Regulation of Ca2+ leak and susceptibility to malignant hyperthermia and heat stroke

<b>Abstract</b><br/><p>Sarcoplasmic reticulum (SR) Ca2+ leak is elevated in many myopathies, but whether Ca2+ leak is a driver or consequence of the disease process is not always clear. The Ryanodine Receptor, RYR1, is the SR Ca2+ release channel required for both muscle contraction and Ca2+ leak. SPEG (striated muscle preferentially expressed protein kinase) regulates the Ca2+ leak properties of RYR1 by phosphorylation of serine 2902. Mutation of Serine S2902 to an aspartic acid to mimic SPEG phosphorylation of RYR1 decreases muscle temperature-dependent SR Ca2+ leak, restores the levels of excitation-contraction coupling proteins, and reduces the heat and volatile anesthetic sensitivity of mice with a malignant hyperthermia susceptibility mutation in RYR1 (Y524S, Y522S in humans). The S2902D mice allow a direct test of the role of SR Ca2+ leak in both normal muscle function (aging, exercise) and mice disease pathophysiology.</p>