Sodium Channelopathies of Skeletal Muscle and Brain

Overview

Journal Physiol Rev

Publisher American Physiological Society

Specialty Physiology

Date 2021 Mar 26

PMID 33769100

Citations 39

Authors

Massimo Mantegazza

Sandrine Cestele

William A Catterall

Affiliations

Soon will be listed here.

Abstract

Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous α-subunits of brain sodium channels that cause epilepsy, migraine, autism, and related comorbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.

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References

Bendahhou S, Cummins T, Kwiecinski H, Waxman S, Ptacek L . Characterization of a new sodium channel mutation at arginine 1448 associated with moderate Paramyotonia congenita in humans. J Physiol. 1999; 518 ( Pt 2):337-44. PMC: 2269438. DOI: 10.1111/j.1469-7793.1999.0337p.x. View

Jones J, Dionne L, DellOrco J, Parent R, Krueger J, Cheng X . Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol Dis. 2016; 89:36-45. PMC: 4991781. DOI: 10.1016/j.nbd.2016.01.018. View

Buzsaki G . Hippocampal sharp wave-ripple: A cognitive biomarker for episodic memory and planning. Hippocampus. 2015; 25(10):1073-188. PMC: 4648295. DOI: 10.1002/hipo.22488. View

ORoak B, Vives L, Girirajan S, Karakoc E, Krumm N, Coe B . Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012; 485(7397):246-50. PMC: 3350576. DOI: 10.1038/nature10989. View

Mantegazza M, Curia G, Biagini G, Ragsdale D, Avoli M . Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010; 9(4):413-24. DOI: 10.1016/S1474-4422(10)70059-4. View

Lossin C, Wang D, Rhodes T, Vanoye C, George Jr A . Molecular basis of an inherited epilepsy. Neuron. 2002; 34(6):877-84. DOI: 10.1016/s0896-6273(02)00714-6. View

Westenbroek R, Merrick D, Catterall W . Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron. 1989; 3(6):695-704. DOI: 10.1016/0896-6273(89)90238-9. View

Rudel R, Ricker K, Lehmann-Horn F . Genotype-phenotype correlations in human skeletal muscle sodium channel diseases. Arch Neurol. 1993; 50(11):1241-8. DOI: 10.1001/archneur.1993.00540110113011. View

Catterall W . Molecular properties of voltage-sensitive sodium channels. Annu Rev Biochem. 1986; 55:953-85. DOI: 10.1146/annurev.bi.55.070186.004513. View

10.

Oakley J, Kalume F, Yu F, Scheuer T, Catterall W . Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy. Proc Natl Acad Sci U S A. 2009; 106(10):3994-9. PMC: 2656193. DOI: 10.1073/pnas.0813330106. View

11.

Enomoto A, Han J, Hsiao C, Chandler S . Sodium currents in mesencephalic trigeminal neurons from Nav1.6 null mice. J Neurophysiol. 2007; 98(2):710-9. DOI: 10.1152/jn.00292.2007. View

12.

Kalume F, Westenbroek R, Cheah C, Yu F, Oakley J, Scheuer T . Sudden unexpected death in a mouse model of Dravet syndrome. J Clin Invest. 2013; 123(4):1798-808. PMC: 3613924. DOI: 10.1172/JCI66220. View

13.

Catterall W . From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000; 26(1):13-25. DOI: 10.1016/s0896-6273(00)81133-2. View

14.

Abriel H, Rougier J, Jalife J . Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death. Circ Res. 2015; 116(12):1971-88. PMC: 4471480. DOI: 10.1161/CIRCRESAHA.116.305017. View

15.

de Kovel C, Meisler M, Brilstra E, van Berkestijn F, van t Slot R, van Lieshout S . Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res. 2014; 108(9):1511-8. PMC: 4490185. DOI: 10.1016/j.eplepsyres.2014.08.020. View

16.

Kaplan M, Cho M, Ullian E, Isom L, Levinson S, Barres B . Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron. 2001; 30(1):105-19. DOI: 10.1016/s0896-6273(01)00266-5. View

17.

Ghovanloo M, Shuart N, Mezeyova J, Dean R, Ruben P, Goodchild S . Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018; 293(43):16546-16558. PMC: 6204917. DOI: 10.1074/jbc.RA118.004929. View

18.

De Fusco M, Marconi R, Silvestri L, Atorino L, Rampoldi L, Morgante L . Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet. 2003; 33(2):192-6. DOI: 10.1038/ng1081. View

19.

Meisler M, Kearney J, Ottman R, Escayg A . Identification of epilepsy genes in human and mouse. Annu Rev Genet. 2001; 35:567-88. PMC: 2765248. DOI: 10.1146/annurev.genet.35.102401.091142. View

20.

Bendahhou S, Cummins T, Kula R, Fu Y, Ptacek L . Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5. Neurology. 2002; 58(8):1266-72. DOI: 10.1212/wnl.58.8.1266. View