Skeletal muscle sodium current is reduced in hypokalemic periodic paralysis

This is the authors' abstract. We don't add key points for this paper.

Hypokalemic periodic paralysis (HypoPP), described a recent issue of PNAS by Jurkat-Rott and colleagues (1), has great scientific and clinical interest because its pathophysiology touches on several important properties of skeletal muscle. Besides providing the force for movement, skeletal muscle is an electrically excitable tissue and an important endocrine target organ as the largest protein store for humans (2). Jurkat-Rott et al. (1) defined some of the abnormalities in surface membrane ionic currents that are responsible for the phenotype of HypoPP. HypoPP is an autosomal dominant disease characterized by episodic attacks of muscle paralysis usually associated with hypokalemia. Paralysis is caused by membrane depolarization triggering sodium channel inactivation, which renders the membrane inexcitable (3–5). Membrane hyperexcitability, such as myotonia, is never associated with HypoPP. Insulin administration may trigger a paralytic attack without appreciable hypokalemia (3–5). The first recognized linkage of HypoPP was to chromosome 1Q31–32 (6–8). The defective gene (CACNA1S) encodes a skeletal muscle dihydropyridine-sensitive or L-type calcium channel. Two mutations have been described in segment 4 of domain 2 (D2/S4, Arg-528→His) and D4/S4 (Arg-1239→His) of the α-subunit of the skeletal muscle L-type calcium channel. A third less common mutation also involves D4/S4 (Arg-1239→Gly) (5, 7, 9, 10). Two recent studies demonstrated that point mutations in the SCN4A gene affecting D2/S4 of the α-subunit of the mature innervated and tetrodotoxin-sensitive isoform of the skeletal muscle sodium channel can produce the phenotype of HypoPP. Bulman et al. (11) described one family with an Arg-669→His mutation. In this issue, Jurkat-Rott et al. (1) described five families, each of which had one of two mutations Arg-672→His or Arg-672→Gly.

This commentary highlights that reduced sodium current amplitude is a common pathophysiological change in both sodium and calcium channel mutation forms of hypokalemic periodic paralysis, explaining reduced muscle fiber excitability.