Developing new anti-arrhythmics: clues from the molecular basis of cardiac ryanodine receptor (RyR2) Ca2+-release channel dysfunction.
Sudden cardiac death (SCD) remains a major cause of mortality, and despite our knowledge of the causative genetic, molecular and biochemical cellular mechanisms involved, effective therapeutic strategies are lacking. Perturbations in cardiac Ca2+ handling promote arrhythmias and there is enormous interest in developing new anti-arrhythmics aimed at correcting Ca2+ release dysfunction. In particular, abnormal Ca2+ release arising as a result of acquired or genetic defects in cardiac ryanodine receptors (RyR2) has emerged as an important arrhythmogenic trigger in heart failure, and in a devastating genetic arrhythmia syndrome termed catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we evaluate how experimental insights into RyR2 structure-function are unravelling the precise molecular basis of channel dysfunction and are advancing the development of new therapeutic strategies. We also discuss the functional role of RyR2 in the context of the exquisite synergism existing between numerous cellular components involved in cardiac Ca2+ signalling, and how these complex interactions may be used to design new anti-arrhythmic approaches that target multiple facets of RyR2 regulation.
George
Christopher H
CH
Wales Heart Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff, Wales, UK CF14 4XN. georgech@cf.ac.uk
Lai
F Anthony
FA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D002986:Clinical Trials as Topic; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D011110:Polymorphism, Genetic; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel