Neuron
Volume 10, Issue 4, April 1993, Pages 667-678
Journal home page for Neuron

Article
Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis

https://doi.org/10.1016/0896-6273(93)90168-QGet rights and content

Abstract

Hyperkalemic periodic paralysis (HYPP), one of several inheritable myotonic diseases, results from genetic defects in the human skeletal muscle Na+ channel. In some pedigrees, HYPP is correlated with a single base pair substitution resulting in a Met replacing Thr704 in the fifth transmembrane segment of the second domain. This region is totally conserved between the human and rat channels. We have introduced the human mutation into the corresponding region of the rat muscle Na+ channel cDNA and expressed it in human embryonic kidney 293 cells. Patch-clamp recordings show that this mutation shifts the voltage dependence of activation by 10–15 mV in the negative direction. The shift results in a persistent Na+ current that activates near −70 mV; this phenomenon could underlie the abnormal muscle activity observed in patients with HYPP.

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      Early studies (prior to the successful expression of human NaV1.4) using heterologous expression of rat NaV1.4 containing mutations corresponding to the human T704M and M1592V, demonstrated a disruption in fast inactivation leading to an increase in persistent non-inactivating sodium currents which allowed sodium current to flow even after tens of milliseconds (Cannon and Strittmatter, 1993). Another early study also using the rat homologue of the T704M mutation found a shift of the voltage dependence of activation in the negative, hyperpolarised direction (Cummins et al., 1993). Subsequent studies of human Nav1.4 channels with the T704M and M1592V mutations however, found no impairment of fast inactivation (Yang et al., 1994; Bendahhou et al., 1999; Rojas et al., 1999; Hayward et al., 1999), but did find a shift of activation in the hyperpolarised direction by 5–10 mV, and a shift of the midpoint of the slow inactivation curve in the depolarised direction.

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      The predominant phenotype can vary even within families with the same SCN4A variant (McClatchey et al., 1992). Mutations in SCN4A causing HyperPP affect the gating behavior of this channel and produce gain-of-function defects characterized by impaired inactivation (Cannon et al., 1991; Cummins and Sigworth, 1996) and/or an enhancement of activation (Cummins et al., 1993). The resultant aberrant persistent Na+ current predisposes to prolonged attacks of depolarization-induced paralysis.

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