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PMID: 9518722 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

Structure and function of voltage-gated sodium channels.

The Journal of physiology ·Vol. 508 ( Pt 3) ·1998-05-01 ·Pages 647-57

Marban E, Yamagishi T, Tomaselli GF

Abstract

1. Sodium channels mediate fast depolarization and conduct electrical impulses throughout nerve, muscle and heart. This paper reviews the links between sodium channel structure and function. 2. Sodium channels have a modular architecture, with distinct regions for the pore and the gates. The separation is far from absolute, however, with extensive interaction among the various parts of the channel. 3. At a molecular level, sodium channels are not static: they move extensively in the course of gating and ion translocation. 4. Sodium channels bind local anaesthetics and various toxins. In some cases, the relevant sites have been partially identified. 5. Sodium channels are subject to regulation at the levels of transcription, subunit interaction and post-translational modification (notably glycosylation and phosphorylation).

MeSH Terms
Amino Acid Sequence Animals Electric Stimulation Ion Channel Gating/physiology Protein Conformation Sodium Channels/chemistry,physiology
Chemicals
Sodium Channels
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Marban E
Section of Molecular and Cellular Cardiology, The Johns Hopkins University, Baltimore, MD 21205, USA. marban@welchlink.welch.jhu.edu
Yamagishi T
Tomaselli G F
References (101)
101 references, click to expand
  1. Phosphorylation of a conserved protein kinase C site is required for modulation of Na+ currents in transfected Chinese hamster ovary cells.
    Biophys J. 1992 Apr;62(1):31-3 PMID: 1318103
  2. Molecular localization of an ion-binding site within the pore of mammalian sodium channels.
    Science. 1992 Jul 10;257(5067):248-51 PMID: 1321496
  3. Sodium channel inactivation from resting states in guinea-pig ventricular myocytes.
    J Physiol. 1991 Nov;443:629-50 PMID: 1668345
  4. Protein kinase A reduces voltage-dependent Na+ current in Xenopus oocytes.
    J Neurosci. 1992 Oct;12(10):3743-52 PMID: 1383476
  5. Protein kinase A phosphorylation enhances sodium channel currents in Xenopus oocytes.
    Am J Physiol. 1992 Sep;263(3 Pt 1):C660-6 PMID: 1329522
  6. Class I and IV antiarrhythmic drugs and cytosolic calcium regulate mRNA encoding the sodium channel alpha subunit in rat cardiac muscle.
    Mol Pharmacol. 1992 Oct;42(4):570-4 PMID: 1331749
  7. Amino acid residues required for fast Na(+)-channel inactivation: charge neutralizations and deletions in the III-IV linker.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10905-9 PMID: 1332059
  8. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10910-4 PMID: 1332060
  9. Macroscopic and unitary properties of physiological ion flux through L-type Ca2+ channels in guinea-pig heart cells.
    J Physiol. 1992 Oct;456:267-84 PMID: 1338098
  10. Modification of the Na+ current conducted by the rat skeletal muscle alpha subunit by coexpression with a human brain beta subunit.
    Pflugers Arch. 1993 Apr;423(1-2):155-7 PMID: 7683789
  11. A molecular basis for gating mode transitions in human skeletal muscle Na+ channels.
    FEBS Lett. 1993 Jul 12;326(1-3):21-4 PMID: 8391996
  12. Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase.
    Science. 1993 Sep 10;261(5127):1439-42 PMID: 8396273
  13. Partial characterization of the rH1 sodium channel protein from rat heart using subtype-specific antibodies.
    Circ Res. 1993 Oct;73(4):735-42 PMID: 8396505
  14. Identification of the sites of selective phosphorylation and dephosphorylation of the rat brain Na+ channel alpha subunit by cAMP-dependent protein kinase and phosphoprotein phosphatases.
    J Biol Chem. 1993 Dec 25;268(36):27355-62 PMID: 8262976
  15. Voltage-gated Na+ channel beta 1 subunit mRNA expressed in adult human skeletal muscle, heart, and brain is encoded by a single gene.
    J Biol Chem. 1994 Mar 11;269(10):7571-8 PMID: 8125980
  16. A structural model of the tetrodotoxin and saxitoxin binding site of the Na+ channel.
    Biophys J. 1994 Jan;66(1):1-13 PMID: 8130328
  17. The microI skeletal muscle sodium channel: mutation E403Q eliminates sensitivity to tetrodotoxin but not to mu-conotoxins GIIIA and GIIIB.
    J Membr Biol. 1994 Jan;137(1):1-8 PMID: 7911843
  18. The adult rat brain beta 1 subunit modifies activation and inactivation gating of multiple sodium channel alpha subunits.
    J Biol Chem. 1994 Jul 1;269(26):17649-55 PMID: 8021275
  19. Modulation of skeletal muscle sodium channels in a satellite cell line by protein kinase C.
    J Neurosci. 1994 Jul;14(7):4226-36 PMID: 8027774
  20. Molecular determinants of state-dependent block of Na+ channels by local anesthetics.
    Science. 1994 Sep 16;265(5179):1724-8 PMID: 8085162
  21. A mutation in segment IVS6 disrupts fast inactivation of sodium channels.
    Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12346-50 PMID: 7991630
  22. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.
    Cell. 1995 Mar 10;80(5):805-11 PMID: 7889574
  23. REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons.
    Cell. 1995 Mar 24;80(6):949-57 PMID: 7697725
  24. Beta-adrenergic modulation of currents produced by rat cardiac Na+ channels expressed in Xenopus laevis oocytes.
    Receptors Channels. 1994;2(4):339-50 PMID: 7536612
  25. Modulation of skeletal muscle sodium channels by human myotonin protein kinase.
    J Clin Invest. 1995 May;95(5):2379-84 PMID: 7738201
  26. A critical role for transmembrane segment IVS6 of the sodium channel alpha subunit in fast inactivation.
    J Biol Chem. 1995 May 19;270(20):12025-34 PMID: 7744852
  27. A mutation in the pore of the sodium channel alters gating.
    Biophys J. 1995 May;68(5):1814-27 PMID: 7612823
  28. Evidence for voltage-dependent S4 movement in sodium channels.
    Neuron. 1995 Jul;15(1):213-8 PMID: 7619524
  29. Modulation of cardiac sodium channel isoform by cyclic AMP dependent protein kinase does not depend on phosphorylation of serine 1504 in the cytosolic loop interconnecting transmembrane domains III and IV.
    Pflugers Arch. 1995 Sep;430(5):751-3 PMID: 7478928
  30. Modulation of cardiac Na+ channel expression in Xenopus oocytes by beta 1 subunits.
    J Biol Chem. 1995 Oct 27;270(43):25696-701 PMID: 7592748
  31. Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif.
    Cell. 1995 Nov 3;83(3):433-42 PMID: 8521473
  32. Serine-1321-independent regulation of the mu 1 adult skeletal muscle Na+ channel by protein kinase C.
    Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12003-7 PMID: 8618832
  33. A molecular link between activation and inactivation of sodium channels.
    J Gen Physiol. 1995 Oct;106(4):641-58 PMID: 8576701
  34. Structure of the sodium channel pore revealed by serial cysteine mutagenesis.
    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):300-4 PMID: 8552626
  35. Coexpression of beta 1 with cardiac sodium channel alpha subunits in oocytes decreases lidocaine block.
    Mol Pharmacol. 1996 Jan;49(1):30-9 PMID: 8569709
  36. Molecular basis of charge movement in voltage-gated sodium channels.
    Neuron. 1996 Jan;16(1):113-22 PMID: 8562074
  37. Phosphorylation of brain sodium channels in the I--II linker modulates channel function in Xenopus oocytes.
    J Neurosci. 1996 Mar 15;16(6):1965-74 PMID: 8604040
  38. Depth asymmetries of the pore-lining segments of the Na+ channel revealed by cysteine mutagenesis.
    Neuron. 1996 May;16(5):1037-47 PMID: 8630242
  39. Control of ion flux and selectivity by negatively charged residues in the outer mouth of rat sodium channels.
    J Physiol. 1996 Feb 15;491 ( Pt 1):51-9 PMID: 9011621
  40. Functional association of the beta 1 subunit with human cardiac (hH1) and rat skeletal muscle (mu 1) sodium channel alpha subunits expressed in Xenopus oocytes.
    J Gen Physiol. 1995 Dec;106(6):1171-91 PMID: 8786355
  41. Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit.
    J Biol Chem. 1996 Jul 5;271(27):15950-62 PMID: 8663157
  42. Three-dimensional solution structure of mu-conotoxin GIIIB, a specific blocker of skeletal muscle sodium channels.
    Biochemistry. 1996 Jul 9;35(27):8824-35 PMID: 8688418
  43. Adjacent pore-lining residues within sodium channels identified by paired cysteine mutagenesis.
    Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7392-6 PMID: 8693004
  44. Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms.
    Physiol Rev. 1996 Jul;76(3):887-926 PMID: 8757791
  45. Interactions between a pore-blocking peptide and the voltage sensor of the sodium channel: an electrostatic approach to channel geometry.
    Neuron. 1996 Feb;16(2):407-13 PMID: 8789955
  46. Characterizing the mu-conotoxin binding site on voltage-sensitive sodium channels with toxin analogs and channel mutations.
    Receptors Channels. 1995;3(3):161-74 PMID: 8821790
  47. Sodium channel defects in myotonia and periodic paralysis.
    Annu Rev Neurosci. 1996;19:141-64 PMID: 8833439
  48. External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels.
    J Physiol. 1996 Jul 15;494 ( Pt 2):431-42 PMID: 8842002
  49. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.
    Circulation. 1996 Oct 15;94(8):1996-2012 PMID: 8873679
  50. cAMP-dependent phosphorylation of two sites in the alpha subunit of the cardiac sodium channel.
    J Biol Chem. 1996 Nov 15;271(46):28837-43 PMID: 8910529
  51. Phosphorylation of S1505 in the cardiac Na+ channel inactivation gate is required for modulation by protein kinase C.
    J Gen Physiol. 1996 Nov;108(5):375-9 PMID: 8923263
  52. A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.
    J Gen Physiol. 1996 Dec;108(6):549-56 PMID: 8972392
  53. Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.
    J Clin Invest. 1996 Dec 15;98(12):2874-86 PMID: 8981936
  54. Modulation of the human cardiac sodium channel alpha-subunit by cAMP-dependent protein kinase and the responsible sequence domain.
    J Physiol. 1997 Jan 15;498 ( Pt 2):309-18 PMID: 9032680
  55. A single zinc finger motif in the silencing factor REST represses the neural-specific type II sodium channel promoter.
    Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1177-82 PMID: 9037026
  56. The effects of external potassium and long duration voltage conditioning on the amplitude of sodium currents in the giant axon of the squid, Loligo pealei.
    J Gen Physiol. 1969 Nov;54(5):589-606 PMID: 5346530
  57. Slow changes in membrane permeability and long-lasting action potentials in axons perfused with fluoride solutions.
    J Physiol. 1970 Dec;211(3):707-28 PMID: 5501058
  58. Interaction of polypeptide neurotoxins with a receptor site associated with voltage-sensitive sodium channels.
    J Supramol Struct. 1980;14(3):295-303 PMID: 6261042
  59. The saxitoxin receptor of the sodium channel from rat brain. Evidence for two nonidentical beta subunits.
    J Biol Chem. 1982 Dec 10;257(23):13888-91 PMID: 6292214
  60. Glycosylation is required for maintenance of functional sodium channels in neuroblastoma cells.
    J Biol Chem. 1983 Apr 25;258(8):5117-23 PMID: 6300116
  61. A reinterpretation of mammalian sodium channel gating based on single channel recording.
    Nature. 1983 Dec 1-7;306(5942):436-41 PMID: 6316158
  62. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence.
    Nature. 1984 Nov 8-14;312(5990):121-7 PMID: 6209577
  63. Conus geographus toxins that discriminate between neuronal and muscle sodium channels.
    J Biol Chem. 1985 Aug 5;260(16):9280-8 PMID: 2410412
  64. The sodium channel from rat brain. Separation and characterization of subunits.
    J Biol Chem. 1985 Sep 5;260(19):10597-604 PMID: 2411726
  65. The voltage-sensitive sodium channel from rabbit skeletal muscle. Chemical characterization of subunits.
    J Biol Chem. 1987 Feb 15;262(5):2298-303 PMID: 2434481
  66. Sodium current in voltage clamped internally perfused canine cardiac Purkinje cells.
    Biophys J. 1987 Jul;52(1):1-11 PMID: 3607218
  67. Palmitylation, sulfation, and glycosylation of the alpha subunit of the sodium channel. Role of post-translational modifications in channel assembly.
    J Biol Chem. 1987 Oct 5;262(28):13713-23 PMID: 2443496
  68. Sodium-channel turnover in rabbit cultured Schwann cells.
    Proc R Soc Lond B Biol Sci. 1988 May 23;233(1273):423-30 PMID: 2456584
  69. Two molecular transitions influence cardiac sodium channel gating.
    Science. 1989 Apr 21;244(4902):349-52 PMID: 2540529
  70. Structural parts involved in activation and inactivation of the sodium channel.
    Nature. 1989 Jun 22;339(6226):597-603 PMID: 2543931
  71. Alpha-(2----8)-polysialic acid immunoreactivity in voltage-sensitive sodium channel of eel electric organ.
    Proc R Soc Lond B Biol Sci. 1989 Jul 22;237(1287):233-45 PMID: 2475874
  72. Phosphorylation of the rat skeletal muscle sodium channel by cyclic AMP-dependent protein kinase.
    J Neurochem. 1990 Mar;54(3):954-62 PMID: 2154554
  73. Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle.
    Neuron. 1990 Feb;4(2):233-42 PMID: 2155010
  74. Glycosylation is required for maintenance of functional voltage-activated channels in growing neocortical neurons of the rat.
    Proc R Soc Lond B Biol Sci. 1990 Mar 22;239(1295):119-27 PMID: 1691854
  75. Functional effects of protein kinase C activation on the human cardiac Na+ channel.
    Circ Res. 1997 Mar;80(3):370-6 PMID: 9048657
  76. Mechanisms of sodium/calcium selectivity in sodium channels probed by cysteine mutagenesis and sulfhydryl modification.
    Biophys J. 1997 Mar;72(3):989-96 PMID: 9138597
  77. Slow inactivation differs among mutant Na channels associated with myotonia and periodic paralysis.
    Biophys J. 1997 Mar;72(3):1204-19 PMID: 9138567
  78. Regulation of sodium channel gene expression by transcriptional silencing.
    Dev Neurosci. 1997;19(1):25-6 PMID: 9078429
  79. Contribution of sialic acid to the voltage dependence of sodium channel gating. A possible electrostatic mechanism.
    J Gen Physiol. 1997 Mar;109(3):327-43 PMID: 9089440
  80. Trapping of organic blockers by closing of voltage-dependent K+ channels: evidence for a trap door mechanism of activation gating.
    J Gen Physiol. 1997 May;109(5):527-35 PMID: 9154902
  81. Topology of the P segments in the sodium channel pore revealed by cysteine mutagenesis.
    Biophys J. 1997 Jul;73(1):195-204 PMID: 9199784
  82. P-loop flexibility in Na+ channel pores revealed by single- and double-cysteine replacements.
    J Gen Physiol. 1997 Jul;110(1):59-72 PMID: 9234171
  83. Phosphorylation at a single site in the rat brain sodium channel is necessary and sufficient for current reduction by protein kinase A.
    J Neurosci. 1997 Aug 15;17(16):6086-93 PMID: 9236220
  84. Molecular motions within the pore of voltage-dependent sodium channels.
    Biophys J. 1997 Aug;73(2):603-13 PMID: 9251780
  85. Myotonic dystrophy kinase modulates skeletal muscle but not cardiac voltage-gated sodium channels.
    FEBS Lett. 1997 Aug 4;412(3):621-4 PMID: 9276478
  86. Dopaminergic modulation of sodium current in hippocampal neurons via cAMP-dependent phosphorylation of specific sites in the sodium channel alpha subunit.
    J Neurosci. 1997 Oct 1;17(19):7330-8 PMID: 9295379
  87. Sodium channel activation gating is affected by substitutions of voltage sensor positive charges in all four domains.
    J Gen Physiol. 1997 Oct;110(4):391-401 PMID: 9379171
  88. Sodium channel inactivation is altered by substitution of voltage sensor positive charges.
    J Gen Physiol. 1997 Oct;110(4):403-13 PMID: 9379172
  89. Probing the outer vestibule of a sodium channel voltage sensor.
    Biophys J. 1997 Nov;73(5):2260-8 PMID: 9370423
  90. Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel.
    Circulation. 1998 Feb 24;97(7):640-4 PMID: 9495298
  91. A quantitative description of membrane current and its application to conduction and excitation in nerve.
    J Physiol. 1952 Aug;117(4):500-44 PMID: 12991237
  92. A mu-conotoxin-insensitive Na+ channel mutant: possible localization of a binding site at the outer vestibule.
    Biophys J. 1995 Nov;69(5):1657-65 PMID: 8580309
  93. Changes in sodium channel gating produced by point mutations in a cytoplasmic linker.
    Science. 1990 Nov 2;250(4981):688-91 PMID: 2173138
  94. Mutations affecting internal TEA blockade identify the probable pore-forming region of a K+ channel.
    Science. 1991 Feb 22;251(4996):939-42 PMID: 2000494
  95. TTX-sensitive and TTX-insensitive sodium channel mRNA transcripts are independently regulated in adult skeletal muscle after denervation.
    Neuron. 1991 Sep;7(3):421-7 PMID: 1654949
  96. Functional modulation of brain sodium channels by protein kinase C phosphorylation.
    Science. 1991 Oct 4;254(5028):115-8 PMID: 1656525
  97. A phosphorylation site in the Na+ channel required for modulation by protein kinase C.
    Science. 1991 Nov 8;254(5033):866-8 PMID: 1658937
  98. Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II.
    FEBS Lett. 1991 Nov 18;293(1-2):93-6 PMID: 1660007
  99. Calcium channel characteristics conferred on the sodium channel by single mutations.
    Nature. 1992 Apr 2;356(6368):441-3 PMID: 1313551
  100. Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel.
    Science. 1992 May 8;256(5058):839-42 PMID: 1375395
  101. A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties.
    Science. 1992 May 22;256(5060):1202-5 PMID: 1375397
Article Info
Journal
The Journal of physiology
Abbr.
J Physiol
ISSN
0022-3751
DOI
10.1111/j.1469-7793.1998.647bp.x
Email
marban@welchlink.welch.jhu.edu
Published
1998-05-01
Pages
647-57
Language
English
Region
England
NLM ID
0266262
PMCID
PMC2230911
Subset
IM
Grants
NHLBI NIH HHS · R01 HL050411 · United States
NHLBI NIH HHS · P50 HL52307 · United States
NHLBI NIH HHS · R01 HL50411 · United States
NHLBI NIH HHS · R01 HL52768 · United States
External Links
PubMed source DOI: 10.1111/j.1469-7793.1998.647bp.x PMC Full Text View journal details
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