Cardiac ryanodine receptor function and regulation in heart disease.
The cardiac ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR) controls intracellular Ca(2+) release and muscle contraction in the heart. Ca(2+) release via RyR2 is regulated by several physiological mediators. Protein kinase (PKA) phosphorylation dissociates the stabilizing FKBP12.6 subunit (calstabin2) from the RyR2 complex, resulting in increased contractility and cardiac output. Congestive heart failure is associated with elevated plasma catecholamine levels, and chronic stimulation of beta-adrenergic receptors leads to PKA hyperphosphorylation of RyR2 in failing hearts. PKA hyperphosphorylation results in calstabin2-depleted RyR2 that displays altered channel gating and may cause aberrant SR Ca(2+) release, depletion of SR Ca(2+) stores, and reduced myocardial contractility in heart failure. Calstabin2-depleted RyR2 may also trigger cardiac arrhythmias that cause sudden cardiac death. In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), RyR2 missense mutations cause reduced calstabin2 binding to RyR2. Increased RyR2 phosphorylation and pathologically increased calstabin2 dissociation during exercise results in aberrant diastolic calcium release, which may trigger ventricular arrhythmias and sudden cardiac death. In conclusion, heart failure and exercise-induced sudden cardiac death have been linked to defects in RyR2-calstabin2 regulation, and this may represent a novel target for the prevention and treatment of these forms of heart disease.
Lehnart
Stephan E
SE
Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Wehrens
Xander H T
XH
Kushnir
Alexander
A
Marks
Andrew R
AR
D006331:Heart Diseases / Q000503:physiopathology*; D006801:Humans; D020125:Mutation, Missense; D011487:Protein Conformation; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D019837:Ryanodine Receptor Calcium Release Channel