Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder triggered by volatile anesthetics and characterized by excessive Ca 2+ release in skeletal muscle. Most MH-associated mutations reside in the type 1 ryanodine receptor (RyR1), the sarcoplasmic reticulum Ca 2+ release channel. However, variants in CaV1.1—the L-type Ca 2+ channel essential for excitation-contraction coupling—have also been implicated, though their pathogenic mechanism remains unclear. We examined four novel CaV1.1 variants identified in MH-susceptible individuals using a reconstituted depolarization-induced Ca 2+ release (DICR) platform in HEK293 cells. Two variants markedly increased sensitivity to extracellular K + , shifting the voltage-sensing process toward more hyperpolarized potentials. In addition, caffeine-induced Ca 2+ release through RyR1 was enhanced in these variants, but this effect was abolished either by hyperpolarizing the membrane potential or by eliminating DICR. These results demonstrate that CaV1.1 mutations can enhance DICR, thereby augmenting RyR1-mediated Ca 2+ release and predisposing to dysregulated Ca 2+ homeostasis. Our findings establish a direct mechanistic link between CaV1.1 variants and MH susceptibility, underscoring the pathological contribution of enhanced DICR to disease pathogenesis.
Murayama et al. (Sun,) studied this question.