Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis.

Conference item

BACKGROUND: The authors reported a mutation, P1158S, of the human skeletal muscle sodium channel gene (SCN4A) in a family with cold-induced hypokalemic periodic paralysis (hypoKPP) and myotonia. OBJECTIVE: To identify mechanisms of temperature dependency in this channelopathy. METHODS: Using the amphotericin B perforated patch clamp method, sodium currents were recorded at 22 and 32 degrees C from the wild-type (WT) and P1158S mutant SCN4A expressed in tsA201 cells. Computer simulation was performed, incorporating the gating parameters of the P1158S mutant SCN4A. RESULTS: P1158S mutant SCN4A exhibited hyperpolarizing shifts in voltage dependence of both activation and inactivation curves at a cold temperature and a slower rate of inactivation than the WT. Computer simulation reproduced the abnormal skeletal muscle electrical activities of both paralysis at a low potassium concentration in the cold and myotonia at a normal potassium concentration. CONCLUSIONS: Both paralysis and myotonia are attributable to the biophysical properties of the SCN4A mutation associated with hypoKPP. This is the first report of an SCN4A mutation that exhibits temperature-dependent shifts of voltage dependence in sodium channel gating.

Authors: Sugiura, Y; Makita, N; Li, L; Noble, P; Kimura, J

• Publication status: Published
• Host title: Neurology
• Volume: 61
• Issue: 7
• Pages: 914-918
• Publication date: 2003-10-01
• Event location: United States
• DOI: 10.1212/01.wnl.0000086820.54065.a0
• EISSN: 1526-632X
• ISSN: 0028-3878
• Keywords: Cold Temperature; Computer Simulation; Action Potentials; Cell Line; Sodium Channels; Humans; Hypokalemic Periodic Paralysis; Temperature; Mutation; Patch-Clamp Techniques; Ion Channel Gating; Transfection; Mutagenesis, Site-Directed; Kidney; Sodium