A malignant hyperthermia-inducing mutation in RYR1 (R163C): Alterations in Ca2+ entry, release, and retrograde signaling to the DHPR

Abstract

Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Horn) RYR1-R163C knock-in mouse myotubes to maintained KT depolarization. The new findings are: (a) For all there genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Horn, (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF9636