title: 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.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, USA.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Wu
authors.forename: Wentao
authors.initials: W
authors.lastname: Mi
authors.forename: Erick O
authors.initials: EO
authors.lastname: Hernández-Ochoa
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Yu
authors.initials: Y
authors.lastname: Fu
authors.forename: Hillery F
authors.initials: HF
authors.lastname: Gray
authors.forename: Arie F
authors.initials: AF
authors.lastname: Struyk
authors.forename: Martin F
authors.initials: MF
authors.lastname: Schneider
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cannon
mesh_terms: D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation; D056966:Excitation Contraction Coupling; D005260:Female; D005947:Glucose; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D066298:In Vitro Techniques; D007328:Insulin; D016464:Lysosomal Storage Diseases / Q000235:genetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D007328:Insulin; D005947:Glucose