The
calcium-activated
protein phosphatase,
calcineurin, lies at the intersection of
protein phosphorylation and calcium signaling cascades, where it provides an essential nodal point for coordination between these two fundamental modes of intracellular communication. In excitatory cells, such as neurons and cardiomyocytes, that experience rapid and frequent changes in cytoplasmic
calcium,
calcineurin protein levels are exceptionally high, suggesting that these cells require high levels of
calcineurin activity. Yet, it is widely recognized that excessive activation of
calcineurin in the heart contributes to pathological hypertrophic remodeling and the progression to failure. How does a
calcium activated
enzyme function in the
calcium-rich environment of the continuously contracting heart without pathological consequences? This review will discuss the wide range of
calcineurin substrates relevant to cardiovascular health and the mechanisms
calcineurin uses to find and act on appropriate substrates in the appropriate location while potentially avoiding others. Fundamental differences in
calcineurin signaling in neonatal verses adult cardiomyocytes will be addressed as well as the importance of maintaining heterogeneity in
calcineurin activity across the myocardium. Finally, we will discuss how circadian oscillations in
calcineurin activity may facilitate integration with other essential but conflicting processes, allowing a healthy heart to reap the benefits of
calcineurin signaling while avoiding the detrimental consequences of sustained
calcineurin activity that can culminate in
heart failure.