Physiological Role(S) of RyR1 in 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. Though RyR1 is preferentially expressed in skeletal muscles recent data has shown that it is also expressed in some areas of the central nervous system, in some cells of the immune system (B-lymphocytes and dendritic cells) and in smooth muscle cells. 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.Using an animal model knocked in for the RYR1Y522S mutation we observed that bleeding times were increased by more than two fold in heterozygous mice compared to their wild type littermates, with no differences in platelet numbers nor aggregation characteristics between heterozygous RYR1Y522S carriers and control littermates. Bleeding abnormalities have also been seen in some patients with dominant RYR1 mutations; as part of a comprehensive study we investigated in detail RyR1 expression in smooth muscle cells isolated from different tissues and if there is a causal link between RYR1 mutations and prolonged bleeding times.