Altered function and regulation of cardiac ryanodine receptors in cardiac disease.
In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum (SR) releases the calcium required for muscle contraction. The magnitude of Ca(2+) release by RyR2, which is subject to regulation by several physiological mediators, determines cardiac contractility. In heart failure, chronic stimulation of the beta-adrenergic signaling pathway leads to hyperphosphorylation of RyR2 by protein kinase A, which dissociates calstabin2 (FKBP12.6) from the receptor. Calstabin2-depleted channels display altered channel gating and can cause diastolic Ca(2+) release from the SR. This release depletes the SR Ca(2+) stores, leading to reduced myocardial contractility. Mutant RyR2, found in patients with catecholaminergic polymorphic ventricular tachycardia, has decreased calstabin2 binding affinity, which can trigger ventricular arrhythmias and sudden cardiac death after stress and exercise. Thus, defects in RyR2 have been linked to heart failure and exercise-induced sudden cardiac death and might provide novel therapeutic targets for the treatment of these common diseases of the heart.
Wehrens
Xander H T
XH
Center for Molecular Cardiology, Departments of Physiology and Cellular Biophysics and Medicine, Columbia University College of Physicians and Surgeons, 630W 168th Street, P&S 9-401, Box 65, New York, NY 10032, USA.
Marks
Andrew R
AR
D016757:Death, Sudden, Cardiac / Q000473:pathology; D006331:Heart Diseases / Q000473:pathology / Q000503:physiopathology*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008954:Models, Biological; D008955:Models, Cardiovascular; D009154:Mutation; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel