Ryanodine receptor-mediated arrhythmias and sudden cardiac death.
The cardiac ryanodine receptor-Ca2+ release channel (RyR2) is an essential sarcoplasmic reticulum (SR) transmembrane protein that plays a central role in excitation-contraction coupling (ECC) in cardiomyocytes. Aberrant spontaneous, diastolic Ca2+ leak from the SR due to dysfunctional RyR2 contributes to the formation of delayed after-depolarisations, which are thought to underlie the fatal arrhythmia that occurs in both heart failure (HF) and in catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is an inherited disorder associated with mutations in either the RyR2 or a SR luminal protein, calsequestrin. RyR2 shows normal function at rest in CPVT but the RyR2 dysfunction is unmasked by physical exercise or emotional stress, suggesting abnormal RyR2 activation as an underlying mechanism. Several potential mechanisms have been advanced to explain the dysfunctional RyR2 observed in HF and CPVT, including enhanced RyR2 phosphorylation status, altered RyR2 regulation at luminal/cytoplasmic sites and perturbed RyR2 intra/inter-molecular interactions. This review considers RyR2 dysfunction in the context of the structural and functional modulation of the channel, and potential therapeutic strategies to stabilise RyR2 function in cardiac pathology.
Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF144XN, UK. blayney@cf.ac.uk
Lynda M
LM
Blayney
F Anthony
FA
Lai
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology
D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium