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A calcium channel mutant mouse model of hypokalemic periodic paralysis.

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.

Pubmed ID: 23187123


  • Wu F
  • Mi W
  • Hern├índez-Ochoa EO
  • Burns DK
  • Fu Y
  • Gray HF
  • Struyk AF
  • Schneider MF
  • Cannon SC


The Journal of clinical investigation

Publication Data

December 3, 2012

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR-055099
  • Agency: NIAMS NIH HHS, Id: AR-063182
  • Agency: NIAMS NIH HHS, Id: AR-42703
  • Agency: NIAMS NIH HHS, Id: R01 AR063182
  • Agency: NIAMS NIH HHS, Id: R37 AR055099

Mesh Terms

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