The ryanodine receptor 1 (RyR1) functions as the primary calcium release channel within the sarcoplasmic reticulum of skeletal muscle, where it plays a central role in excitation-contraction coupling. Dysregulation of RyR1 activity underlies numerous neuromuscular disorders, most notably malignant hyperthermia (MH), a life-threatening condition triggered by volatile anesthetics. To elucidate the molecular basis of MH, we investigated the T4826I mutation in the RyR1 transmembrane domain through structural and functional studies. Using a miniaturized purification workflow, we isolated native RyR1 channels from knock-in mice and determined high-resolution cryo-EM structures in both ligand-free and inhibitor-bound states. Unlike other MH mutations that enhance channel activity by destabilizing the closed state, the T4826I substitution promotes channel activation by stabilizing the open state. Dantrolene, the FDA-approved treatment for MH, binds cooperatively with ATP to the peripheral repeat1 and 2 domain, inducing local conformational changes but failing to close the pore. In contrast, a distinct inhibitor binds directly within the pore, acting as a pore blocker and inducing a C2-symmetric, semi-closed state. Single-channel recordings of this inhibitor reveal voltage-dependent inhibition independent of ATP, unlike dantrolene. Collectively, these findings provide mechanistic insights into RyR1 dysregulation in MH and reveal new opportunities for therapeutic targeting of skeletal muscle RyR1 as well as the homologous cardiac isoform, RyR2.
Chen et al. (Sun,) studied this question.
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