Phosphorylation of RYR1 at Ser2902 Decreases Ca2+ Leak in Skeletal Muscle and Susceptibility to Malignant Hyperthermia and Heat Stroke

Authors

Rachel Sue Zhen Yee
Chang Seok Lee
Ting Chang
Sung Yun Jung
Omar Yousif
Courtney Cavazos
John Colyer
Filip Van Petegem
George G Rodney
Susan L Hamilton

Language

English

Publication Date

10-7-2025

Journal

Science Signaling

DOI

10.1126/scisignal.adx3087

PMID

41056385

PMCID

PMC12614350

PubMedCentral® Posted Date

11-14-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The 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 SPEG (striated muscle preferentially expressed protein). 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 desensitization 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.

Keywords

Ryanodine Receptor Calcium Release Channel, Animals, Malignant Hyperthermia, Muscle, Skeletal, Mice, Phosphorylation, Calcium, Heat Stroke, Point Mutation, Calcium Signaling, Serine, Sarcoplasmic Reticulum

Published Open-Access

yes

Recommended Citation

Yee, Rachel Sue Zhen; Lee, Chang Seok; Chang, Ting; et al., "Phosphorylation of RYR1 at Ser2902 Decreases Ca2+ Leak in Skeletal Muscle and Susceptibility to Malignant Hyperthermia and Heat Stroke" (2025). Faculty and Staff Publications. 4995.
https://digitalcommons.library.tmc.edu/baylor_docs/4995