Role of PP1 in the regulation of Ca cycling in cardiac physiology and pathophysiology.

Type 1 protein phosphatase (PP1) is a critical regulator of several cellular processes. In the heart, it mediates restoration of contractility to basal levels by dephosphorylating key phospho-proteins, after beta-adrenergic stimulation. PP1 is a holoenzyme consisting of its catalytic and regulatory subunits, which anchor the catalytic subunit to desired subcellular locations, define substrate specificity and modulate catalytic activity. At the level of the cardiac sarcoplasmic reticulum (SR), PP1 is regulated by Inhibitor-1 (I-1) and Inhibitor-2 (I-2), which modulate its activity, and the striated muscle-specific glycogen-targeting subunit, GM/RGL, which targets it to the SR vicinity. PP1 regulation is highly important in maintaining cardiac function under physiological conditions. In fact, aberrant Ca handling and depressed contractility in heart failure have been, at least partly, attributed to increases in PP1 activity, mediated by impaired regulation via its inhibitors. Importantly, increases in the level and activity of I-1 and I-2 in animal models have been successful in ameliorating dysfunction and remodeling in heart failure, suggesting that PP1 inhibition may be a plausible therapeutic strategy in heart failure.