plasma membrane, ion channels or AQPs can sense and respond to extracellular environment changes; thus, they play a crucial role in cell signaling and cancer progression. These findings have expanded a new area of pharmaceutical exploration for various types of cancer, including GC. The involvement of multiple ion channels, such as voltage-gated potassium and sodium channels, intracellular chloride channels, 'transient receptor potential' channels, and AQPs, which have been shown to facilitate the pathogenesis of other tumors, also plays a role in GC. In this review, an overview of ion channel and aquaporin expression and function in carcinogenesis of GC is presented. Studies of ion channels or AQPs will advance our understanding of the molecular genesis of GC and may identify novel and effective targets for the clinical application of GC.

  12. Ion densities and magnetic signatures of dust pickup at Enceladus

    NASA Astrophysics Data System (ADS)

    Kriegel, Hendrik; Simon, Sven; Meier, Patrick; Motschmann, Uwe; Saur, Joachim; Wennmacher, Alexandre; Strobel, Darrell F.; Dougherty, Michele K.

    2014-04-01

    Encedalus' plume of charged dust has been shown to strongly modify the plasma structures. Therefore, we analyze the magnetic signatures of dust to constrain the dust plume. For the first time, the mutual feedback between the nanograins and their plasma environment is investigated. Our model combines plasma simulations by means of the A.I.K.E.F. (Adaptive Ion-Kinetic Electron-Fluid) code with Monte Carlo simulations of the 3-D profiles of the gas and dust plumes. Data from several instruments of Cassini are considered: the neutral plume model is in good agreement with INMS data, whereas theoretical predictions of the peak ion density are compared against CAPS data, and properties of the dust are obtained by comparing our results with MAG data from the recent E14-E19 flybys. Our main results are (1) due to the ion-neutral chemistry, H3O+ is the predominant ion species within the plume; (2) the high nanograin densities observed by CAPS require an increased effective ionization frequency to fulfill quasi-neutrality; (3) the nanograin pickup current makes only a minor contribution to the current systems; i.e., the major contribution of the dust arises from electron absorption; (4) the pickup of nanograins is clearly visible in the magnetic field signatures, even including the distant encounter E15; (5) MAG data indicate a southward extension of the charged dust plume of at least 4 Enceladus radii; (6) the modification of the currents by the nanograins is responsible for the surprising fact that Cassini did not detect a region with a reduced magnetic field strength.

  13. Acid stress mediated adaptive divergence in ion channel function during embryogenesis in Rana arvalis

    PubMed Central

    Shu, Longfei; Laurila, Anssi; Räsänen, Katja

    2015-01-01

    Ion channels and pumps are responsible for ion flux in cells, and are key mechanisms mediating cellular function. Many environmental stressors, such as salinity and acidification, are known to severely disrupt ionic balance of organisms thereby challenging fitness of natural populations. Although ion channels can have several vital functions during early life-stages (e.g. embryogenesis), it is currently not known i) how developing embryos maintain proper intracellular conditions when exposed to environmental stress and ii) to what extent environmental stress can drive intra-specific divergence in ion channels. Here we studied the moor frog, Rana arvalis, from three divergent populations to investigate the role of different ion channels and pumps for embryonic survival under acid stress (pH 4 vs 7.5) and whether populations adapted to contrasting acidities differ in the relative role of different ion channel/pumps. We found that ion channels that mediate Ca2+ influx are essential for embryonic survival under acidic pH, and, intriguingly, that populations differ in calcium channel function. Our results suggest that adaptive divergence in embryonic acid stress tolerance of amphibians may in part be mediated by Ca2+ balance. We suggest that ion flux may mediate adaptive divergence of natural populations at early life-stages in the face of environmental stress. PMID:26381453

  14. Organic toxins as tools to understand ion channel mechanisms and structure.

    PubMed

    Morales-Lázaro, Sara Luz; Hernández-García, Enrique; Serrano-Flores, Barbara; Rosenbaum, Tamara

    2015-01-01

    Ion channels constitute a varied class of membrane proteins with pivotal roles in cellular physiology and that are fundamental for neuronal signaling, hormone secretion and muscle contractility. Hence, it is not unanticipated that toxins from diverse organisms have evolved to modulate the activity of ion channels. For instance, animals such as cone snails, scorpions, spiders and snakes use toxins to immobilize and capture their prey by affecting ion channel function. This is a beautiful example of an evolutionary process that has led to the development of an injection apparatus from predators and to the existence of toxins with high affinity and specificity for a given target. Toxins have been used in the field of ion channel biophysics for several decades to gain insight into the gating mechanisms and the structure of ion channels. Through the use of these peptides, much has been learned about the ion conduction pathways, voltage-sensing mechanisms, pore sizes, kinetics, inactivation processes, etc. This review examines an assortment of toxins that have been used to study different ion channels and describes some key findings about the structure-function relationships in these proteins through the details of the toxin-ion channel interactions.

  15. Simulation of charge transport in ion channels and nanopores with anisotropic permittivity

    PubMed Central

    Mashl, R. Jay; Lee, Kyu Il; Jakobsson, Eric; Ravaioli, Umberto

    2010-01-01

    Ion channels are part of nature's solution for regulating biological environments. Every ion channel consists of a chain of amino acids carrying a strong and sharply varying permanent charge, folded in such a way that it creates a nanoscopic aqueous pore spanning the otherwise mostly impermeable membranes of biological cells. These naturally occurring proteins are particularly interesting to device engineers seeking to understand how such nanoscale systems realize device-like functions. Availability of high-resolution structural information from X-ray crystallography, as well as large-scale computational resources, makes it possible to conduct realistic ion channel simulations. In general, a hierarchy of simulation methodologies is needed to study different aspects of a biological system like ion channels. Biology Monte Carlo (BioMOCA), a three-dimensional coarse-grained particle ion channel simulator, offers a powerful and general approach to study ion channel permeation. BioMOCA is based on the Boltzmann Transport Monte Carlo (BTMC) and Particle-Particle-Particle-Mesh (P3M) methodologies developed at the University of Illinois at Urbana-Champaign. In this paper we briefly discuss the various approaches to simulating ion flow in channel systems that are currently being pursued by the biophysics and engineering communities, and present the effect of having anisotropic dielectric constants on ion flow through a number of nanopores with different effective diameters. PMID:20445807

  16. Density bunching effects in a laser-driven, near-critical density plasma for ion acceleration

    NASA Astrophysics Data System (ADS)

    Ettlinger, Oliver; Sahai, Aakash; Hicks, George; Ditter, Emma-Jane; Dover, Nicholas; Chen, Yu-Hsin; Helle, Michael; Gordon, Daniel; Ting, Antonio; Polyanskiy, Mikhail; Pogorelsky, Igor; Babzien, Marcus; Najmudin, Zulfikar

    2016-10-01

    We present work investigating the interaction of relativistic laser pulses with near-critical density gas targets exhibiting pre-plasma scale lengths of several laser wavelengths. Analytical and computational modelling suggest that the interaction dynamics in a low-Z plasma is a direct result of induced density bunching up to the critical surface. In fact, these bunches can themselves become overcritical and experience significant radiation pressure, accelerating ions to higher energies compared to an ``idealised'' plasma slab target. This work will be used to help explain the observation of ion energies exceeding those predicted by radiation pressure driven hole-boring in recent experiments using the TW CO2 laser at the Accelerator Test Facility at Brookhaven National Laboratory.

  17. Coarse Grained Model for Exploring Voltage Dependent Ion Channels

    PubMed Central

    Dryga, Anatoly; Chakrabarty, Suman; Vicatos, Spyridon; Warshel, Arieh

    2011-01-01

    The relationship between the membrane voltage and the gating of voltage activated ion channels and other systems have been a problem of great current interest. Unfortunately, reliable molecular simulations of external voltage effects present a major challenge, since meaningful converging microscopic simulations are not yet available and macroscopic treatments involve major uncertainties in terms of the dielectric used and other key features. This work extends our coarse grained (CG) model to simulations of membrane/protein systems under external potential. Special attention has been devoted to a consistent modeling of the effect of external potential due to the electrodes, emphasizing semimacroscopic description of the electrolytes in the solution regions between the membranes and the electrodes, as well as the coupling between the combined potential from the electrodes and electrolytes, and the protein ionization states. We also provide a clear connection to microscopic treatment of the electrolytes and thus can explore possible conceptual problems that are hard to resolve by other current approaches. For example, we obtain a clear description of the charge distribution in the entire electrolyte system, including near the electrodes in membrane/electrodes systems (where continuum models do not seem to provide the relevant results). Furthermore, the present treatment provides an insight on the distribution of the electrolyte charges before and after equilibration across the membrane, and thus on the nature of the gating charge. The different aspects of the model have been carefully validated by considering problems ranging for the simple Debye-Huckel, Gouy-Chapman models to the evaluation of the electrolyte distribution between two electrodes, as well as the effect of extending the simulation system by periodic replicas. Overall the clear connection to microscopic descriptions combined with the power of the CG modeling seems to offer a powerful tool for exploring

  18. Ab initio electronic stopping power and threshold effect of channeled slow light ions in HfO2

    NASA Astrophysics Data System (ADS)

    Li, Chang-Kai; Wang, Feng; Liao, Bin; OuYang, Xiao-Ping; Zhang, Feng-Shou

    2017-09-01

    We present an ab initio study of the electronic stopping power of protons and helium ions in an insulating material, HfO2. The calculations are carried out in channeling conditions with different impact parameters by employing Ehrenfest dynamics and real-time, time-dependent density functional theory. The satisfactory comparison with available experiments demonstrates that this approach provides an accurate description of electronic stopping power. The velocity-proportional stopping power is predicted for protons and helium ions in the low-energy region, which conforms to the linear response theory. Due to the existence of a wide band gap, a threshold effect in the extremely low velocity regime below excitation is expected. For protons, the threshold velocity is observable, while it does not appear in the case of helium ions. This indicates the existence of extra energy-loss channels beyond the electron-hole pair excitation when helium ions are moving through the crystal. To analyze it, we checked the charge state of the moving projectiles and an explicit charge exchange behavior between the ions and host atoms was found. The missing threshold effect for helium ions is attributed to the charge transfer, which also contributes to energy loss of the ion.

  19. Effect of metal ions on radical type and proton-coupled electron transfer channel: sigma-radical vs pi-radical and sigma-channel vs pi-channel in the imide units.

    PubMed

    Chen, Xiaohua; Xing, Dianxiang; Zhang, Liang; Cukier, Robert I; Bu, Yuxiang

    2009-12-01

    The mechanism of proton transfer (PT)/electron transfer (ET) in imide units, and its regulation by hydrated metal ions, was explored theoretically using density functional theory in a representative model (a nearly planar and cisoid complex between uracil and its N(3)-dehydrogenated radical, UU). In UU (sigma-radical), PT/ET normally occurs via a seven-center, cyclic proton-coupled sigma-electron sigma-channel transfer (PC(sigma)E(sigma)T) mechanism (3.8 kcal/mol barrier height) with a N(3)-->N(3') PT and an O(4)-->O(4') ET. Binding of hydrated metal ions to the dioxygen sites (O(2)/O(2') or/and O(4)/O(4')) of UU may significantly affect its PT/ET cooperative reactivity by changing the radical type (sigma-radical <--> pi-radical) and ET channel (sigma-channel <--> pi-channel), leading to different mechanisms, ranging from PC(sigma)E(sigma)T, to proton-coupled pi-electron sigma-channel transfer (PC(pi)E(sigma)T) to proton-coupled pi-electron pi-channel transfer (PC(pi)E(pi)T). This change originates from an alteration of the ordering of the UU moiety SOMO/HDMO (the singly occupied molecular orbital and the highest doubly occupied molecular orbital), induced by binding of the hydrated metal ions. It is a consequence of three associated factors: the asymmetric reactant structure, electron cloud redistribution, and fixing role of metal ions to structural backbone. The findings regarding the modulation of the PT/ET pathway via hydrated metal ions may provide valuable information for a greater understanding of PT/ET cooperative mechanisms, and an alternative way for designing imide-based molecular devices, such as molecular switches and molecular wires.

  20. Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis

    PubMed Central

    Nieto-Torres, Jose L.; Verdiá-Báguena, Carmina; Castaño-Rodriguez, Carlos; Aguilella, Vicente M.; Enjuanes, Luis

    2015-01-01

    Modification of host-cell ionic content is a significant issue for viruses, as several viral proteins displaying ion channel activity, named viroporins, have been identified. Viroporins interact with different cellular membranes and self-assemble forming ion conductive pores. In general, these channels display mild ion selectivity, and, eventually, membrane lipids play key structural and functional roles in the pore. Viroporins stimulate virus production through different mechanisms, and ion channel conductivity has been proved particularly relevant in several cases. Key stages of the viral cycle such as virus uncoating, transport and maturation are ion-influenced processes in many viral species. Besides boosting virus propagation, viroporins have also been associated with pathogenesis. Linking pathogenesis either to the ion conductivity or to other functions of viroporins has been elusive for a long time. This article summarizes novel pathways leading to disease stimulated by viroporin ion conduction, such as inflammasome driven immunopathology. PMID:26151305

  1. Relevance of Viroporin Ion Channel Activity on Viral Replication and Pathogenesis.

    PubMed

    Nieto-Torres, Jose L; Verdiá-Báguena, Carmina; Castaño-Rodriguez, Carlos; Aguilella, Vicente M; Enjuanes, Luis

    2015-07-03

    Modification of host-cell ionic content is a significant issue for viruses, as several viral proteins displaying ion channel activity, named viroporins, have been identified. Viroporins interact with different cellular membranes and self-assemble forming ion conductive pores. In general, these channels display mild ion selectivity, and, eventually, membrane lipids play key structural and functional roles in the pore. Viroporins stimulate virus production through different mechanisms, and ion channel conductivity has been proved particularly relevant in several cases. Key stages of the viral cycle such as virus uncoating, transport and maturation are ion-influenced processes in many viral species. Besides boosting virus propagation, viroporins have also been associated with pathogenesis. Linking pathogenesis either to the ion conductivity or to other functions of viroporins has been elusive for a long time. This article summarizes novel pathways leading to disease stimulated by viroporin ion conduction, such as inflammasome driven immunopathology.

  2. Physiologic and pathophysiologic consequences of altered sialylation and glycosylation on ion channel function.

    PubMed

    Baycin-Hizal, Deniz; Gottschalk, Allan; Jacobson, Elena; Mai, Sunny; Wolozny, Daniel; Zhang, Hui; Krag, Sharon S; Betenbaugh, Michael J

    2014-10-17

    Voltage-gated ion channels are transmembrane proteins that regulate electrical excitability in cells and are essential components of the electrically active tissues of nerves, muscle and the heart. Potassium channels are one of the largest subfamilies of voltage sensitive channels and are among the most-studied of the voltage-gated ion channels. Voltage-gated channels can be glycosylated and changes in the glycosylation pattern can affect ion channel function, leading to neurological and neuromuscular disorders and congenital disorders of glycosylation (CDG). Alterations in glycosylation can also be acquired and appear to play a role in development and aging. Recent studies have focused on the impact of glycosylation and sialylation on ion channels, particularly for voltage-gated potassium and sodium channels. The terminal step of sialylation often affects channel activation and inactivation kinetics. The presence of sialic acids on O or N-glycans can alter the gating mechanism and cause conformational changes in the voltage-sensing domains due to sialic acid's negative charges. This manuscript will provide an overview of sialic acids, potassium and sodium channel function, and the impact of sialylation on channel activation and deactivation.

  3. How ion channels sense mechanical force: insights from mechanosensitive K2P channels TRAAK, TREK1, and TREK2.

    PubMed

    Brohawn, Stephen G

    2015-09-01

    The ability to sense and respond to mechanical forces is essential for life and cells have evolved a variety of systems to convert physical forces into cellular signals. Within this repertoire are the mechanosensitive ion channels, proteins that play critical roles in mechanosensation by transducing forces into ionic currents across cellular membranes. Understanding how these channels work, particularly in animals, remains a major focus of study. Here, I review the current understanding of force gating for a family of metazoan mechanosensitive ion channels, the two-pore domain K(+) channels (K2Ps) TRAAK, TREK1, and TREK2. Structural and functional insights have led to a physical model for mechanical activation of these channels. This model of force sensation by K2Ps is compared to force sensation by bacterial mechanosensitive ion channels MscL and MscS to highlight principles shared among these evolutionarily unrelated channels, as well as differences of potential functional relevance. Recent advances address fundamental questions and stimulate new ideas about these unique mechanosensors.

  4. 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.

  5. Heteromultimerization of prokaryotic bacterial cyclic nucleotide-gated (bCNG) ion channels, members of the mechanosensitive channel of small conductance (MscS) superfamily.

    PubMed

    Malcolm, Hannah R; Heo, Yoon-Young; Elmore, Donald E; Maurer, Joshua A

    2014-12-30

    Traditionally, prokaryotic channels are thought to exist as homomultimeric assemblies, while many eukaryotic ion channels form complex heteromultimers. Here we demonstrate that bacterial cyclic nucleotide-gated channels likely form heteromultimers in vivo. Heteromultimer formation is indicated through channel modeling, pull-down assays, and real-time polymerase chain reaction analysis. Our observations demonstrate that prokaryotic ion channels can display complex behavior and regulation akin to that of their eukaryotic counterparts.

  6. Ion flux, ion energy distribution and neutral density in an inductively coupled argon discharge

    NASA Astrophysics Data System (ADS)

    Chevolleau, T.; Fukarek, W.

    2000-11-01

    The dependence of ion flux, ion energy distribution and neutral density of a planar radiofrequency (RF) driven inductively coupled plasma source on pressure and power is analysed using a plasma monitor and a Faraday cup. The ion flux is about 7 mA cm-2 at 5 Pa and 300 W and increases as RF power and argon pressure increase. The ion energy distribution consists of a single peak with a full width at half maximum of 3 eV for a discharge power in the range from 50 to 300 W and for a pressure in the range from 0.5 to 5 Pa. This indicates that inductive coupling mainly drives the discharge while capacitive coup