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

From the Departments of Neurology (Drs. Sugiura, Kumagai, Soeda, and Yamamoto) and Pharmacology (Drs. Li and Kimura), Fukushima Medical University School of Medicine, and Department of Cardiovascular Medicine (Dr. Makita), Hokkaido University Graduate School of Medicine, Sapporo, Japan; and University Laboratory of Physiology (P.J. Noble), Oxford, UK.

Address correspondence and reprint requests to Dr. Yoshihiro Sugiura, Department of Neurology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295 Japan; e-mail: sugiura{at}fmu.ac.jp

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 °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.

Received February 19, 2003. Accepted in final form June 16, 2003.

Part of the Results was presented at the 2002 American Academy of Neurology 54th Annual Meeting in Denver, Colorado.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 14 issue to find the title link for this article.

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