title: Arrhythmogenic mechanisms in ryanodine receptor channelopathies.
abstract: Ryanodine receptors (RyRs) are the calcium release channels of sarcoplasmic reticulum (SR) that provide the majority of calcium ions (Ca(2+)) necessary to induce contraction of cardiac and skeletal muscle cells. In their intracellular environment, RyR channels are regulated by a variety of cytosolic and luminal factors so that their output signal (Ca(2+)) induces finely-graded cell contraction without igniting cellular processes that may lead to aberrant electrical activity (ventricular arrhythmias) or cellular remodeling. The importance of RyR dysfunction has been recently highlighted with the demonstration that point mutations in RYR2, the gene encoding for the cardiac isoform of the RyR (RyR2), are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic syndrome characterized by the development of adrenergically-mediated ventricular tachycardia in individuals with an apparently normal heart. Here we summarize the state of the field in regards to the main arrhythmogenic mechanisms triggered by RyR2 channels harboring mutations linked to CPVT. Most CPVT mutations characterized to date endow RyR2 channels with a gain of function, resulting in hyperactive channels that release Ca(2+) spontaneously, especially during diastole. The spontaneous Ca(2+) release is extruded by the electrogenic Na(+)/Ca(2+) exchanger, which depolarizes the external membrane (delayed afterdepolarization or DAD) and may trigger untimely action potentials. However, a rare set of CPVT mutations yield RyR2 channels that are intrinsically hypo-active and hypo-responsive to stimuli, and it is unclear whether these channels release Ca(2+) spontaneously during diastole. We discuss novel cellular mechanisms that appear more suitable to explain ventricular arrhythmias due to RyR2 loss-of-function mutations.
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, Cardiovascular Division, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Zhao
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Valdivia
authors.forename: Georgina B
authors.initials: GB
authors.lastname: Gurrola
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Hernández
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
mesh_terms: D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D006801:Humans; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000502:physiology*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel