CMYA5 modulates ryanodine receptor 2 (RYR2) activity in cardiomyocytes

About This Grant

PROJECT SUMMARY/ABSTRACT Calcium ion (Ca2+) play a crucial role in regulating striated muscle contraction. Intricate nanoscopic structures, known as dyads in cardiomyocytes, efficiently coupling membrane excitation with Ca2+ release and sarcomere contraction. However, the mechanisms that regulate the activity of dyads remain poorly understood. Ryanodine receptor (RYR2) is the dyadic component responsible for the majority of intracellular Ca2+ release in cardiomyocytes. Dysregulation of RYR2 contributes to the pathogenesis of several human diseases, including heart failure and arrhythmias. For example, dominant variants in RYR2 cause catecholaminergic polymorphic ventricular tachycardia (CPVT), in which excessive diastolic Ca2+ release triggers potentially lethal cardiac arrhythmias. We discovered that CMYA5 (Cardiomyopathy-associated protein 5) is a little studied component of dyads. CMYA5 ablation disrupts dyad organization and positioning, resulting in cardiomyopathy and abnormal Ca2+ release. In our preliminary data, we show that CMYA5 interacts with RYR2 via an RYR2 interaction domain (RID). RID binding significantly reduces the open probability of both wild-type and CPVT mutant RYR2 channels. Based on these findings, we hypothesize that CMYA5 is a novel endogenous regulator of RYR2 channel activity. Targeting RID-mediated inhibition of these channels could potentially treat CPVT caused by RYR mutations. To test this hypothesis, we will investigate CMYA5-RID’s role in regulating RYR2 activity in cardiomyocytes (Aim 1), and test its therapeutic potential to reduce aberrant Ca2+ release and arrhythmias in CPVT (Aim 2). This study is significant as it will elucidate the physiological roles of CMYA5 in modulating ryanodine receptor activity, and explore therapeutic strategies based on CMYA5 inhibition of RYR2 activity. These efforts will lay the groundwork for development of more effective therapies for more common forms of heart disease.