A calcium channel mutant mouse model of hypokalemic periodic paralysis

Fenfen Wu, Wentao Mi, Erick O. Hernández-Ochoa, Dennis K. Burns, Yu Fu, Hillery F. Gray, Arie F. Struyk, Martin F. Schneider, Stephen C. Cannon

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K+). HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (Ca V1.1) or a sodium channel (NaV1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between CaV1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in HypoPP is unknown. To address this question, we developed a mouse model for HypoPP with a targeted CaV1.1 R528H mutation. The Cav1.1 R528H mice had a HypoPP phenotype for which low K+ challenge produced a paradoxical depolarization of the resting potential, loss of muscle excitability, and weakness. A vacuolar myopathy with dilated transverse tubules and disruption of the triad junctions impaired Ca2+ release and likely contributed to the mild permanent weakness. Fibers from the Ca V1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the NaV1.4 R669H HypoPP mouse model. This "gating pore current" may be a common mechanism for paradoxical depolarization and susceptibility to HypoPP arising from missense mutations in the S4 voltage sensor of either calcium or sodium channels.

Original languageEnglish (US)
Pages (from-to)4580-4591
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'A calcium channel mutant mouse model of hypokalemic periodic paralysis'. Together they form a unique fingerprint.

  • Cite this

    Wu, F., Mi, W., Hernández-Ochoa, E. O., Burns, D. K., Fu, Y., Gray, H. F., Struyk, A. F., Schneider, M. F., & Cannon, S. C. (2012). A calcium channel mutant mouse model of hypokalemic periodic paralysis. Journal of Clinical Investigation, 122(12), 4580-4591. https://doi.org/10.1172/JCI66091