[HTML][HTML] A calcium channel mutant mouse model of hypokalemic periodic paralysis

F Wu, W Mi, EO Hernández-Ochoa… - The Journal of …, 2012 - Am Soc Clin Investig
F Wu, W Mi, EO Hernández-Ochoa, DK Burns, Y Fu, HF Gray, AF Struyk, MF Schneider…
The Journal of clinical investigation, 2012Am Soc Clin Investig
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 (CaV1. 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 …
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 (CaV1.1) 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 CaV1.1 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.
The Journal of Clinical Investigation