title: Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction.
abstract: The cardiac ryanodine receptor (RyR2) mediates rapid Ca(2+) efflux from intracellular stores to effect myocyte contraction during the process of EC (excitation-contraction) coupling. It is now known that mutations in this channel perturb Ca(2+) release function, leading to triggered arrhythmias that may cause SCD (sudden cardiac death). Resolving the precise molecular mechanisms by which SCD-linked RyR2 dysfunction occurs currently constitutes a burgeoning area of cardiac research. So far, defective channel phosphorylation, accessory protein binding, luminal/cytosolic Ca(2+) sensing, and the disruption of interdomain interactions represent the main candidate mechanisms for explaining aberrant SR (sarcoplasmic reticulum) Ca(2+) release via mutants of RyR2. It appears increasingly unlikely that a single exclusive common mechanism underlies every case of mutant channel dysfunction, and that each of these potential mechanisms may contribute to the resultant phenotype. The present review will consider very recent mechanistic developments in this field, including new observations from mutant RyR2 transgenic mouse models, peptide-probe studies, and the implications of functional and phenotypic heterogeneity of RyR2 mutations and polymorphisms.
authors.affiliation: Department of Cardiology, Wales Heart Research Institute, Cardiff University School of Medicine, Cardiff CF14 4XN, U.K. thomasnl1@cardiff.ac.uk
authors.forename: N L
authors.initials: NL
authors.lastname: Thomas
authors.forename: C H
authors.initials: CH
authors.lastname: George
authors.forename: A J
authors.initials: AJ
authors.lastname: Williams
authors.forename: F A
authors.initials: FA
authors.lastname: Lai
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: D007473:Ion Channels; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B