Calstabin deficiency, ryanodine receptors, and sudden cardiac death.
Altered cardiac ryanodine receptor (RyR2) function has an important role in heart failure and genetic forms of arrhythmias. RyR2 constitutes the major intracellular Ca2+ release channel in the cardiac sarcoplasmic reticulum (SR). The peptidyl-prolyl isomerase calstabin2 (FKBP12.6) is a component of the RyR2 macromolecular signaling complex. Calstabin2 binding to RyR2 is regulated by PKA phosphorylation of Ser2809 in RyR2. PKA phosphorylation of RyR2 decreases the binding affinity for calstabin2 and increases RyR2 open probability and sensitivity to Ca2+-dependent activation. In heart failure, a majority of studies have found that RyR2 becomes chronically PKA hyper-phosphorylated which depletes calstabin2 from the channel complex. Calstabin2 dissociation causes a diastolic SR Ca2+ leak contributing to depressed intracellular Ca2+ cycling and decreased cardiac contractility. Missense mutations linked to genetic forms of exercise-induced arrhythmias and sudden cardiac death also cause decreased calstabin2-binding affinity and leaky RyR2 channels. We review the importance of calstabin2 for RyR2 function and excitation-contraction coupling, and discuss new observations that implicate dysregulation of calstabin2 binding as a central mechanism for abnormal calcium cycling in heart failure and triggered arrhythmias.
Lehnart
Stephan E
SE
Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, 630W 168th Street, P&S 9-401, New York, NY 10032, USA. sel2004@columbia.edu
Wehrens
Xander H T
XH
Marks
Andrew R
AR
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D002303:Cardiac Output, Low / Q000150:complications / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D006801:Humans; D009200:Myocardial Contraction; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium