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The Journal of Neuroscience, June 15, 1999, 19(12):4762-4771

Activation and Inactivation of the Voltage-Gated Sodium Channel: Role of Segment S5 Revealed by a Novel Hyperkalaemic Periodic Paralysis Mutation

Saïd Bendahhou¹, Theodore R. Cummins^{2, 3}, Rabi Tawil⁴, Stephen G. Waxman^{2, 3}, and Louis J. Ptácek¹

¹ Howard Hughes Medical Institute, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah 84112, ² Departments of Neurology and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, ³ Neuroscience Research Center, Veterans Administration Medical Center, West Haven, Connecticut 06516, and ⁴ Department of Neurology, University of Rochester, Rochester, New York 14642

Hyperkalaemic periodic paralysis, paramyotonia congenita, and potassium-aggravated myotonia are three autosomal dominant skeletal muscle disorders linked to the SCN4A gene encoding the -subunit of the human voltage-sensitive sodium channel. To date, ~20 point mutations causing these disorders have been described. We have identified a new point mutation, in the SCN4A gene, in a family with a hyperkalaemic periodic paralysis phenotype. This mutation predicts an isoleucine-to-phenylalanine substitution at position 1495 located in the transmembrane segment S5 in the fourth homologous domain of the human -subunit sodium channel. Introduction of the I1495F mutation into the wild-type channels disrupted the macroscopic current inactivation decay and shifted both steady-state activation and inactivation to the hyperpolarizing direction. The recovery from fast inactivation was slowed, and there was no effect on channel deactivation. Additionally, a significant enhancement of slow inactivation was observed in the I1495F mutation. In contrast, the T704M mutation, a hyperkalaemic periodic paralysis mutation located in the cytoplasmic interface of the S5 segment of the second domain, also shifted activation in the hyperpolarizing direction but had little effect on fast inactivation and dramatically impaired slow inactivation. These results, showing that the I1495F and T704M hyperkalaemic periodic paralysis mutations both have profound effects on channel activation and fast-slow inactivation, suggest that the S5 segment maybe in a location where fast and slow inactivation converge.

Key words: Na channel; SCN4A; disorders; activation; slow inactivation; expression

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19124762-10$05.00/0

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