The Malignant Hyperthermia RYR1Y522S Mutation affects Calcium Homeostasis in Arterial Smooth Muscle Cells

Abstract

Type 1 ryanodine receptor (RyR1) is a key protein involved in the regulation of the intracellular Ca2+ concentration in skeletal muscle cells, playing a crucial role in muscle contraction by releasing Ca2+ from the sarcoplasmic reticulum after plasma membrane depolarization. Dysregulation of calcium signals due to defects in RyR1 have been associated with a wide range of primary neuromuscular disorders, including Malignant Hyperthermia Susceptibility and a number of congenital myopathies including Core Myopathies, some forms of Centronuclear myopathy and Congenital Fiber Type Disproportion. Thus mutations in RYR1 (the gene encoding RyR1) may lead to alterations of Ca2+ homeostasis not only in skeletal muscle, but also in other tissues expressing this intracellular calcium release channel. In the present report we performed the biochemical characterization and immunofluorescence analysis of RyR1 in arterial smooth muscle cells. We found that smooth muscle cells isolated from the RYR1Y522S knock in mouse exhibited increased frequency of localized calcium release events (sparks) and smaller intracellular Ca2+ stores compared to WT littermates, although the resting calcium was not affected. In conclusion we show that a RYR1 mutation associated with Malignant Hyperthermia alters vascular smooth muscle cell function by affecting calcium homeostasis.