New Cause of Intractable Disease Occurring During Surgery Elucidated

A research group led by Associate Professor Takashi Murayama of the Department of Pharmacology at Juntendo University and Associate Professor Takuro Tomida of the Department of Molecular Pharmacology at Shinshu University, in collaboration with Hiroshima University and Toho University, has clarified a new mechanism for malignant hyperthermia (MH) caused by genetic mutations in the skeletal muscle-type voltage-dependent calcium channel (CaV1.1). The study demonstrated that CaV1.1 mutations enhance the voltage dependence of depolarization-induced Ca2+ release (DICR), a physiological calcium release mechanism in skeletal muscle, resulting in DICR occurring at rest and strengthening Ca2+-induced Ca2+ release (CICR). This achievement significantly advances the understanding of the MH onset mechanism caused by CaV1.1 mutations, which had been unknown for many years, and is expected to lead to the development of new therapeutic strategies. The research results were published in the online version of Communications Biology on May 29, 2026. Malignant hyperthermia (MH) is a serious condition that causes fever, muscle rigidity, and hypermetabolism due to inhaled anesthetics or muscle relaxants used during surgery. The main cause is abnormal Ca2+ release from the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in the sarcoplasmic reticulum of skeletal muscle. While RyR1 gain-of-function mutations have been reported in many MH patients, genetic mutations in CaV1.1 have been identified in some patients, but the mechanism of onset remained unclear. The research group performed functional analysis of four types of CaV1.1 mutations identified at Hiroshima University using a DICR reconstitution system. The results showed that certain mutations increase the voltage dependence of DICR, causing weak DICR even in a resting state, which enhances CICR via local Ca2+ concentration increases near RyR1, potentially triggering MH. Future efforts are expected to focus on developing new MH treatments that normalize the enhanced DICR.