Calcineurin in the heart: New horizons for an old friend

Calcineurin, also known as PP2B or PPP3, is a member of the PPP family of protein phosphatases that also includes PP1 and PP2A. Together these three phosphatases carryout the majority of dephosphorylation events in the heart. Calcineurin is distinct in that it is activated by the binding of calcium/calmodulin (Ca2+/CaM) and therefore acts as a node for integrating Ca2+ signals with changes in phosphorylation, two fundamental intracellular signaling cascades. In the heart, calcineurin is primarily thought of in the context of pathological cardiac remodeling, acting through the Nuclear Factor of Activated T-cell (NFAT) family of transcription factors. However, calcineurin activity is also essential for normal heart development and homeostasis in the adult heart. Furthermore, it is clear that NFAT-driven changes in transcription are not the only relevant processes initiated by calcineurin in the setting of pathological remodeling. There is a growing appreciation for the diversity of calcineurin substrates that can impact cardiac function as well as the diversity of mechanisms for targeting calcineurin to specific sub-cellular domains in cardiomyocytes and other cardiac cell types. Here, we will review the basics of calcineurin structure, regulation, and function in the context of cardiac biology. Particular attention will be given to: the development of improved tools to identify and validate new calcineurin substrates; recent studies identifying new calcineurin isoforms with unique properties and targeting mechanisms; and the role of calcineurin in cardiac development and regeneration. Calcineurin (CN) signaling plays diverse roles in cardiac development, from (A) early steps in lineage commitment to (B) critical processes during cardiac morphogenesis. (C) In the adult heart, calcineurin activity is heterogeneous across the ventricular wall following a gradient of increasing stress from the epicardium (Epi) to the endocardium (Endo), as well as displaying a robust 24-h oscillation. Green arrows indicate steps dependent on CN. Red arrows indicate steps inhibited by CN. embryonic stem cells (ES), mesoderm (ME). [Display omitted] •Calcineurin activity is not always pathological.•Calcineurin and its substrates are anchored near specific Ca2+ release microdomains.•Mechanisms of activation and substrate choice depend on developmental stage and cardiac health.•Calcineurin activity is heterogeneous relative to location and timing.•Sustained calcineurin activity acce