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

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.