Phosphorylation of RYR1 at Ser2902 decreases Ca2+ leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke.

Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca2+ release channel required for both skeletal muscle contraction and Ca2+ leak. Mutations in RYR1 cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser2902 by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser2902→Asp2902 (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca2+ sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca2+ transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr524→Ser524 point mutation in RYR1, show increased Ca2+ leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca2+ leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca2+ leak in skeletal muscle by phosphorylating Ser2902 on RYR1, and mutation of Ser2902 to Asp2902 to mimic this phosphorylation event rescues YS mice from heat-induced death.