Original articleRegulation of sarcoplasmic reticulum Ca2+ release by serine-threonine phosphatases in the heart

- Serine-threonine phosphatases regulate RyR2 activity and thereby SR Ca2+ release.
- Phosphatases PP1, PP2A and PP2B are associated with RyR2 macromolecular complex.
- Local RyR2-bound phosphatase activities are altered in broad range of cardiac diseases.
- Manipulation of RyR2-bound phosphatase activity is an attractive therapeutic strategy.

The amount and timing of Ca2+ release from the sarcoplasmic reticulum (SR) during cardiac cycle are the main determinants of cardiac contractility. Reversible phosphorylation of the SR Ca2+ release channel, ryanodine receptor type 2 (RyR2) is the central mechanism of regulation of Ca2+ release in cardiomyocytes. Three major serine-threonine phosphatases including PP1, PP2A and PP2B (calcineurin) have been implicated in modulation of RyR2 function. Changes in expression levels of these phosphatases, their activity and targeting to the RyR2 macromolecular complex were demonstrated in many animal models of cardiac disease and humans and are implicated in cardiac arrhythmia and heart failure. Here we review evidence in support of regulation of RyR2-mediated SR Ca2+ release by serine-threonine phosphatases and the role and mechanisms of dysregulation of phosphatases in various disease states.