title: Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies.
abstract: It has been six years since the first reported link between mutations in the cardiac ryanodine receptor Ca(2+) release channel (RyR2) and catecholaminergic polymorphic ventricular tachycardia (CPVT), a malignant stress-induced arrhythmia. In this time, rapid advances have been made in identifying new mutations, and in understanding how these mutations disrupt normal channel function to cause VT that frequently degenerates into ventricular fibrillation (VF) and sudden death. Functional characterisation of these RyR2 Ca(2+) channelopathies suggests that mutations alter the ability of RyR2 to sense its intracellular environment, and that channel modulation via covalent modification, Ca(2+)- and Mg(2+)-dependent regulation and structural feedback mechanisms are catastrophically disturbed. This review reconciles the current status of RyR2 mutation-linked etiopathology, the significance of mutational clustering within the RyR2 polypeptide and the mechanisms underlying channel dysfunction. We will also review new data that explores the link between abnormal Ca(2+) release and the resultant cardiac electrical instability in VT and VF, and how these recent developments impact on novel anti-arrhythmic therapies. Finally, we evaluate the concept that mechanistic differences between CPVT and other arrhythmogenic disorders may preclude a common therapeutic strategy to normalise RyR2 function in cardiac disease.
authors.affiliation: Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. georgech@cf.ac.uk
authors.forename: Christopher H
authors.initials: CH
authors.lastname: George
authors.forename: Hala
authors.initials: H
authors.lastname: Jundi
authors.forename: N Lowri
authors.initials: NL
authors.lastname: Thomas
authors.forename: Debra L
authors.initials: DL
authors.lastname: Fry
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Lai
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D046912:Multiprotein Complexes; D009154:Mutation; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology / Q000628:therapy
chemical_list: D046912:Multiprotein Complexes; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases