A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation
Saïd Bendahhou, … , Stephen G. Waxman, Louis J. Ptácek
Saïd Bendahhou, … , Stephen G. Waxman, Louis J. Ptácek
Published August 1, 2000
Citation Information: J Clin Invest. 2000;106(3):431-438. https://doi.org/10.1172/JCI9654.
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Article

A double mutation in families with periodic paralysis defines new aspects of sodium channel slow inactivation

Abstract

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant skeletal muscle disorder caused by single mutations in the SCN4A gene, encoding the human skeletal muscle voltage-gated Na+ channel. We have now identified one allele with two novel mutations occurring simultaneously in the SCN4A gene. These mutations are found in two distinct families that had symptoms of periodic paralysis and malignant hyperthermia susceptibility. The two nucleotide transitions predict phenylalanine 1490→leucine and methionine 1493→isoleucine changes located in the transmembrane segment S5 in the fourth repeat of the α-subunit Na+ channel. Surprisingly, this mutation did not affect fast inactivation parameters. The only defect produced by the double mutant (F1490L-M1493I, expressed in human embryonic kidney 293 cells) is an enhancement of slow inactivation, a unique behavior not seen in the 24 other disease-causing mutations. The behavior observed in these mutant channels demonstrates that manifestation of HyperKPP does not necessarily require disruption of slow inactivation. Our findings may also shed light on the molecular determinants and mechanism of Na+ channel slow inactivation and help clarify the relationship between Na+ channel defects and the long-term paralytic attacks experienced by patients with HyperKPP.

Authors

Saïd Bendahhou, Theodore R. Cummins, Angelika F. Hahn, Sylvie Langlois, Stephen G. Waxman, Louis J. Ptácek

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Recovery from fast inactivation and deactivation. (a) Recovery from fast...
Recovery from fast inactivation and deactivation. (a) Recovery from fast inactivation. Cells were prepulsed to 0 mV for 200 milliseconds to inactivate all of the current, then recovery potentials from –120 to –60 mV (–120 mV is shown) for increasing recovery duration were applied before the test pulse to 0 mV (20 milliseconds) to assay the fraction of current recovered. Traces obtained at the test pulse were fitted to a single-exponential function. (b) Tail currents were elicited by a 0.5-millisecond test pulse to +40 mV followed by a repolarization pulse ranging from –120 to –60 mV. Resulting currents were fitted by a single-exponential decay and expressed as a function of the voltage for WT (filled circles; n = 20), F1490L (filled diamonds; n = 20), M1493I (filled squares; n = 20), and F1490L-M1493I (open circles; n = 20). Values represent mean ± SEM.