Calmodulin and Ca(2+) Control of Voltage Gated Na(+) Channels

Overview

Journal Channels (Austin)

Specialty Biochemistry

Date 2015 Jul 29

PMID 26218606

Citations 19

Authors

Sandra B Gabelli

Jesse B Yoder

Gordon F Tomaselli

L Mario Amzel

Affiliations

Soon will be listed here.

Abstract

The structures of the cytosolic portion of voltage activated sodium channels (CTNav) in complexes with calmodulin and other effectors in the presence and the absence of calcium provide information about the mechanisms by which these effectors regulate channel activity. The most studied of these complexes, those of Nav1.2 and Nav1.5, show details of the conformations and the specific contacts that are involved in channel regulation. Another voltage activated sodium channel, Nav1.4, shows significant calcium dependent inactivation, while its homolog Nav1.5 does not. The available structures shed light on the possible localization of the elements responsible for this effect. Mutations in the genes of these 3 Nav channels are associated with several disease conditions: Nav1.2, neurological conditions; Nav1.4, syndromes involving skeletal muscle; and Nav1.5, cardiac arrhythmias. Many of these disease-specific mutations are located at the interfaces involving CTNav and its effectors.

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References

Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P . Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001; 276(33):30623-30. DOI: 10.1074/jbc.M104471200. View

Ackerman M, Siu B, STURNER W, Tester D, Valdivia C, Makielski J . Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001; 286(18):2264-9. DOI: 10.1001/jama.286.18.2264. View

Haug K, Hallmann K, Rebstock J, Dullinger J, Muth S, Haverkamp F . The voltage-gated sodium channel gene SCN2A and idiopathic generalized epilepsy. Epilepsy Res. 2001; 47(3):243-6. DOI: 10.1016/s0920-1211(01)00312-6. View

Deschenes I, Neyroud N, DiSilvestre D, Marban E, Yue D, Tomaselli G . Isoform-specific modulation of voltage-gated Na(+) channels by calmodulin. Circ Res. 2002; 90(4):E49-57. DOI: 10.1161/01.res.0000012502.92751.e6. View

Kapplinger J, Tester D, Alders M, Benito B, Berthet M, Brugada J . An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010; 7(1):33-46. PMC: 2822446. DOI: 10.1016/j.hrthm.2009.09.069. View

Chagot B, Chazin W . Solution NMR structure of Apo-calmodulin in complex with the IQ motif of human cardiac sodium channel NaV1.5. J Mol Biol. 2010; 406(1):106-19. PMC: 3030672. DOI: 10.1016/j.jmb.2010.11.046. View

Wilde A, Brugada R . Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res. 2011; 108(7):884-97. DOI: 10.1161/CIRCRESAHA.110.238469. View

Feldkamp M, Yu L, Shea M . Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na(V)1.2 voltage-dependent sodium channel. Structure. 2011; 19(5):733-47. PMC: 3094505. DOI: 10.1016/j.str.2011.02.009. View

Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D . Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell. 2011; 145(7):1036-48. PMC: 3131217. DOI: 10.1016/j.cell.2011.05.025. View

10.

Sanders S, Murtha M, Gupta A, Murdoch J, Raubeson M, Willsey A . De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397):237-41. PMC: 3667984. DOI: 10.1038/nature10945. View

11.

Wang C, Chung B, Yan H, Lee S, Pitt G . Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin. Structure. 2012; 20(7):1167-76. PMC: 3610540. DOI: 10.1016/j.str.2012.05.001. View

12.

Senguen F, Grabarek Z . X-ray structures of magnesium and manganese complexes with the N-terminal domain of calmodulin: insights into the mechanism and specificity of metal ion binding to an EF-hand. Biochemistry. 2012; 51(31):6182-94. PMC: 3448793. DOI: 10.1021/bi300698h. View

13.

Sundaram S, Chugani H, Tiwari V, Huq A . SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism. Pediatr Neurol. 2013; 49(1):46-9. PMC: 3868437. DOI: 10.1016/j.pediatrneurol.2013.03.002. View

14.

Chichili V, Xiao Y, Seetharaman J, Cummins T, Sivaraman J . Structural basis for the modulation of the neuronal voltage-gated sodium channel NaV1.6 by calmodulin. Sci Rep. 2013; 3:2435. PMC: 3743062. DOI: 10.1038/srep02435. View

15.

Biswas S, DiSilvestre D, Dong P, Tomaselli G . Mechanisms of a human skeletal myotonia produced by mutation in the C-terminus of NaV1.4: is Ca2+ regulation defective?. PLoS One. 2013; 8(12):e81063. PMC: 3855693. DOI: 10.1371/journal.pone.0081063. View

16.

Hoshi M, Du X, Shinlapawittayatorn K, Liu H, Chai S, Wan X . Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ Cardiovasc Genet. 2014; 7(2):123-31. PMC: 3989843. DOI: 10.1161/CIRCGENETICS.113.000292. View

17.

Ben-Johny M, Yang P, Niu J, Yang W, Joshi-Mukherjee R, Yue D . Conservation of Ca2+/calmodulin regulation across Na and Ca2+ channels. Cell. 2014; 157(7):1657-70. PMC: 4349408. DOI: 10.1016/j.cell.2014.04.035. View

18.

Robert X, Gouet P . Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014; 42(Web Server issue):W320-4. PMC: 4086106. DOI: 10.1093/nar/gku316. View

19.

Wang C, Chung B, Yan H, Wang H, Lee S, Pitt G . Structural analyses of Ca²⁺/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation. Nat Commun. 2014; 5:4896. PMC: 4170523. DOI: 10.1038/ncomms5896. View

20.

Gabelli S, Boto A, Kuhns V, Bianchet M, Farinelli F, Aripirala S . Regulation of the NaV1.5 cytoplasmic domain by calmodulin. Nat Commun. 2014; 5:5126. PMC: 4223872. DOI: 10.1038/ncomms6126. View