Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia.

摘要: Naturally occurring mutations in the skeletal muscle Ca2+ release channel/ryanodine receptor RyR1 are linked to malignant hyperthermia (MH), a life-threatening complication of general anesthesia. Although it has long been recognized that MH results from uncontrolled or spontaneous sarcoplasmic reticulum, how render reticulum susceptible volatile anesthetic-induced is unclear. Here we investigated impact porcine mutation, R615C, human equivalent which also causes MH, on intrinsic properties channel and propensity for during store overload, process refer as overload-induced (SOICR). Single analyses revealed R615C mutation markedly enhanced luminal activation RyR1. Moreover, HEK293 cells expressing mutant displayed reduced threshold SOICR compared with wild type Furthermore, MH-triggering agent, halothane, potentiated response SOICR. Conversely, dantrolene, an effective treatment suppressed mutant, but not RyR2 mutant. These data suggest confers susceptibility by reducing SOICR, whereas anesthetics trigger further threshold, dantrolene suppresses increasing threshold. Together, our support view altered regulation represents primary causal mechanism MH.