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Sodium Channel Structure
Published by Anonymous on 2007/9/27 (2106 reads)
1: 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]

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2: Mol Neurobiol. 2002 Oct-Dec;26(2-3):235-50.


Structure of the sodium channel gene SCN11A: evidence for intron-to-exon conversion model and implications for gene evolution.

Dib-Hajj SD, Tyrrell L, Waxman SG.

Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.

Exon/intron boundaries in the regions encoding the trans-membrane segments of voltage-gated Na channel genes are conserved, supporting their proposed evolution from a single domain channel, while the exons encoding the cytoplasmic loops are less conserved with their evolutionary heritage being less defined. SCN11A encodes the tetrodotoxin-resistant (TTX-R) sodium channel Nav1.9a/NaN, which is preferentially expressed in nociceptive primary sensory neurons of dorsal root ganglia (DRG) and trigeminal ganglia. SCN11A is localized to human chromosome 3 (3p21-24) close to the other TTX-R sodium channel genes SCN5A and SCN10A. An alternative transcript, Nav1.9b, has been detected in rat DRG and trigeminal ganglion. Nav1.9b is predicted to produce a truncated protein due to a frame-shift, which is introduced by the new sequence of exon 23c (E23c). In human and mouse SCN11A, divergent splicing signals prevent utilization of E23c. Unlike exons 5A/N in genes encoding TTX-sensitive sodium channels, which appear to have resulted from exon duplication, E23c might have evolved from the conversion of an intronic sequence. Although a functional role for Nav1.9b has yet to be established, intron-to-exon conversion may represent a mechanism for ion channels to acquire novel features.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

PMID: 12428758 [PubMed - indexed for MEDLINE]

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3: Physiol Rev. 2002 Jul;82(3):735-67.


Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure.

Kellenberger S, Schild L.

Institut de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland.

The recently discovered epithelial sodium channel (ENaC)/degenerin (DEG) gene family encodes sodium channels involved in various cell functions in metazoans. Subfamilies found in invertebrates or mammals are functionally distinct. The degenerins in Caenorhabditis elegans participate in mechanotransduction in neuronal cells, FaNaC in snails is a ligand-gated channel activated by neuropeptides, and the Drosophila subfamily is expressed in gonads and neurons. In mammals, ENaC mediates Na+ transport in epithelia and is essential for sodium homeostasis. The ASIC genes encode proton-gated cation channels in both the central and peripheral nervous system that could be involved in pain transduction. This review summarizes the physiological roles of the different channels belonging to this family, their biophysical and pharmacological characteristics, and the emerging knowledge of their molecular structure. Although functionally different, the ENaC/DEG family members share functional domains that are involved in the control of channel activity and in the formation of the pore. The functional heterogeneity among the members of the ENaC/DEG channel family provides a unique opportunity to address the molecular basis of basic channel functions such as activation by ligands, mechanotransduction, ionic selectivity, or block by pharmacological ligands.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 12087134 [PubMed - indexed for MEDLINE]

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4: 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]

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5: Ion Channels. 1996;4:115-67.


Structure and regulation of the amiloride-sensitive epithelial sodium channel.

Barbry P, Lazdunski M.

Institute of Molecular and Cellular Pharmacology, CNRS, Valbonne, France.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8744208 [PubMed - indexed for MEDLINE]

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6: Tanpakushitsu Kakusan Koso. 1995 Mar;40(4):370-88.


[Sodium channel functioning based on an octagonal structure model]

[Article in Japanese]

Sato C, Hirota K, Kimura T, Shono O, Matsumoto G.

Supermolecular Science Division, Electrotechnical Laboratory, Ibaraki, Japan.

Publication Types:
Review

PMID: 7724811 [PubMed - indexed for MEDLINE]

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7: 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]

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8: 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]

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9: 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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10: Annu Rev Neurosci. 1988;11:455-95.


Probing the molecular structure of the voltage-dependent sodium channel.

Barchi RL.

David Mahoney Institute of Neurological Sciences, University of Pennsylvania School of Medicine, Philadelphia 19104.

Publication Types:
Review

PMID: 2452597 [PubMed - indexed for MEDLINE]
 

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