Complex functionality of protein phosphatase 1 isoforms in the heart.

ABSTRACT

Protein phosphatase 1(PP1) is a key regulator of cardiac function through dephosphorylating serine/threonine residues within target proteins to oppose the function of protein kinases. Studies from failing hearts of animal models and human patients have demonstrated significant increase of PP1 activity in myocardium, while elevated PP1 activity in transgenic mice leads to cardiac dysfunction, suggesting that PP1 might be a therapeutic target to ameliorate cardiac dysfunction in failing hearts. In fact, cardiac overexpression of inhibitor 1, the endogenous inhibitor of PP1, increases cardiac contractility and suppresses heart failure progression. However, this notion of PP1 inhibition for heart failure treatment has been challenged by recent studies on the isoform-specific roles of PP1 in the heart. PP1 is a holoenzyme composed of catalytic subunits (PP1α, PP1ß, or PP1γ) and regulatory proteins that target them to distinct subcellular locations for functional specificity. This review will summarize how PP1 regulates phosphorylation of some of the key cardiac proteins involved in Ca2+ handling and cardiac contraction, and the potential role of PP1 isoforms in controlling cardiac physiology and pathophysiology.