Neuronal calcium regulation and cell stress in Malignant Hyperthermia

Calcium ions (Ca2+) are essential signaling molecules and must be carefully regulated to preserve specificity in function. One indispensible Ca2+ signaling protein is the ryanodine receptor (RyR) calcium release channel. RyR1 is essential for muscle contraction, and RyR1mutations can lead to severe muscle disorders such as malignant hyperthermia (MH). Recently, a mouse model of human MH (Y522S-RyR1) has been developed. In skeletal muscle, Y522S-RyR1 exhibits an increased sensitivity to activation resulting in Ca2+ leak, mitochondrial disorganization, and cellular stress. Although RyR1 expression is limited in the brain, the cerebellum may be particularly vulnerable to this disease because RyR1 is highly expressed in Purkinje neurons. In this study, Y522S-RyR1 in Purkinje cells exhibits a lower threshold for activation, but does not cause severe cellular stress and damage. Future investigation of compensatory mechanisms for increased Ca2+ release in Purkinje cells could be of therapeutic value for many neurological and muscular disorders.