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Ion Channels (ion + channel)
Kinds of Ion Channels Terms modified by Ion Channels Selected AbstractsGABAC RECEPTOR ION CHANNELSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2004M Chebib SUMMARY 1.,The present review gives an overview of studies conducted on GABAC receptors over the past 10 years since the author started at the University of Sydney. It concentrates on the structure,activity relationship profiles of the receptor and how these studies were used to: (i) develop selective GABAC receptor ligands; and (ii) understand the impact of amino acid changes on GABAC receptor pharmacology and function. 2.,Structure,activity relationship studies involving variations of both ligands and their receptor targets are vital to the discovery of drugs that interact selectively with particular native and mutant receptor subtypes. Such agents may be useful for treating anxiety, depression, epilepsyand memory related disorders, such as Alzheimer's disease. [source] Inside Front Cover: Novel Engineered Ion Channel Provides Controllable Ion Permeability for Polyelectrolyte Microcapsules Coated with a Lipid Membrane (Adv. Funct.ADVANCED FUNCTIONAL MATERIALS, Issue 2 2009Mater. In their Full Paper on page 201, Donald Martin and co-workers describe the covering of polyelectrolyte microcapsules with a lipid bilayer that incorporates a novel engineered ion channel to provide a functional capability to control transport across the microcapsule wall. The cover image shows atomic-force microscopy images of these 8-layer polyelectroctrolyte capsules recorded using tapping mode in an aqueous environment. The capsules can be seen to collapse in a folded manner, with an occasional wrinkle that "absorbs" the extra surface area when flattening the spherical surface. [source] Novel Engineered Ion Channel Provides Controllable Ion Permeability for Polyelectrolyte Microcapsules Coated with a Lipid MembraneADVANCED FUNCTIONAL MATERIALS, Issue 2 2009Andrew R. Battle Abstract The development of nanostructured microcapsules based on a biomimetic lipid bilayer membrane (BLM) coating of poly(sodium styrenesulfonate) (PSS)/poly(allylamine hydrochloride) (PAH) polyelectrolyte hollow microcapsules is reported. A novel engineered ion channel, gramicidin (bis-gA), incorporated into the lipid membrane coating provides a functional capability to control transport across the microcapsule wall. The microcapsules provide transport and permeation for drug-analog neutral species, as well as positively and negatively charged ionic species. This controlled transport can be tuned for selective release biomimetically by controlling the gating of incorporated bis-gA ion channels. This system provides a platform for the creation of "smart" biomimetic delivery vessels for the effective and selective therapeutic delivery and targeting of drugs. [source] Expression of Acid-Sensing Ion Channel 3 (ASIC3) in Nucleus Pulposus Cells of the Intervertebral Disc Is Regulated by p75NTR and ERK Signaling,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2007Yoshiyasu Uchiyama Abstract Although a recent study has shown that skeletal tissues express ASICs, their function is unknown. We show that intervertebral disc cells express ASIC3; moreover, expression is uniquely regulated and needed for survival in a low pH and hypoeromsotic medium. These findings suggest that ASIC3 may adapt disc cells to their hydrodynamically stressed microenvironment. Introduction: The nucleus pulposus is an avascular, hydrated tissue that permits the intervertebral disc to resist compressive loads to the spine. Because the tissue is hyperosmotic and avascular, the pH of the nucleus pulposus is low. To determine the mechanisms by which the disc cells accommodate to the low pH and hypertonicity, the expression and regulation of the acid sensing ion channel (ASIC)3 was examined. Materials and Methods: Expression of ASICs in cells of the intervertebral disc was analyzed. To study its regulation, we cloned the 2.8-kb rat ASIC3 promoter and performed luciferase reporter assays. The effect of pharmacological inhibition of ASICs on disc cell survival was studied by measuring MTT and caspase-3 activities. Results: ASIC3 was expressed in discal tissues and cultured disc cells in vitro. Because studies of neuronal cells have shown that ASIC3 expression and promoter activity is induced by nerve growth factor (NGF), we examined the effect of NGF on nucleus pulposus cells. Surprisingly, ASIC3 promoter activity did not increase after NGF treatment. The absence of induction was linked to nonexpression of tropomyosin-related kinase A (TrkA), a high-affinity NGF receptor, although a modest expression of p75NTR was seen. When treated with p75NTR antibody or transfected with dominant negative-p75NTR plasmid, there was significant suppression of ASIC3 basal promoter activity. To further explore the downstream mechanism of control of ASIC3 basal promoter activity, we blocked p75NTR and measured phospho extracellular matrix regulated kinase (pERK) levels. We found that DN-p75NTR suppressed NGF mediated transient ERK activation. Moreover, inhibition of ERK activity by dominant negative-mitogen activated protein kinase kinase (DN-MEK) resulted in a dose-dependent suppression of ASIC3 basal promoter activity, whereas overexpression of constitutively active MEK1 caused an increase in ASIC3 promoter activity. Finally, to gain insight in the functional importance of ASIC3, we suppressed ASIC activity in nucleus pulposus cells. Noteworthy, under both hyperosmotic and acidic conditions, ASIC3 served to promote cell survival and lower the activity of the pro-apoptosis protein, caspase-3. Conclusions: Results of this study indicate that NGF serves to maintain the basal expression of ASIC3 through p75NTR and ERK signaling in discal cells. We suggest that ASIC3 is needed for adaptation of the nucleus pulposus and annulus fibrosus cells to the acidic and hyperosmotic microenvironment of the intervertebral disc. [source] Tetrahydropyran-Amino Acids: Novel Building Blocks for Gramicidin-Hybrid Ion ChannelsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 12 2006Sabine Schröder Abstract The stereoselective synthesis of a cis -2,6-disubstituted tetrahydropyran bearing a ,-amino acid has been achieved starting from N -Boc-leucinal. The THP amino acid was incorporated into peptide sequences and the structural consequences were studied by X-ray crystallography and NMR analysis. Single-channel current measurements showed that the THP amino acid is a suitable substitute for positions 11 and 12 of the gramicidin ion channel. The resulting hybrid ion channel revealed Eisenman I ion selectivity and an ion-dependence of the channel dwell time. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Behavior of Nonselective Cation Channels and Large-Conductance Ca2+ -Activated K+ Channels Induced by Dynamic Changes in Membrane Stretch in Cultured Smooth Muscle Cells of Human Coronary ArteryJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 1 2003PH.D., SHENG-NAN WU M.D. Stretch-Activated Ion Channels. Introduction: The effects of membrane stretch on ion channels were investigated in cultured smooth muscle cells of human coronary artery. Methods and Results: In the cell-attached configuration, membrane stretch with negative pressure induced two types of stretch-activated (SA) ion channels: a nonselective cation channel and a large-conductance Ca2+ -activated K+ (BKCa) channel. The single-channel conductances of SA cation and BKCa channels were 26 and 203 pS, respectively. To elucidate the mechanism of activation of these SA channels and to minimize mechanical disruption, a sinusoidal change in pipette pressure was applied to the on-cell membrane patch. During dynamic changes in pipette pressure, increases in SA cation channel activity was found to coincide with increases in BKCa channel activity. In the continued presence of cyclic stretch, the activity of SA cation channels gradually diminished. However, after termination of cyclic stretch, BKCa channel activity was greatly enhanced, but the activity of SA cation channels disappeared. Conclusion: This study is the first to demonstrate that the behavior of SA cation and BKCa channels in coronary smooth muscle cells is differentially susceptible to dynamic changes in membrane tension. [source] Atrial Fibrillation in the Goat Induces Changes in Monophasic Action Potential and mRNA Expression of Ion Channels Involved in RepolarizationJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 11 2000HUUB M.W. VAN DER VELDEN PH.D. MAP Changes and Ion Channel Expression in Goat AF. Introduction: Sustained atrial fibrillation (AF) is characterized by a marked shortening of the atrial effective refractory period (AKRP) and a decrease or reversal of its physiolonic adaptation to heart rate. The aim of the present study was to investigate whether the AF-induced changes in AKKP in the goat are associated with changes in the atrial monophasic action potential (MAP) and whether an abnormal expression of specific ion channels underlies such changes. Methods and Results: Following thoracotomy, MAPs were recorded from the free wall of the right atrium hoth before induction of AF (control) and after cardioversion of sustained AF (>2 months) in chronically instrumented goats. In control goats. MAP duration at 80% repolarization (MAPD80) shortened (P < 0.01) from 132 ± 4 msec during slow pacing (400-msec interval) to 86 ± 10 msec during fast pacing (180 msec). After cardioversion of sustained AF, the MAPD80, during slow pacing was as short as 67 ± 5 msec (electrical remodeling). Increasing the pacing rate resulted in prolongation (P = 0.02) of the MAPD80 to 91 ± 6 msec. Also. MAPD20 (20% repolarization) shortened (P = 0.05) from 32 ± 4 msec (400 msec) to 14 ± 7 msec (180 msec) in the control goats, whereas it prolonged (P = 0.03) from 20 ± 3 msec (400 msec) to 33 ± 5 msec (180 msec) in sustained AF, mRNA expression of the L-type Ca2+ channel ,1c gene and Kv1.5 potassium channel gene, which underlie Ica, and Ikur respectively, was reduced in sustained.AF compared with sinus rhythm hy 32% (P = 0.01) and 45% (P < 0.01). respectively. No significant changes were found in the mRNA levels of the rapid Na+ channel, the Na+/Ca2+ exchanger, or the Kv4.2/4.3 channels responsible for I10. Conclusion: AF-induced electrical remodeling in the goat comprises shortening of MAPD and reversal of its physiologic rate adaptation. Changes in the time course of reploarization of the action potential are associated with changes in mRNA expression of the , subunit genes of the L.-type Ca2+ channel and the Kvl.5 potassium channel. [source] Sensor Mechanism and Afferent Signal Transduction of the Urinary Bladder: Special Focus on transient receptor potential Ion ChannelsLUTS, Issue 2 2010Masayuki TAKEDA In the urine storage phase, mechanical stretch stimulates bladder afferents. These urinary bladder afferent sensory nerves consist of small diameter A, - and C-fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. The exact mechanisms that underline mechano-sensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g. TTX-resistant Na+ channels, Kv channels and hyperpolarization-activated cyclic nucleotidegated cation channels, degenerin/epithelial Na+ channel), and receptors (e.g. TRPV1, TRPM8, TRPA1, P2X2/3, etc.) have been identified at bladder afferent terminals and have implicated in the generation and modulation of afferent signals, which are elcited by a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The mammalian transient receptor potential (TRP) family consists of 28 channels that can be subdivided into six different classes: TRPV (Vanilloid), TRPC (Canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 among TRPs has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels, ion channels, and receptors in the pathophysiology of the urogenital tract, and may provide a new strategy for the treatment of bladder dysfunction. [source] New Expression Profiles of Voltage-gated Ion Channels in Arteries Exposed to High Blood PressureMICROCIRCULATION, Issue 4 2002Robert H. Cox The diameters of small arteries and arterioles are tightly regulated by the dynamic interaction between Ca2+ and K+ channels in the vascular smooth muscle cells. Calcium influx through voltage-gated Ca2+ channels induces vasoconstriction, whereas the opening of K+ channels mediates hyperpolarization, inactivation of voltage-gated Ca2+ 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 Ca2+ (CaL) channels, voltage-gated K+ (KV) channels, and high-conductance voltage- and Ca2+ -sensitive K+ (BKCa) 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 CaL, KV, and BKCa 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. [source] Single Nucleotide Polymorphisms and Haplotype of Four Genes Encoding Cardiac Ion Channels in Chinese and their Association with ArrhythmiaANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2008Yu Zhang Ph.D. Background: Many studies revealed that variations in cardiac ion channels would cause cardiac arrhythmias or act as genetic risk factors. We hypothesized that specific single nucleotide polymorphisms in cardiac ion channels were associated with cardiac rhythm disturbance in the Chinese population. Method: We analyzed 160 nonfamilial cardiac arrhythmia patients and 176 healthy individuals from which 81 individuals were selected for association study, and a total of 19 previously reported SNPs in four cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1) were genotyped. Results: The frequency of KCNQ1 1638G>A, as well as the haplotype harboring KCNQ1 1638A, KCNQ1 1685 + 23G and 1732 + 43T (haplotype AGT) was significantly higher in healthy controls than in arrhythmia patients. This finding implicated that this haplotype (AGT) might be a protective factor against arrhythmias. Conclusions: Our study provided important information to elucidate the effect of SNPs of cardiac ion channel genes on channel function and susceptibility to cardiac arrhythmias in Chinese population. [source] Functional Studies of Synthetic Gramicidin Hybrid Ion Channels in CHO CellsCHEMBIOCHEM, Issue 5 2007Ryszard Wesolowski Abstract The function of a gramicidin hybrid ion channel in living Chinese hamster ovary (CHO) cells was investigated by the patch clamp method. The synthetic ion channel 1 consists of two cyclohexyl ether amino acids that link two minigramicidin strands. With 1 at a concentration of 1.0 ,M, an increase in the whole-cell membrane conductance was observed after 1.37 min. The conductance showed larger currents when Cs+ was used as charge carrier than when Na+ and K+ were used. In single-channel recordings with Cs+ as charge carrier, the substance showed comparable single-channel amplitudes in the membrane of living cells and artificial black lipid bilayers. In addition to functioning as a cation channel, compound 1 appeared to be a water channel. Exposure of the CHO cells to an extracellular hypoosmotic solution did not substantially change the cell volume. Extracellular hypoosmotic conditions in the presence of 1 increased the cell size to 146.5,% that of the control. Thus, the synthetic hybrid channel 1 can function as a cation channel with some Cs+ specificity, and as a water channel in CHO cells. [source] Ligand-Gated Synthetic Ion ChannelsCHEMISTRY - A EUROPEAN JOURNAL, Issue 22 2005Pinaki Talukdar Abstract Supramolecular ,-stack architecture is fundamental in DNA chemistry but absent in biological and synthetic ion channels and pores. Here, a novel rigid-rod ,-stack architecture is introduced to create synthetic ion channels with characteristics that are at the forefront of rational design, that is, ligand gating by a conformational change of the functional supramolecule. Namely, the intercalation of electron-rich aromatics is designed to untwist inactive electron-poor helical ,-stacks without internal space into open barrel-stave ion channels. Conductance experiments in planar lipid bilayers corroborate results from spherical bilayers and molecular modeling: Highly cooperative and highly selective ligand gating produces small, long-lived, weakly anion selective, ohmic ion channels. Structural studies conducted under conditions relevant for function provide experimental support for helix,barrel transition as origin of ligand gating. Control experiments demonstrate that minor structural changes leading to internal decrowding suffice to cleanly annihilate chiral self-organization and function. [source] Ion channel remodeling in gastrointestinal inflammationNEUROGASTROENTEROLOGY & MOTILITY, Issue 10 2010H. I. Akbarali Abstract Background,Gastrointestinal inflammation significantly affects the electrical excitability of smooth muscle cells. Considerable progress over the last few years have been made to establish the mechanisms by which ion channel function is altered in the setting of gastrointestinal inflammation. Details have begun to emerge on the molecular basis by which ion channel function may be regulated in smooth muscle following inflammation. These include changes in protein and gene expression of the smooth muscle isoform of L-type Ca2+ channels and ATP-sensitive K+ channels. Recent attention has also focused on post-translational modifications as a primary means of altering ion channel function in the absence of changes in protein/gene expression. Protein phosphorylation of serine/theronine or tyrosine residues, cysteine thiol modifications, and tyrosine nitration are potential mechanisms affected by oxidative/nitrosative stress that alter the gating kinetics of ion channels. Collectively, these findings suggest that inflammation results in electrical remodeling of smooth muscle cells in addition to structural remodeling. Purpose,The purpose of this review is to synthesize our current understanding regarding molecular mechanisms that result in altered ion channel function during gastrointestinal inflammation and to address potential areas that can lead to targeted new therapies. [source] Na+/Ca2+ exchanger modulates the flagellar wave pattern for the regulation of motility activation and chemotaxis in the ascidian spermatozoaCYTOSKELETON, Issue 10 2006Kogiku Shiba Abstract Ion channels and ion exchangers are known to be important participants in various aspects of sperm physiology, e.g. motility activation, chemotaxis, the maintenance of motility and the acrosome reaction in the sperm. We report here on a role of the K+ -independent Na+/Ca2+ exchanger (NCX) on ascidian sperm. Reverse-transcriptase PCR reveals that the NCX is expressed in the testis while immunoblotting and immunolocalization demonstrate that the NCX exists on the sperm in the ascidian Ciona savignyi and C. intestinalis. A potent blocker of the NCX, KB-R7943 was found to block sperm-activating and -attracting factor (SAAF)-induced motility activation, sperm motility and sperm chemotaxis. We further analyzed the effects of this blocker on motility parameters such as the flagellar waveform, curvature, beat frequency, amplitude and wavelength of the sperm flagella. Inhibition of the NCX caused two distinct effects: a low concentration of KB-R7943 induced symmetric bending, whereas a high concentration of KB-R7943 resulted in asymmetric flagellar bending. These findings suggest that the NCX plays important roles in the regulation of SAAF-induced sperm chemotaxis, motility activation and motility maintenance in the ascidian. This study provides new information toward an understanding of Ca2+ transport systems in sperm motility and chemotaxis. Cell Motil. Cytoskeleton 2006. © 2006 Wiley-Liss, Inc. [source] Ion channels in toxicologyJOURNAL OF APPLIED TOXICOLOGY, Issue 6 2010Iván Restrepo-Angulo Abstract Ion channels play essential roles in human physiology and toxicology. Cardiac contraction, neural transmission, temperature sensing, insulin release, regulation of apoptosis, cellular pH and oxidative stress, as well as detection of active compounds from chilli, are some of the processes in which ion channels have an important role. Regulation of ion channels by several chemicals including those found in air, water and soil represents an interesting potential link between environmental pollution and human diseases; for instance, de novo expression of ion channels in response to exposure to carcinogens is being considered as a potential tool for cancer diagnosis and therapy. Non-specific binding of several drugs to ion channels is responsible for a huge number of undesirable side-effects, and testing guidelines for several drugs now require ion channel screening for pharmaceutical safety. Animal toxins targeting human ion channels have serious effects on the population and have also provided a remarkable tool to study the molecular structure and function of ion channels. In this review, we will summarize the participation of ion channels in biological processes extensively used in toxicological studies, including cardiac function, apoptosis and cell proliferation. Major findings on the adverse effects of drugs on ion channels as well as the regulation of these proteins by different chemicals, including some pesticides, are also reviewed. Association of ion channels and toxicology in several biological processes strongly suggests these proteins to be excellent candidates to follow the toxic effects of xenobiotics, and as potential early indicators of life-threatening situations including chronic degenerative diseases. Copyright © 2010 John Wiley & Sons, Ltd. [source] Formation of cellular projections in neural progenitor cells depends on SK3 channel activityJOURNAL OF NEUROCHEMISTRY, Issue 5 2007Stefan Liebau Abstract Ion channels are potent modulators for developmental processes in progenitor cells. In a screening approach for different ion channels in neural progenitor cells (NPCs) we observed a 1-ethyl-2-benzimidazolinone (1-EBIO) activated inward current, which could be blocked by scyllatoxin (ScTX, IC50 = 2 ± 0.3 nmol/L). This initial evidence for the expression of the small conductance Ca2+ activated K+ -channel SK3 was confirmed by the detection of SK3 transcripts and protein in NPCs. Interestingly, SK3 proteins were highly expressed in non-differentiated NPCs with a focused localization in lamellipodia as well as filopodial structures. The activation of SK3 channels using 1-EBIO lead to an immediate filopodial sprouting and the translocation of the protein into these novel filopodial protrusions. Both effects could be prevented by the pre-incubation of NPCs with ScTX. Our study gives first evidence that the formation and prolongation of filopodia in NPCs is, at least in part, effectively induced and regulated by SK3 channels. [source] Ion channels and the transduction of light signalsPLANT CELL & ENVIRONMENT, Issue 7 2000E. P. Spalding ABSTRACT 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. [source] Role of mitochondrial ion channels in cell deathBIOFACTORS, Issue 4 2010Shin-Young Ryu Abstract Ion channels located in the outer and inner mitochondrial membranes are key regulators of cellular signaling for life and death. Permeabilization of mitochondrial membranes is one of the most critical steps in the progression of several cell death pathways. The mitochondrial apoptosis-induced channel (MAC) and the mitochondrial permeability transition pore (mPTP) play major roles in these processes. Here, the most recent progress and current perspectives about the roles of MAC and mPTP in mitochondrial membrane permeabilization during cell death are presented. The crosstalk signaling of MAC and mPTP formation/activation mediated by cytosolic Ca2+ signaling, Bcl-2 family proteins, and other mitochondrial ion channels is also discussed. Understanding the mechanisms that regulate opening and closing of MAC and mPTP has revealed new therapeutic targets that potentially could control cell death in pathologies such as cancer, ischemia/reperfusion injuries, and neurodegenerative diseases. [source] Targeted cell-ablation in Xenopus embryos using the conditional, toxic viral protein M2(H37A)DEVELOPMENTAL DYNAMICS, Issue 8 2007Stuart J. Smith Abstract Harnessing toxic proteins to destroy selective cells in an embryo is an attractive method for exploring details of cell fate and cell,cell interdependency. However, no existing "suicide gene" system has proved suitable for aquatic vertebrates. We use the M2(H37A) toxic ion channel of the influenza-A virus to induce cell-ablations in Xenopus laevis. M2(H37A) RNA injected into blastomeres of early stage embryos causes death of their progeny by late-blastula stages. Moreover, M2(H37A) toxicity can be controlled using the M2 inhibitor rimantadine. We have tested the ablation system using transgenesis to target M2(H37A) expression to selected cells in the embryo. Using the myocardial MLC2 promoter, M2(H37A)-mediated cell death causes dramatic loss of cardiac structure and function by stage 39. With the LURP1 promoter, we induce cell-ablations of macrophages. These experiments demonstrate the effectiveness of M2(H37A)-ablation in Xenopus and its utility in monitoring the progression of developmental abnormalities during targeted cell death experiments. Developmental Dynamics 236:2159,2171, 2007. © 2007 Wiley-Liss, Inc. [source] Individual variation and hormonal modulation of a sodium channel , subunit in the electric organ correlate with variation in a social signalDEVELOPMENTAL NEUROBIOLOGY, Issue 10 2007He Liu Abstract The sodium channel ,1 subunit affects sodium channel gating and surface density, but little is known about the factors that regulate ,1 expression or its participation in the fine control of cellular excitability. In this study we examined whether graded expression of the ,1 subunit contributes to the gradient in sodium current inactivation, which is tightly controlled and directly related to a social behavior, the electric organ discharge (EOD), in a weakly electric fish Sternopygus macrurus. We found the mRNA and protein levels of ,1 in the electric organ both correlate with EOD frequency. We identified a novel mRNA splice form of this gene and found the splicing preference for this novel splice form also correlates with EOD frequency. Androgen implants lowered EOD frequency and decreased the ,1 mRNA level but did not affect splicing. Coexpression of each splice form in Xenopus oocytes with either the human muscle sodium channel gene, hNav1.4, or a Sternopygus ortholog, smNav1.4b, sped the rate of inactivation of the sodium current and shifted the steady-state inactivation toward less negative membrane potentials. The translational product of the novel mRNA splice form lacks a previously identified important tyrosine residue but still functions normally. The properties of the fish , and coexpressed ,1 subunits in the oocyte replicate those of the electric organ's endogenous sodium current. These data highlight the role of ion channel , subunits in regulating cellular excitability. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007. [source] Activation of a calcium entry pathway by sodium pyrithione in the bag cell neurons of AplysiaDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2004Ronald J. Knox Abstract The ability of sodium pyrithione (NaP), an agent that produces delayed neuropathy in some species, to alter neuronal physiology was accessed using ratiometric imaging of cytosolic free Ca2+ concentration ([Ca2+]i) in fura PE-filled cultured Aplysia bag cell neurons. Bath-application of NaP evoked a [Ca2+]i elevation in both somata and neurites with an EC50 of ,300 nM and a Hill coefficient of ,1. The response required the presence of external Ca2+, had an onset of 3,5 min, and generally reached a maximum within 30 min. 2-Methyl-sulfonylpyridine, a metabolite and close structural analog of NaP, did not elevate [Ca2+]i. Under whole-cell current-clamp recording, NaP produced a ,14 mV depolarization of resting membrane potential that was dependent on external Ca2+. These data suggested that NaP stimulates Ca2+ entry across the plasma membrane. To minimize the possibility that a change in cytosolic pH was the basis for NaP-induced Ca2+ entry, bag cell neuron intracellular pH was estimated with the dye 2,,7,-bis(carboxyethyl-5(6)-carboxy-fluorescein acetoxy methylester. Exposure of the neurons to NaP did not alter intracellular pH. The slow onset and sustained nature of the NaP response suggested that a cation exchange mechanism coupled either directly or indirectly to Ca2+ entry could underlie the phenomenon. However, neither ouabain, a Na+/K+ ATPase inhibitor, nor removal of extracellular Na+, which eliminates Na+/Ca2+ exchanger activity, altered the NaP-induced [Ca2+]i elevation. Finally, the possibility that NaP gates a Ca2+ -permeable ion channel in the plasma membrane was examined. NaP did not appear to activate two major forms of bag cell neuron Ca2+ -permeable ion channels, as Ca2+ entry was unaffected by inhibition of voltage-gated Ca2+ channels using nifedipine or by inhibition of a voltage-dependent, nonselective cation channel using a high concentration of tetrodotoxin. In contrast, two potential store-operated Ca2+ entry current inhibitors, SKF-96365 and Ni2+, attenuated NaP-induced Ca2+ entry. We conclude that NaP activates a slow, persistent Ca2+ influx in Aplysia bag cell neurons. © 2004 Wiley Periodicals, Inc. J Neurobiol 411,423, 2004 [source] NTPDase1 governs P2X7 -dependent functions in murine macrophagesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010Sébastien A. Lévesque Abstract P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7 -dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1,/,) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1+/+). Entpd1,/, macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1, and IL-18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo-Pro-1 more efficiently (suggestive of increased pore formation) than Entpd1+/+ cells. Consistent with these observations, NTPDase1 regulated P2X7 -associated IL-1, release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1, release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1,/, mice had significantly higher IL-1, levels when compared with Entpd1+/+ mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7 -dependent macrophage responses. [source] Tetrahydropyran-Amino Acids: Novel Building Blocks for Gramicidin-Hybrid Ion ChannelsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 12 2006Sabine Schröder Abstract The stereoselective synthesis of a cis -2,6-disubstituted tetrahydropyran bearing a ,-amino acid has been achieved starting from N -Boc-leucinal. The THP amino acid was incorporated into peptide sequences and the structural consequences were studied by X-ray crystallography and NMR analysis. Single-channel current measurements showed that the THP amino acid is a suitable substitute for positions 11 and 12 of the gramicidin ion channel. The resulting hybrid ion channel revealed Eisenman I ion selectivity and an ion-dependence of the channel dwell time. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Towards predictive modelling of the electrophysiology of the heartEXPERIMENTAL PHYSIOLOGY, Issue 5 2009Edward Vigmond The simulation of cardiac electrical function is an example of a successful integrative multiscale modelling approach that is directly relevant to human disease. Today we stand at the threshold of a new era, in which anatomically detailed, tomographically reconstructed models are being developed that integrate from the ion channel to the electromechanical interactions in the intact heart. Such models hold high promise for interpretation of clinical and physiological measurements, for improving the basic understanding of the mechanisms of dysfunction in disease, such as arrhythmias, myocardial ischaemia and heart failure, and for the development and performance optimization of medical devices. The goal of this article is to present an overview of current state-of-art advances towards predictive computational modelling of the heart as developed recently by the authors of this article. We first outline the methodology for constructing electrophysiological models of the heart. We then provide three examples that demonstrate the use of these models, focusing specifically on the mechanisms for arrhythmogenesis and defibrillation in the heart. These include: (1) uncovering the role of ventricular structure in defibrillation; (2) examining the contribution of Purkinje fibres to the failure of the shock; and (3) using magnetic resonance imaging reconstructed heart models to investigate the re-entrant circuits formed in the presence of an infarct scar. [source] Mechanisms of channel gating of the ligand-gated ion channel superfamily inferred from protein structureEXPERIMENTAL PHYSIOLOGY, Issue 2 2004Nathan L. Absalom The nicotinic-like ligand-gated ion channel superfamily consists of a group of structurally related receptors that activate an ion channel after the binding of extracellular ligand. The recent publications of the crystal structure of an acetylcholine binding protein and a refined electron micrograph structure of the membrane-bound segment of an acetylcholine receptor have led to insights into the molecular determinants of receptor function. Although the structures confirmed much biochemical and electrophysiological data obtained about the receptors, they also provide opportunities to study further the mechanisms that allow channel activation stimulated by ligand-binding. Here we review the mechanisms of channel gating that have been elucidated by information gained from the structures of the acetylcholine binding protein and membrane-bound segment of the acetylcholine receptor. [source] Computational physiology and the physiome projectEXPERIMENTAL PHYSIOLOGY, Issue 1 2004Edmund J. Crampin Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization , from proteins to cells, tissues, organs and organ systems , these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline. [source] Crystal structure of the soluble form of the redox-regulated chloride ion channel protein CLIC4FEBS JOURNAL, Issue 19 2005Dene R. Littler The structure of CLIC4, a member of the CLIC family of putative intracellular chloride ion channel proteins, has been determined at 1.8 Ĺ resolution by X-ray crystallography. The protein is monomeric and it is structurally similar to CLIC1, belonging to the GST fold class. Differences between the structures of CLIC1 and CLIC4 are localized to helix 2 in the glutaredoxin-like N-terminal domain, which has previously been shown to undergo a dramatic structural change in CLIC1 upon oxidation. The structural differences in this region correlate with the sequence differences, where the CLIC1 sequence appears to be atypical of the family. Purified, recombinant, wild-type CLIC4 is shown to bind to artificial lipid bilayers, induce a chloride efflux current when associated with artificial liposomes and produce an ion channel in artificial bilayers with a conductance of 30 pS. Membrane binding is enhanced by oxidation of CLIC4 while no channels were observed via tip-dip electrophysiology in the presence of a reducing agent. Thus, recombinant CLIC4 appears to be able to form a redox-regulated ion channel in the absence of any partner proteins. [source] The product of the gene GEF1 of Saccharomyces cerevisiae transports Cl, across the plasma membraneFEMS YEAST RESEARCH, Issue 8 2007Angélica López-Rodríguez Abstract Expression of GEF1 in Xenopus laevis oocytes and HEK-293 cells gave rise to a Cl, channel that remained permanently open and was blocked by nitro-2-(3-phenylpropylamino) benzoic acid and niflumic acid. NPPB induced petite -like colonies, resembling the GEF1 knock-out. The fluorescent halide indicator SPQ was quenched in a wild-type strain, in contrast to both a GEF1 knock-out strain and yeast grown in the presence of NPPB. Immunogold and electron microscopy located Gef1p in the plasma membrane, vacuole, endoplasmic reticulum and Golgi apparatus. Eleven substitutions in five residues forming the ion channel of GEF1 were introduced; some of them (S186A, I188N, Y459D, Y459F, Y459V, I467A, I467N and F468N) did not rescue the pet phenotype, whereas F468A, A558F and A558Y formed normal colonies. All the pet mutants showed reduced O2 consumption, small mitochondria and mostly disrupted organelles. Finally, electron microscopy revealed that the plasma membrane of the mutants develop multiple foldings and highly ordered cylindrical protein-membrane complexes. All the experiments above suggest that Gef1p transports Cl, through the plasma membrane and reveal the importance of critical amino acids for the proper function of the protein as suggested by structural models. However, the mechanism of activation of the channel has yet to be defined. [source] Dronedarone: a new option in atrial fibrillationFUTURE PRESCRIBER, Issue 1 2009Professor A. John Camm MD Many antiarrhythmic agents exploiting new mechanisms of action (as well as modified analogues of traditional antiarrhythmic drugs, with different combinations of ion channel- and receptor-blocking effects and less complicated metabolic profiles) are currently being investigated. Dronedarone is an amiodarone derivative that is devoid of iodine atoms and is believed to have a better safety profile than amiodarone. It is the only antiarrhythmic drug for the treatment of atrial fibrillation (AF) that has been shown to improve survival in high-risk patients. This review provides a contemporary insight into the clinical development of dronedarone, its efficacy and safety in preventing recurrent AF, and its potential additional advantage of improving outcome in patients with AF. Copyright © 2009 John Wiley & Sons, Ltd. [source] Inside Front Cover: Novel Engineered Ion Channel Provides Controllable Ion Permeability for Polyelectrolyte Microcapsules Coated with a Lipid Membrane (Adv. Funct.ADVANCED FUNCTIONAL MATERIALS, Issue 2 2009Mater. In their Full Paper on page 201, Donald Martin and co-workers describe the covering of polyelectrolyte microcapsules with a lipid bilayer that incorporates a novel engineered ion channel to provide a functional capability to control transport across the microcapsule wall. The cover image shows atomic-force microscopy images of these 8-layer polyelectroctrolyte capsules recorded using tapping mode in an aqueous environment. The capsules can be seen to collapse in a folded manner, with an occasional wrinkle that "absorbs" the extra surface area when flattening the spherical surface. [source] | ||||||||||||||||||||||||||||||||||||||||