Stopping a Calcium Leak

Abstract

The reduced contractile function that occurs during heart failure is associated with abnormalities in intracellular calcium dynamics. Calcium is released from stores in the sarcoplasmic reticulum through type 2 ryanodine receptors (RyR2), which form a homotetrameric channel in which each subunit is bound by a stabilizing subunit, calstabin-2. Increased sympathetic activity (a compensatory response to heart failure) leads to increased phosphorylation of RyR2 and calstabin-2 dissociation. The ensuing "leakiness" of the RyR2 channel could contribute to the disrupted calcium dynamics and impaired contractility of the failing heart. Wehrens et al . investigated whether the 1,4-benzothiazepine JTV519, which increases calstabin-2 binding to phosphorylated RyR2, could restore calstabin-2 binding and ameliorate heart failure in a mouse model of ischemia-induced heart failure. Wild-type mice treated with JTV519 showed improved cardiac function 21 and 28 days after myocardial infarction (MI), whereas mice lacking calstabin-2 did not. Immunoblot analysis of immunoprecipitates indicated that JTV519 increased calstabin-2 association with RyR2 in MI mice. Single-channel analysis indicated that RyR2 channels from wild-type mice treated with JTV519 had a low open probability at calcium concentrations similar to those found during diastole (that is, they would not be leaky), whereas channels from untreated wild-type mice or treated mice lacking calstabin-2 had a higher open probability. Skeletal muscle, which contains RyR1 and calstabin-1, also becomes dysfunctional during heart failure, contributing to shortness of breath and exercise intolerance; JTV519 increased calstabin-1 binding to RyR1 and improved skeletal muscle function in wild-type and calstabin-2 −/− mice with heart failure. Thus, JTV519, by enhancing calstabin binding to cardiac and skeletal RyR, could provide a therapeutic approach to cardiac and skeletal muscle dysfunction in heart failure. X. H. T. Wehrens, S. E. Lehnart, S. Reiken, R. van der Nagel, R. Morales, J. Sun, Z. Cheng, S.-X. Deng, L. J. de Windt, D. W. Landry, A. R. Marks, Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. Proc. Natl. Acad. Sci. U.S.A. 102 , 9607-9612 (2005). [Abstract] [Full Text]