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Carol Ann Remme - One of the best experts on this subject based on the ideXlab platform.
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cardiac Sodium Channel dys function and inherited arrhythmia syndromes
2018Co-Authors: Carol Ann RemmeAbstract:Normal cardiac Sodium Channel function is essential for ensuring excitability of myocardial cells and proper conduction of the electrical impulse within the heart. Cardiac Sodium Channel dysfunction is associated with an increased risk of arrhythmias and sudden cardiac death. Over the last 20 years, (combined) genetic, electrophysiological, and molecular studies have provided insight into the (dys)function and (dys)regulation of the cardiac Sodium Channel under physiological circumstances and in the setting of SCN5A mutations identified in patients with inherited arrhythmia syndromes. Although our understanding of these Sodium Channelopathies has increased substantially, important issues remain incompletely understood. It has become increasingly clear that Sodium Channel distribution, function, and regulation are more complicated than traditionally assumed. Moreover, recent evidence suggests that the Sodium Channel may play additional, as of yet unrecognized, roles in cardiomyocyte function, which in turn may ultimately also impact on arrhythmogenesis. In this chapter, an overview is provided of the structure and function of the cardiac Sodium Channel and the clinical and biophysical characteristics of inherited Sodium Channel dysfunction. In addition, more recent insights into the electrophysiological and molecular aspects of Sodium Channel dysregulation and dysfunction in the setting of SCN5A mutations are discussed.
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review Sodium Channel dys function and cardiac arrhythmias
Cardiovascular Therapeutics, 2010Co-Authors: Carol Ann Remme, Connie R BezzinaAbstract:SUMMARY Cardiac voltage-gated Sodium Channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of Sodium ions through these ion Channels is responsible for the initial fast upstroke of the cardiac action potential. This inward Sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of Sodium Channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired Sodium Channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered Sodium Channel function causes conduction disturbances and ventricular arrhythmias. In addition, Sodium Channel dysfunction caused by mutations in the SCN5A gene, encoding the major Sodium Channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac Sodium Channel, the clinical and biophysical characteristics of inherited and acquired Sodium Channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac Sodium Channel disease.
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Sodium Channel dys function and cardiac arrhythmias
Cardiovascular Therapeutics, 2010Co-Authors: Carol Ann Remme, Connie R BezzinaAbstract:Cardiac voltage-gated Sodium Channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of Sodium ions through these ion Channels is responsible for the initial fast upstroke of the cardiac action potential. This inward Sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of Sodium Channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired Sodium Channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered Sodium Channel function causes conduction disturbances and ventricular arrhythmias. In addition, Sodium Channel dysfunction caused by mutations in the SCN5A gene, encoding the major Sodium Channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac Sodium Channel, the clinical and biophysical characteristics of inherited and acquired Sodium Channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac Sodium Channel disease.
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the cardiac Sodium Channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium
Basic Research in Cardiology, 2009Co-Authors: Carol Ann Remme, Arthur A M Wilde, Arie O Verkerk, Willem M H Hoogaars, Wim T J Aanhaanen, Brendon P Scicluna, C Annink, M J B Van Den Hoff, T A B Van VeenAbstract:Cardiac Sodium Channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of Sodium Channel expression and function in the myocardium. Sodium Channel Scn5a mRNA and Nav1.5 protein distri- bution was investigated in adult and embryonic mouse heart through immunohistochemistry and in situ hybridization. Functional Sodium Channel availability in subepicardial and subendocardial myocytes was assessed using patch-clamp technique. Adult and embryonic (ED14.5) mouse heart sections showed low expression of Nav1.5 in the HCN4- positive sinoatrial and atrioventricular nodes. In contrast, high expression levels of Nav1.5 were observed in the HCN4-positive and Cx43-negative AV or His bundle, bundle branches and Purkinje fibers. In both ventricles, a transmural gradient was observed, with a low Nav1.5 labeling intensity in the subepicardium as compared to the subendocardium. Similar Scn5a mRNA expression patterns were observed on in situ hybridization of embryonic and adult tissue. Maximal action potential upstroke velocity was significantly lower in subepicardial myocytes (mean ± SEM 309 ± 32 V/s; n = 14) compared to subendocardial myocytes (394 ± 32 V/s; n = 11; P \ 0.05), indicating decreased Sodium Channel availability in subepicardium compared to subendocardium. Scn5a and Nav1.5 show heterogeneous distribution patterns within the cardiac conduction system and across the ventricular wall. This differential distribution of the cardiac Sodium Channel may have profound consequences for conduction disease phenotypes and arrhythmogenesis in the setting of Sodium Channel disease.
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cardiac Sodium Channel overlap syndromes different faces of scn5a mutations
Trends in Cardiovascular Medicine, 2008Co-Authors: Carol Ann Remme, Arthur A M Wilde, Connie R BezzinaAbstract:Cardiac Sodium Channel dysfunction caused by mutations in the SCN5A gene is associated with a number of relatively uncommon arrhythmia syndromes, including long-QT syndrome type 3 (LQT3), Brugada syndrome, conduction disease, sinus node dysfunction, and atrial standstill, which potentially lead to fatal arrhythmias in relatively young individuals. Although these various arrhythmia syndromes were originally considered separate entities, recent evidence indicates more overlap in clinical presentation and biophysical defects of associated mutant Channels than previously appreciated. Various SCN5A mutations are now known to present with mixed phenotypes, a presentation that has become known as "overlap syndrome of cardiac Sodium Channelopathy." In many cases, multiple biophysical defects of single SCN5A mutations are suspected to underlie the overlapping clinical manifestations. Here, we provide an overview of current knowledge on SCN5A mutations associated with Sodium Channel overlap syndromes and discuss a possible role for modifiers in determining disease expressivity in the individual patient.
Ke Dong - One of the best experts on this subject based on the ideXlab platform.
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Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti
Insects, 2016Co-Authors: Yoshiko Nomura, Boris S Zhorov, Ke DongAbstract:Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated Sodium Channels are the primary targets of pyrethroid insecticides. Mutations in the Sodium Channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr), in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the Sodium Channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated Sodium Channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the Sodium Channel.
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The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides
Journal of Biological Chemistry, 2016Co-Authors: Yongqiang Zhang, Yoshiko Nomura, Boris S Zhorov, Dingxin Jiang, Caitlyn Behnke, Ke DongAbstract:Sodium Channels are excellent targets of both natural and synthetic insecticides with high insect selectivity. Indoxacarb, its active metabolite DCJW, and metaflumizone (MFZ) belong to a relatively new class of Sodium Channel blocker insecticides (SCBIs) with a mode of action distinct from all other Sodium Channel-targeting insecticides, including pyrethroids. Electroneutral SCBIs preferably bind to and trap Sodium Channels in the inactivated state, a mechanism similar to that of cationic local anesthetics. Previous studies identified several SCBI-sensing residues that face the inner pore of Sodium Channels. However, the receptor site of SCBIs, their atomic mechanisms, and the cause of selective toxicity of MFZ remain elusive. Here, we have built a homology model of the open-state cockroach Sodium Channel BgNav1-1a. Our computations predicted that SCBIs bind in the inner pore, interact with a Sodium ion at the focus of P1 helices, and extend their aromatic moiety into the III/IV domain interface (fenestration). Using model-driven mutagenesis and electrophysiology, we identified five new SCBI-sensing residues, including insect-specific residues. Our study proposes the first three-dimensional models of Channel-bound SCBIs, sheds light on the molecular basis of MFZ selective toxicity, and suggests that a Sodium ion located in the inner pore contributes to the receptor site for electroneutral SCBIs.
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mutations in the transmembrane helix s6 of domain iv confer cockroach Sodium Channel resistance to Sodium Channel blocker insecticides and local anesthetics
Insect Biochemistry and Molecular Biology, 2015Co-Authors: Yoshiko Nomura, Boris S Zhorov, Dingxin Jiang, Xingliang Wang, Ke DongAbstract:Indoxacarb and metaflumizone are two Sodium Channel blocker insecticides (SCBIs). They preferably bind to and trap Sodium Channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (LAs). Recently, two Sodium Channel mutations, F1845Y (F(4i15)Y) and V1848I (V(4i18)I), in the transmembrane segment 6 of domain IV (IVS6), were identified to be associated with indoxacarb resistance in Plutella xylostella. F(4i15) is known to be critical for the action of LAs on mammalian Sodium Channels. Previously, mutation F(4i15)A in a cockroach Sodium Channel, BgNav1-1a, has been shown to reduce the action of lidocaine, a LA, but not the action of SCBIs. In this study, we introduced mutations F(4i15)Y and V(4i18)A/I individually into the cockroach Sodium Channel, BgNav1-1a, and conducted functional analysis of the three mutants in Xenopus oocytes. We found that both the F(4i15)Y and V(4i18)I mutations reduced the inhibition of Sodium current by indoxacarb, DCJW (an active metabolite of indoxacarb) and metaflumizone. F(4i15)Y and V(4i18)I mutations also reduced the use-dependent block of Sodium current by lidocaine. In contrast, substitution V(4i18)A enhanced the action metaflumizone and lidocaine. These results show that both F(4i15)Y and V(4i18)I mutations may contribute to target-site resistance to SCBIs, and provide the first molecular evidence for common amino acid determinants on insect Sodium Channels involved in action of SCBIs and LA.
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molecular evidence for dual pyrethroid receptor sites on a mosquito Sodium Channel
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Yoshiko Nomura, Gul Satar, Ralf Nauen, Boris S Zhorov, Ke DongAbstract:Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and mosquito-borne diseases, including malaria and dengue. They exert toxic effects by altering the function of voltage-gated Sodium Channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of pyrethroids for vector control is the emergence of mosquito resistance to pyrethroids worldwide. Here, we report the successful expression of a Sodium Channel, AaNav1–1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine Sodium Channel mutations that are associated with pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNav1–1 sensitivity to pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed pyrethroid-receptor site in the house fly Sodium Channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of pyrethroid action and resistance as well as the high selectivity of pyrethroids on insect vs. mammalian Sodium Channels. Results from this study could impact future prediction and monitoring of pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.
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diversity and convergence of Sodium Channel mutations involved in resistance to pyrethroids
Pesticide Biochemistry and Physiology, 2013Co-Authors: Frank D Rinkevich, Ke DongAbstract:Pyrethroid insecticides target voltage-gated Sodium Channels, which are critical for electrical signaling in the nervous system. The intensive use of pyrethroids in controlling arthropod pests and disease vectors has led to many instances of pyrethroid resistance around the globe. In the past two decades, studies have identified a large number of Sodium Channel mutations that are associated with resistance to pyrethroids. The purpose of this review is to summarize both common and unique Sodium Channel mutations that have been identified in arthropod pests of importance to agriculture or human health. Identification of these mutations provides valuable molecular markers for resistance monitoring in the field and helped the discovery of the elusive pyrethroid receptor site(s) on the Sodium Channel.
Connie R Bezzina - One of the best experts on this subject based on the ideXlab platform.
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review Sodium Channel dys function and cardiac arrhythmias
Cardiovascular Therapeutics, 2010Co-Authors: Carol Ann Remme, Connie R BezzinaAbstract:SUMMARY Cardiac voltage-gated Sodium Channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of Sodium ions through these ion Channels is responsible for the initial fast upstroke of the cardiac action potential. This inward Sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of Sodium Channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired Sodium Channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered Sodium Channel function causes conduction disturbances and ventricular arrhythmias. In addition, Sodium Channel dysfunction caused by mutations in the SCN5A gene, encoding the major Sodium Channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac Sodium Channel, the clinical and biophysical characteristics of inherited and acquired Sodium Channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac Sodium Channel disease.
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Sodium Channel dys function and cardiac arrhythmias
Cardiovascular Therapeutics, 2010Co-Authors: Carol Ann Remme, Connie R BezzinaAbstract:Cardiac voltage-gated Sodium Channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of Sodium ions through these ion Channels is responsible for the initial fast upstroke of the cardiac action potential. This inward Sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of Sodium Channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired Sodium Channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered Sodium Channel function causes conduction disturbances and ventricular arrhythmias. In addition, Sodium Channel dysfunction caused by mutations in the SCN5A gene, encoding the major Sodium Channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac Sodium Channel, the clinical and biophysical characteristics of inherited and acquired Sodium Channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac Sodium Channel disease.
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cardiac Sodium Channel overlap syndromes different faces of scn5a mutations
Trends in Cardiovascular Medicine, 2008Co-Authors: Carol Ann Remme, Arthur A M Wilde, Connie R BezzinaAbstract:Cardiac Sodium Channel dysfunction caused by mutations in the SCN5A gene is associated with a number of relatively uncommon arrhythmia syndromes, including long-QT syndrome type 3 (LQT3), Brugada syndrome, conduction disease, sinus node dysfunction, and atrial standstill, which potentially lead to fatal arrhythmias in relatively young individuals. Although these various arrhythmia syndromes were originally considered separate entities, recent evidence indicates more overlap in clinical presentation and biophysical defects of associated mutant Channels than previously appreciated. Various SCN5A mutations are now known to present with mixed phenotypes, a presentation that has become known as "overlap syndrome of cardiac Sodium Channelopathy." In many cases, multiple biophysical defects of single SCN5A mutations are suspected to underlie the overlapping clinical manifestations. Here, we provide an overview of current knowledge on SCN5A mutations associated with Sodium Channel overlap syndromes and discuss a possible role for modifiers in determining disease expressivity in the individual patient.
William A. Catterall - One of the best experts on this subject based on the ideXlab platform.
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Dravet Syndrome: A Sodium Channel Interneuronopathy.
Current Opinion in Physiology, 2018Co-Authors: William A. CatterallAbstract:Dravet Syndrome is a devastating childhood epilepsy disorder with high incidence of premature death plus comorbidities of ataxia, circadian rhythm disorder, impaired sleep quality, autistic-like social-interaction deficits and severe cognitive impairment. It is primarily caused by heterozygous loss-of-function mutations in the SCN1A gene that encodes brain voltage-gated Sodium Channel type-1, termed NaV1.1. Here I review experiments on mouse genetic models that implicate specific loss of Sodium currents and action potential firing in GABAergic inhibitory interneurons as the fundamental cause of Dravet Syndrome. The resulting imbalance of excitatory to inhibitory neurotransmission in neural circuits causes both epilepsy and co-morbidities. Promising therapeutic approaches involving atypical Sodium Channel blockers, novel drug combinations, and cannabidiol give hope for improved outcomes for Dravet Syndrome patients.
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localization of Sodium Channel subtypes in mouse ventricular myocytes using quantitative immunocytochemistry
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Ruth E Westenbroek, Sebastian Bischoff, Sebastian K G Maier, Ying Fu, William A. Catterall, Todd ScheuerAbstract:Voltage-gated Sodium Channels are responsible for the rising phase of the action potential in cardiac muscle. Previously, both TTX-sensitive neuronal Sodium Channels (NaV1.1, NaV1.2, NaV1.3, NaV1.4 and NaV1.6) and the TTX-resistant cardiac Sodium Channel (NaV1.5) have been detected in cardiac myocytes, but relative levels of protein expression of the isoforms were not determined. Using a quantitative approach, we analyzed z-series of confocal microscopy images from individual mouse myocytes stained with either anti-NaV1.1, anti-NaV1.2, anti-NaV1.3, anti-NaV1.4, anti-NaV1.5, or anti-NaV1.6 antibodies and calculated the relative intensity of staining for these Sodium Channel isoforms. Our results indicate that the TTX-sensitive Channels represented approximately 23% of the total Channels, whereas the TTX-resistant NaV1.5 Channel represented 77% of the total Channel staining in mouse ventricular myocytes. These ratios are consistent with previous electrophysiological studies in mouse ventricular myocytes. NaV1.5 was located at the cell surface, with high density at the intercalated disc, but was absent from the transverse (t)-tubular system, suggesting that these Channels support surface conduction and inter-myocyte transmission. Low-level cell surface staining of NaV1.4 and NaV1.6 Channels suggest a minor role in surface excitation and conduction. Conversely, NaV1.1 and NaV1.3 Channels are localized to the t-tubules and are likely to support t-tubular transmission of the action potential to the myocyte interior. This quantitative immunocytochemical approach for assessing Sodium Channel density and localization provides a more precise view of the relative importance and possible roles of these individual Sodium Channel protein isoforms in mouse ventricular myocytes and may be applicable to other species and cardiac tissue types.
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correlations in timing of Sodium Channel expression epilepsy and sudden death in dravet syndrome
Channels, 2013Co-Authors: Christine S Cheah, Ruth E Westenbroek, William H Roden, Franck Kalume, John C Oakley, Laura A Jansen, William A. CatterallAbstract:Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss‐of‐function mutations in SCN1A, the gene encoding brain Sodium Channel Nav1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the time course of declining expression of the murine embryonic Sodium Channel Nav1.3 and the rise in expression of the adult Sodium Channel Nav1.1 with susceptibility to epileptic seizures and increased incidence of sudden death in DS mice. Parallel studies with unaffected human brain tissue demonstrate similar decline in Nav1.3 and increase in Nav1.1 with age. In light of these results, we introduce the hypothesis that the natural loss Nav1.3 Channel expression in brain development, coupled with the failure of increase in functional Nav1.1 Channels in DS, defines a tipping point that leads to disinhibition of neural circuits, intractable seizures, co‐morbidities, and premature death in this disease.
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distribution and function of Sodium Channel subtypes in human atrial myocardium
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Susann G Kaufmann, Ruth E Westenbroek, Volkmar Lange, Andre Renner, Andreas Bonz, Alexander H Maass, Erhard Wischmeyer, Jenny Muck, Georg Ertl, William A. CatterallAbstract:Voltage-gated Sodium Channels composed of a pore-forming α subunit and auxiliary β subunits are responsible for the upstroke of the action potential in cardiac muscle. However, their localization and expression patterns in human myocardium have not yet been clearly defined. We used immunohistochemical methods to define the level of expression and the subcellular localization of Sodium Channel α and β subunits in human atrial myocytes. Nav1.2 Channels are located in highest density at intercalated disks where β1 and β3 subunits are also expressed. Nav1.4 and the predominant Nav1.5 Channels are located in a striated pattern on the cell surface at the z-lines together with β2 subunits. Nav1.1, Nav1.3, and Nav1.6 Channels are located in scattered puncta on the cell surface in a pattern similar to β3 and β4 subunits. Nav1.5 comprised approximately 88% of the total Sodium Channel staining, as assessed by quantitative immunohistochemistry. Functional studies using whole cell patch-clamp recording and measurements of contractility in human atrial cells and tissue showed that TTX-sensitive (non-Nav1.5) α subunit isoforms account for up to 27% of total Sodium current in human atrium and are required for maximal contractility. Overall, our results show that multiple Sodium Channel α and β subunits are differentially localized in subcellular compartments in human atrial myocytes, suggesting that they play distinct roles in initiation and conduction of the action potential and in excitation–contraction coupling. TTX-sensitive Sodium Channel isoforms, even though expressed at low levels relative to TTX-sensitive Nav1.5, contribute substantially to total cardiac Sodium current and are required for normal contractility. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.
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Overview of the voltage-gated Sodium Channel family
Genome biology, 2003Co-Authors: William A. CatterallAbstract:Selective permeation of Sodium ions through voltage-dependent Sodium Channels is fundamental to the generation of action potentials in excitable cells such as neurons. These Channels are large integral membrane proteins and are encoded by at least ten genes in mammals. The different Sodium Channels have remarkably similar functional properties, but small changes in Sodium-Channel function are biologically relevant, as underscored by mutations that cause several human diseases of hyperexcitability.
Alan L Goldin - One of the best experts on this subject based on the ideXlab platform.
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novel Sodium Channel gene mutations in blattella germanica reduce the sensitivity of expressed Channels to deltamethrin
Insect Biochemistry and Molecular Biology, 2002Co-Authors: Jianguo Tan, Alan L Goldin, Zhiqi Liu, T D Tsai, Steven M Valles, Ke DongAbstract:Pyrethroid insecticides alter the normal gating of voltage-gated Sodium Channels in the nervous system. Three Sodium Channel mutations (E434K, C764R, L993F) were recently identified in pyrethroid resistant German cockroach populations. In this report, we show that the L993F mutation decreased Sodium Channel sensitivity to the pyrethroid, deltamethrin, by five-fold in Xenopus oocytes. In contrast, neither E434K nor C764R alone decreased Channel sensitivity to deltamethrin. However, E434K or C764R combined with L993F reduced deltamethrin sensitivity by 100-fold. Furthermore, concomitant presence of all three mutations (KRF) reduced Channel sensitivity to deltamethrin by 500-fold. None of the mutations significantly affected Channel gating. However, Sodium current amplitudes from the mutant Sodium Channel carrying either E434K or C764R alone were much reduced compared to those of the wild-type Channel or the Channel carrying the double or triple mutations (KF, RF and KRF). These results indicated that evolution of Sodium Channel insensitivity in the German cockroach is achieved by sequential selection of a primary mutation L993F and two secondary mutations E434K and C764R, and concomitant presence of all three mutations dramatically reduced Sodium Channel sensitivity to deltamethrin.
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resurgence of Sodium Channel research
Annual Review of Physiology, 2001Co-Authors: Alan L GoldinAbstract:▪ Abstract A variety of isoforms of mammalian voltage-gated Sodium Channels have been described. Ten genes encoding Sodium Channel α subunits have been identified, and nine of those isoforms have been functionally expressed in exogenous systems. The α subunit is associated with accessory β subunits in some tissues, and three genes encoding different β subunits have been identified. The α subunit isoforms have distinct patterns of development and localization in the nervous system, skeletal and cardiac muscle. In addition, many of the isoforms demonstrate subtle differences in their functional properties. However, there are no clear subfamilies of the Channels, unlike the situation with potassium and calcium Channels. The subtle differences in the functional properties of the Sodium Channel isoforms result in unique conductances in specific cell types, which have important physiological effects for the organism. Small alterations in the electrophysiological properties of the Channel resulting from mutation...
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resurgence of Sodium Channel research
Annual Review of Physiology, 2001Co-Authors: Alan L GoldinAbstract:A variety of isoforms of mammalian voltage-gated Sodium Channels have been described. Ten genes encoding Sodium Channel alpha subunits have been identified, and nine of those isoforms have been functionally expressed in exogenous systems. The alpha subunit is associated with accessory beta subunits in some tissues, and three genes encoding different beta subunits have been identified. The alpha subunit isoforms have distinct patterns of development and localization in the nervous system, skeletal and cardiac muscle. In addition, many of the isoforms demonstrate subtle differences in their functional properties. However, there are no clear subfamilies of the Channels, unlike the situation with potassium and calcium Channels. The subtle differences in the functional properties of the Sodium Channel isoforms result in unique conductances in specific cell types, which have important physiological effects for the organism. Small alterations in the electrophysiological properties of the Channel resulting from mutations in specific isoforms cause human diseases such as periodic paralysis, long QT syndrome, and epilepsy.
