Sodium Channel Function
Published by Anonymous on 2007/9/27 (2654 reads)
1: Nat Neurosci. 2007 Apr;10(4):405-9.
Erratum in:
Nat Neurosci. 2007 Jun;10(6):798.
Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype.
Waxman SG.
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA. stephen.waxman@yale.edu
What is the relationship between sodium channel function, neuronal function and clinical status in channelopathies of the nervous system? Given the central role of sodium channels in the generation of neuronal activity, channelopathies involving sodium channels might be expected to cause either enhanced sodium channel function and neuronal hyperexcitability associated with positive clinical manifestations such as seizures, or attenuated channel function and neuronal hypoexcitability associated with negative clinical manifestations such as paralysis. In this article, I review observations showing that changes in neuronal function and clinical status associated with channelopathies are not necessarily predictable solely from the altered physiological properties of the mutated channel itself. I discuss evidence showing that cell background acts as a filter that can strongly influence the effects of ion channel mutations.
Publication Types:
Review
PMID: 17387329 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Neuroreport. 2005 Jan 19;16(1):1-3.
Epilepsy and sodium channel gene mutations: gain or loss of function?
Yamakawa K.
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan. yamakawa@brain.riken.jp
Mutations in voltage-gated sodium channel genes (SCN1A, SCN2A, SCN1B) have been reported to be responsible for some epilepsies. Although studying such mutations to elucidate the disease mechanisms would be indispensable for the development of effective therapies, the functional consequences of these mutations remain controversial. Here, I propose a novel hypothesis for an epileptic disease mechanism which could drive the design of further studies to understand the molecular pathology of these diseases.
Publication Types:
Review
PMID: 15618878 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Opin Nephrol Hypertens. 2004 Sep;13(5):541-8.
New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis.
Thomas CP, Itani OA.
Department of Internal Medicine and the Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. christie-thomas@uiowa.edu
PURPOSE OF REVIEW: The epithelial sodium channel (ENaC) sets the rate of Na+ reabsorption in the collecting duct. This review describes recent advances in our understanding of ENaC function. RECENT FINDINGS: First, collecting duct-specific deletion of alphaENaC does not cause Na wasting in mice, suggesting that other regions can compensate. Second, Nedd4 and Nedd4-2 are ubiquitin ligases that reduce surface expression of ENaC and inhibit Na+ transport. Nedd4-2, but not Nedd4, is negatively regulated by serum- and glucocorticoid-inducible kinase 1, an aldosterone-induced kinase, providing an attractive mechanism for the stimulatory effect of aldosterone on Na+ transport. However, mice with germline ablation of serum- and glucocorticoid-inducible kinase 1 show only modest hypotension and are able to decrease Na+ excretion rates substantially. Third, maturation of ENaC is associated with processing at consensus furin cleavage sites and this cleavage is critical for channel activity. A separate class of serine proteases, the channel-activating proteases, also stimulates ENaC activity. SUMMARY: The connecting tubule of the kidney has abundant ENaC and Na(+)- and K(+)-transport capacity and may provide much of ENaC-mediated Na+ transport in the kidney. Aldosterone may increase Na transport, in part, by serum- and glucocorticoid-inducible kinase 1-mediated inhibition of Nedd4-2 but this has not been demonstrated in the native collecting duct or connecting tubule. The mild phenotype of the serum- and glucocorticoid-inducible kinase 1-knockout mouse points to serum- and glucocorticoid-inducible kinase 1-independent mechanisms that regulate Na+ transport. Two separate classes of protease appear to regulate Na+ transport: one is furin or furin-like and cleaves ENaC subunits to stimulate transport; the other, the channel-activating proteases, may act on ENaC or a regulatory molecule.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15300161 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Toxicon. 2004 Apr;43(5):587-99.
Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.
Nicholson GM, Little MJ, Birinyi-Strachan LC.
Neurotoxin Research Group, Department of Heath Sciences, University of Technology, Sydney, PO Box 123, Broadway, NSW 2007, Australia. graham.nicholson@uts.edu.au
Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15066415 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Cardiovasc Res. 2003 Mar 15;57(4):961-73.
Erratum in:
Cardiovasc Res. 2003 Sep 1;59(3):802.
Genetic control of sodium channel function.
Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA.
Experimental and Molecular Cardiology Group, Department of Cardiology, Academic Medical Center, Room M0-052, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands. h.l.tan@amc.uva.nl <h.l.tan@amc.uva.nl>
Sodium ion (Na) influx through cardiac Na channels triggers the action potential in cells of the working myocardium and the specialized conduction system. Na channels thus act as key molecular determinants of cardiac excitability and impulse propagation. Na channel dysfunction may cause life-threatening arrhythmias. Here, we review the ways in which Na channel function can be aberrant due to genetic changes. We discuss how biophysical studies of mutant Na channels combined with precise clinical phenotyping may improve our understanding of Na channel function in health and disease and may be useful as a model from which to derive improved treatment strategies for common disease.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12650874 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: J Mol Cell Cardiol. 2001 Apr;33(4):599-613.
The cardiac sodium channel: gating function and molecular pharmacology.
Balser JR.
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA. jeff.balser@mcmail.vanderbilt.edu
Cardiac sodium (Na) channels are dynamic molecules that undergo rapid structural changes in response to the changing electrical field in the myocardium. Inherited mutations in SCN5A, the gene encoding the cardiac Na channel, provoke life-threatening cardiac arrhythmias, often by modifying these voltage-dependent conformational changes. These disorders (i.e. the long QT syndrome and Brugada syndrome) may serve as valuable models for understanding the mechanistic linkages between Na channel dysfunction and cardiac arrhythmias in more common, acquired conditions such as cardiac ischemia. In addition, the balance between therapeutic and adverse effects from Na channel blockade by antiarrhythmic compounds may be shifted by subtle alterations in Na channel function. This review examines recent studies that tie key loci in the Na channel primary sequence to its dynamic function, while examining the emerging themes linking Na channel structure, function, and pharmacology to inherited and acquired disorders of cardiac excitability.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11273715 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Exp Nephrol. 1998 Jul-Aug;6(4):265-71.
Reversal of convention: from man to experimental animal in elucidating the function of the renal amiloride-sensitive sodium channel.
Hummler E.
Institut de Pharmacologie et de Toxicologie de l'Université, Lausanne, Switzerland. Edith.HummlerBeermann@ipharm.unil.ch
The kidney plays a dominant role in maintaining sodium homeostasis. Despite wide variation in environmental exposure, the osmolality of the extracellular fluid that is determined by the sodium ion concentration is maintained within narrow margins. Derangement in function of proteins that transport Na+ and of those regulating the activity of these sodium-transporting proteins are likely to be responsible for a number of clinical disorders of fluid and electrolyte homeostasis. The amiloride-sensitive epithelial sodium channel (ENaC) is implicated in the control of blood pressure as demonstrated by the analysis of two genetic diseases, Liddle's syndrome and pseudohypoaldosteronism (PHA-1). Mutations have been identified in the genes coding for the alpha-, beta- or gamma-subunit of ENaC. ENaC constitutes the limiting step for sodium reabsorption in epithelial cells that line the distal nephron, distal colon, ducts of several exocrine glands and lung airways and might play an important role in pathophysiological and clinical conditions such as hypertension or lung edema.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9690087 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Tanpakushitsu Kakusan Koso. 1997 Feb;42(3 Suppl):208-12.
[Structure, function and regulation of voltage-gated sodium channel]
[Article in Japanese]
Okamura Y.
National Institute of Bioscience and Human-technology, Agency of Industrial Sciences and Technology and Intelligence and Synthesis, PRESTO, Ibaraki, Japan.
Publication Types:
Review
PMID: 9162952 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Soc Gen Physiol Ser. 1995;50:77-88.
In vivo sodium channel structure/function studies: consecutive Arg1448 changes to Cys, His, and Pro at the extracellular surface of IVS4.
Wang J, Dubowitz V, Lehmann-Horn F, Ricker K, Ptacek L, Hoffman EP.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Structure/function relationships in ion channels have been intensively studied through expression of cloned channel subunits in heterologous cellular environments. Considerable information has been gleaned via this approach. However, it is prominent role in vivo: there are many differences between heterologous systems and functioning nerves and muscle in vivo, any one of which is likely to affect channel function. Examples of such variables include glycosylation status of the channel protein, association of muscle-specific membrane or cytoskeletal proteins, and fluctuations of intracellular and extracellular fluid milieu as a function of fluctuating cellular physiology. The identification of single amino acid changes in the voltage-sensitive muscle sodium channel alpha subunit in human and horse genetic disease has permitted a new approach to the study of structure/function relationships in ion channels. Importantly, the interactions between the environment and the abnormal channel can be studied in this in vivo system. Here we report the identification of a novel human sodium channel mutation (R1448P), which causes a severe type of cold-sensitive myotonia and weakness. This patient is compared to a series of other patients having R1448C, and R1448H mutations. We show that the severity of the amino acid change correlates with the severity of clinical symptoms. This data shows that different amino acid replacements in the extracellular surface of domain IV S4 are important for channel function, despite the paucity of heterologous expression data suggesting functional importance of this region. The extreme cold sensitivity of the proline substitution at R1443 suggests that cold temperatures may affect the structural integrity of the channel, and that proline may destabilize the normal structure.
Publication Types:
Review
PMID: 7676326 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Clin Invest Med. 1991 Oct;14(5):458-65.
Class I anti-arrhythmic drugs: structure and function at the cardiac sodium channel.
Sheldon RS, Duff HJ, Hill RJ.
Cardiovascular Research Group, University of Calgary, Alberta.
The major electrophysiologic effect of Class I anti-arrhythmic drugs is blockade of the cardiac sodium channel thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs, our understanding of their mechanism of action is incomplete. Models based on electrophysiologic studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes sodium channel blockade. Recent radioligand studies with [3H]batrachotoxin A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1660368 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Toxicon. 1991;29(9):1051-84.
Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel.
Norton RS.
School of Biochemistry, University of New South Wales, Kensington, Australia.
Sea anemones produce a series of toxic polypeptides and proteins with molecular weights in the range 3000-5000 that act by binding to specific receptor sites on the voltage-gated sodium channel of excitable tissue. This article reviews our current knowledge of the molecular basis for activity of these molecules, with particular emphasis on recent results on their receptor binding properties, the role of individual residues in activity and receptor binding, and their three-dimensional structures as determined by nuclear magnetic resonance spectroscopy. A region of these molecules that constitutes at least part of the receptor binding domain is proposed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1686683 [PubMed - indexed for MEDLINE]
Erratum in:
Nat Neurosci. 2007 Jun;10(6):798.
Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype.
Waxman SG.
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA. stephen.waxman@yale.edu
What is the relationship between sodium channel function, neuronal function and clinical status in channelopathies of the nervous system? Given the central role of sodium channels in the generation of neuronal activity, channelopathies involving sodium channels might be expected to cause either enhanced sodium channel function and neuronal hyperexcitability associated with positive clinical manifestations such as seizures, or attenuated channel function and neuronal hypoexcitability associated with negative clinical manifestations such as paralysis. In this article, I review observations showing that changes in neuronal function and clinical status associated with channelopathies are not necessarily predictable solely from the altered physiological properties of the mutated channel itself. I discuss evidence showing that cell background acts as a filter that can strongly influence the effects of ion channel mutations.
Publication Types:
Review
PMID: 17387329 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Neuroreport. 2005 Jan 19;16(1):1-3.
Epilepsy and sodium channel gene mutations: gain or loss of function?
Yamakawa K.
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan. yamakawa@brain.riken.jp
Mutations in voltage-gated sodium channel genes (SCN1A, SCN2A, SCN1B) have been reported to be responsible for some epilepsies. Although studying such mutations to elucidate the disease mechanisms would be indispensable for the development of effective therapies, the functional consequences of these mutations remain controversial. Here, I propose a novel hypothesis for an epileptic disease mechanism which could drive the design of further studies to understand the molecular pathology of these diseases.
Publication Types:
Review
PMID: 15618878 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Opin Nephrol Hypertens. 2004 Sep;13(5):541-8.
New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis.
Thomas CP, Itani OA.
Department of Internal Medicine and the Graduate Program in Molecular Biology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. christie-thomas@uiowa.edu
PURPOSE OF REVIEW: The epithelial sodium channel (ENaC) sets the rate of Na+ reabsorption in the collecting duct. This review describes recent advances in our understanding of ENaC function. RECENT FINDINGS: First, collecting duct-specific deletion of alphaENaC does not cause Na wasting in mice, suggesting that other regions can compensate. Second, Nedd4 and Nedd4-2 are ubiquitin ligases that reduce surface expression of ENaC and inhibit Na+ transport. Nedd4-2, but not Nedd4, is negatively regulated by serum- and glucocorticoid-inducible kinase 1, an aldosterone-induced kinase, providing an attractive mechanism for the stimulatory effect of aldosterone on Na+ transport. However, mice with germline ablation of serum- and glucocorticoid-inducible kinase 1 show only modest hypotension and are able to decrease Na+ excretion rates substantially. Third, maturation of ENaC is associated with processing at consensus furin cleavage sites and this cleavage is critical for channel activity. A separate class of serine proteases, the channel-activating proteases, also stimulates ENaC activity. SUMMARY: The connecting tubule of the kidney has abundant ENaC and Na(+)- and K(+)-transport capacity and may provide much of ENaC-mediated Na+ transport in the kidney. Aldosterone may increase Na transport, in part, by serum- and glucocorticoid-inducible kinase 1-mediated inhibition of Nedd4-2 but this has not been demonstrated in the native collecting duct or connecting tubule. The mild phenotype of the serum- and glucocorticoid-inducible kinase 1-knockout mouse points to serum- and glucocorticoid-inducible kinase 1-independent mechanisms that regulate Na+ transport. Two separate classes of protease appear to regulate Na+ transport: one is furin or furin-like and cleaves ENaC subunits to stimulate transport; the other, the channel-activating proteases, may act on ENaC or a regulatory molecule.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15300161 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Toxicon. 2004 Apr;43(5):587-99.
Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.
Nicholson GM, Little MJ, Birinyi-Strachan LC.
Neurotoxin Research Group, Department of Heath Sciences, University of Technology, Sydney, PO Box 123, Broadway, NSW 2007, Australia. graham.nicholson@uts.edu.au
Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 15066415 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Cardiovasc Res. 2003 Mar 15;57(4):961-73.
Erratum in:
Cardiovasc Res. 2003 Sep 1;59(3):802.
Genetic control of sodium channel function.
Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA.
Experimental and Molecular Cardiology Group, Department of Cardiology, Academic Medical Center, Room M0-052, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands. h.l.tan@amc.uva.nl <h.l.tan@amc.uva.nl>
Sodium ion (Na) influx through cardiac Na channels triggers the action potential in cells of the working myocardium and the specialized conduction system. Na channels thus act as key molecular determinants of cardiac excitability and impulse propagation. Na channel dysfunction may cause life-threatening arrhythmias. Here, we review the ways in which Na channel function can be aberrant due to genetic changes. We discuss how biophysical studies of mutant Na channels combined with precise clinical phenotyping may improve our understanding of Na channel function in health and disease and may be useful as a model from which to derive improved treatment strategies for common disease.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12650874 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: J Mol Cell Cardiol. 2001 Apr;33(4):599-613.
The cardiac sodium channel: gating function and molecular pharmacology.
Balser JR.
Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA. jeff.balser@mcmail.vanderbilt.edu
Cardiac sodium (Na) channels are dynamic molecules that undergo rapid structural changes in response to the changing electrical field in the myocardium. Inherited mutations in SCN5A, the gene encoding the cardiac Na channel, provoke life-threatening cardiac arrhythmias, often by modifying these voltage-dependent conformational changes. These disorders (i.e. the long QT syndrome and Brugada syndrome) may serve as valuable models for understanding the mechanistic linkages between Na channel dysfunction and cardiac arrhythmias in more common, acquired conditions such as cardiac ischemia. In addition, the balance between therapeutic and adverse effects from Na channel blockade by antiarrhythmic compounds may be shifted by subtle alterations in Na channel function. This review examines recent studies that tie key loci in the Na channel primary sequence to its dynamic function, while examining the emerging themes linking Na channel structure, function, and pharmacology to inherited and acquired disorders of cardiac excitability.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11273715 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Exp Nephrol. 1998 Jul-Aug;6(4):265-71.
Reversal of convention: from man to experimental animal in elucidating the function of the renal amiloride-sensitive sodium channel.
Hummler E.
Institut de Pharmacologie et de Toxicologie de l'Université, Lausanne, Switzerland. Edith.HummlerBeermann@ipharm.unil.ch
The kidney plays a dominant role in maintaining sodium homeostasis. Despite wide variation in environmental exposure, the osmolality of the extracellular fluid that is determined by the sodium ion concentration is maintained within narrow margins. Derangement in function of proteins that transport Na+ and of those regulating the activity of these sodium-transporting proteins are likely to be responsible for a number of clinical disorders of fluid and electrolyte homeostasis. The amiloride-sensitive epithelial sodium channel (ENaC) is implicated in the control of blood pressure as demonstrated by the analysis of two genetic diseases, Liddle's syndrome and pseudohypoaldosteronism (PHA-1). Mutations have been identified in the genes coding for the alpha-, beta- or gamma-subunit of ENaC. ENaC constitutes the limiting step for sodium reabsorption in epithelial cells that line the distal nephron, distal colon, ducts of several exocrine glands and lung airways and might play an important role in pathophysiological and clinical conditions such as hypertension or lung edema.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9690087 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Tanpakushitsu Kakusan Koso. 1997 Feb;42(3 Suppl):208-12.
[Structure, function and regulation of voltage-gated sodium channel]
[Article in Japanese]
Okamura Y.
National Institute of Bioscience and Human-technology, Agency of Industrial Sciences and Technology and Intelligence and Synthesis, PRESTO, Ibaraki, Japan.
Publication Types:
Review
PMID: 9162952 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Soc Gen Physiol Ser. 1995;50:77-88.
In vivo sodium channel structure/function studies: consecutive Arg1448 changes to Cys, His, and Pro at the extracellular surface of IVS4.
Wang J, Dubowitz V, Lehmann-Horn F, Ricker K, Ptacek L, Hoffman EP.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Structure/function relationships in ion channels have been intensively studied through expression of cloned channel subunits in heterologous cellular environments. Considerable information has been gleaned via this approach. However, it is prominent role in vivo: there are many differences between heterologous systems and functioning nerves and muscle in vivo, any one of which is likely to affect channel function. Examples of such variables include glycosylation status of the channel protein, association of muscle-specific membrane or cytoskeletal proteins, and fluctuations of intracellular and extracellular fluid milieu as a function of fluctuating cellular physiology. The identification of single amino acid changes in the voltage-sensitive muscle sodium channel alpha subunit in human and horse genetic disease has permitted a new approach to the study of structure/function relationships in ion channels. Importantly, the interactions between the environment and the abnormal channel can be studied in this in vivo system. Here we report the identification of a novel human sodium channel mutation (R1448P), which causes a severe type of cold-sensitive myotonia and weakness. This patient is compared to a series of other patients having R1448C, and R1448H mutations. We show that the severity of the amino acid change correlates with the severity of clinical symptoms. This data shows that different amino acid replacements in the extracellular surface of domain IV S4 are important for channel function, despite the paucity of heterologous expression data suggesting functional importance of this region. The extreme cold sensitivity of the proline substitution at R1443 suggests that cold temperatures may affect the structural integrity of the channel, and that proline may destabilize the normal structure.
Publication Types:
Review
PMID: 7676326 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Clin Invest Med. 1991 Oct;14(5):458-65.
Class I anti-arrhythmic drugs: structure and function at the cardiac sodium channel.
Sheldon RS, Duff HJ, Hill RJ.
Cardiovascular Research Group, University of Calgary, Alberta.
The major electrophysiologic effect of Class I anti-arrhythmic drugs is blockade of the cardiac sodium channel thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs, our understanding of their mechanism of action is incomplete. Models based on electrophysiologic studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes sodium channel blockade. Recent radioligand studies with [3H]batrachotoxin A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1660368 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Toxicon. 1991;29(9):1051-84.
Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel.
Norton RS.
School of Biochemistry, University of New South Wales, Kensington, Australia.
Sea anemones produce a series of toxic polypeptides and proteins with molecular weights in the range 3000-5000 that act by binding to specific receptor sites on the voltage-gated sodium channel of excitable tissue. This article reviews our current knowledge of the molecular basis for activity of these molecules, with particular emphasis on recent results on their receptor binding properties, the role of individual residues in activity and receptor binding, and their three-dimensional structures as determined by nuclear magnetic resonance spectroscopy. A region of these molecules that constitutes at least part of the receptor binding domain is proposed.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1686683 [PubMed - indexed for MEDLINE]
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