When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis

 Involvement of monovalent cations currents carried by muscle Ca²⁺ channels in type 1 hypokalaemic periodic paralysis (HypoPP1). A, HypoPP1 mutations in voltage‐sensing segments or in segments potentially interacting with voltage‐sensing segments generate resting inward currents through voltage‐sensing domains called gating pores carrying H⁺ or Na⁺, respectively. In normokalaemia, muscle fibres remain excitable and emit action potentials (bottom trace). B, Na⁺ or H⁺ gating pore currents when associated with hypokalaemia or with hypokalaemia plus acidosis, respectively, induced sustained depolarization and subsequent abolition of action potentials leading to muscle paralysis (bottom trace). Trains of action potentials correspond to actual recordings in an isolated mouse skeletal muscle fibre using the silicone clamp technique in the current clamp mode (C. Fuster, unpublished data).

Abstract

Patients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1 subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca²⁺ from sarcoplasmic reticulum and also functions as a Ca²⁺ channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1 subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K⁺ to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage‐gated Na⁺ and K⁺ channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca²⁺ channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H⁺ for the R1239H arginine‐to‐histidine mutation in a S4 segment and Na⁺ for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.

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