A calcium channel mutant mouse model of hypokalemic periodic paralysis.

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(V)1.1) or a sodium channel (Na(V)1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between Ca(V)1.1 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 Ca(V)1.1 R528H mutation. The Ca(V)1.1 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(V)1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the Na(V)1.4 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.

• Authors: 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 12 Pg. 4580-91 (Dec 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 23187123 (Publication Type: Journal Article, Research Support, American Recovery and Reinvestment Act, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CACNA1S protein, mouse
• Calcium Channels, L-Type
• Insulin
• Glucose

Topics

• Action Potentials
• Analysis of Variance
• Animals
• Calcium Channels, L-Type (genetics, metabolism)
• Disease Models, Animal
• Electric Stimulation
• Excitation Contraction Coupling
• Female
• Glucose
• Humans
• Hypokalemic Periodic Paralysis (chemically induced, genetics, pathology)
• In Vitro Techniques
• Insulin
• Lysosomal Storage Diseases (genetics)
• Male
• Mice
• Mice, 129 Strain
• Muscle Contraction
• Muscle Fibers, Skeletal (metabolism, pathology, physiology)
• Muscle Weakness (genetics)
• Muscle, Skeletal (pathology, physiopathology)
• Muscular Diseases (genetics)
• Mutation, Missense
• Phenotype