Sodium Channelopathies of Skeletal Muscle Result from Gain or Loss of Function

Overview

Journal Pflugers Arch

Specialty Physiology

Date 2010 Mar 19

PMID 20237798

Citations 68

Authors

Karin Jurkat-Rott

Boris Holzherr

Michael Fauler

Frank Lehmann-Horn

Affiliations

Soon will be listed here.

Abstract

Five hereditary sodium channelopathies of skeletal muscle have been identified. Prominent symptoms are either myotonia or weakness caused by an increase or decrease of muscle fiber excitability. The voltage-gated sodium channel NaV1.4, initiator of the muscle action potential, is mutated in all five disorders. Pathogenetically, both loss and gain of function mutations have been described, the latter being the more frequent mechanism and involving not just the ion-conducting pore, but aberrant pores as well. The type of channel malfunction is decisive for therapy which consists either of exerting a direct effect on the sodium channel, i.e., by blocking the pore, or of restoring skeletal muscle membrane potential to reduce the fraction of inactivated channels.

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References

Dice M, Abbruzzese J, Wheeler J, Groome J, Fujimoto E, Ruben P . Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M. Muscle Nerve. 2004; 30(3):277-88. DOI: 10.1002/mus.20080. View

Mohammadi B, Jurkat-Rott K, Alekov A, Dengler R, Bufler J, Lehmann-Horn F . Preferred mexiletine block of human sodium channels with IVS4 mutations and its pH-dependence. Pharmacogenet Genomics. 2005; 15(4):235-44. DOI: 10.1097/01213011-200504000-00007. View

Fontaine B, Jurkat-Rott K, Reboul J, Plassart E, Rime C, Elbaz A . Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nat Genet. 1994; 6(3):267-72. DOI: 10.1038/ng0394-267. View

Engel A, Ohno K, Shen X, Sine S . Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junction. Ann N Y Acad Sci. 2003; 998:138-60. DOI: 10.1196/annals.1254.016. View

Fontaine B, Khurana T, Hoffman E, BRUNS G, Haines J, Trofatter J . Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene. Science. 1990; 250(4983):1000-2. DOI: 10.1126/science.2173143. View

Lerche H, Heine R, Pika U, George Jr A, Mitrovic N, Browatzki M . Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J Physiol. 1993; 470:13-22. PMC: 1143902. DOI: 10.1113/jphysiol.1993.sp019843. View

Heine R, Pika U, Lehmann-Horn F . A novel SCN4A mutation causing myotonia aggravated by cold and potassium. Hum Mol Genet. 1993; 2(9):1349-53. DOI: 10.1093/hmg/2.9.1349. View

Lehmann-Horn F, Kuther G, Ricker K, Grafe P, Ballanyi K, Rudel R . Adynamia episodica hereditaria with myotonia: a non-inactivating sodium current and the effect of extracellular pH. Muscle Nerve. 1987; 10(4):363-74. DOI: 10.1002/mus.880100414. View

Popa M, Alekov A, Bail S, Lehmann-Horn F, Lerche H . Cooperative effect of S4-S5 loops in domains D3 and D4 on fast inactivation of the Na+ channel. J Physiol. 2004; 561(Pt 1):39-51. PMC: 1665345. DOI: 10.1113/jphysiol.2004.065912. View

10.

Sokolov S, Scheuer T, Catterall W . Gating pore current in an inherited ion channelopathy. Nature. 2007; 446(7131):76-8. DOI: 10.1038/nature05598. View

11.

West J, Patton D, Scheuer T, Wang Y, Goldin A, Catterall W . A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. Proc Natl Acad Sci U S A. 1992; 89(22):10910-4. PMC: 50452. DOI: 10.1073/pnas.89.22.10910. View

12.

Jurkat-Rott K, Weber M, Fauler M, Guo X, Holzherr B, Paczulla A . K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci U S A. 2009; 106(10):4036-41. PMC: 2644652. DOI: 10.1073/pnas.0811277106. View

13.

Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg R, Hogan K . A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet. 1994; 3(8):1415-9. DOI: 10.1093/hmg/3.8.1415. View

14.

Tombola F, Pathak M, Isacoff E . How does voltage open an ion channel?. Annu Rev Cell Dev Biol. 2006; 22:23-52. DOI: 10.1146/annurev.cellbio.21.020404.145837. View

15.

Adrian R, Marshall M . Action potentials reconstructed in normal and myotonic muscle fibres. J Physiol. 1976; 258(1):125-43. PMC: 1308963. DOI: 10.1113/jphysiol.1976.sp011410. View

16.

Wu F, Gordon E, Hoffman E, Cannon S . A C-terminal skeletal muscle sodium channel mutation associated with myotonia disrupts fast inactivation. J Physiol. 2005; 565(Pt 2):371-80. PMC: 1464529. DOI: 10.1113/jphysiol.2005.082909. View

17.

Tsujino A, Maertens C, Ohno K, Shen X, Fukuda T, Harper C . Myasthenic syndrome caused by mutation of the SCN4A sodium channel. Proc Natl Acad Sci U S A. 2003; 100(12):7377-82. PMC: 165883. DOI: 10.1073/pnas.1230273100. View

18.

Hayward L, Brown Jr R, Cannon S . Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. J Gen Physiol. 1996; 107(5):559-76. PMC: 2217015. DOI: 10.1085/jgp.107.5.559. View

19.

Ricker K, Bohlen R, Rohkamm R . Different effectiveness of tocainide and hydrochlorothiazide in paramyotonia congenita with hyperkalemic episodic paralysis. Neurology. 1983; 33(12):1615-8. DOI: 10.1212/wnl.33.12.1615. View

20.

Goldman L . On mutations that uncouple sodium channel activation from inactivation. Biophys J. 1999; 76(5):2553-9. PMC: 1300225. DOI: 10.1016/S0006-3495(99)77408-4. View