Function and regulation of phosphatase 1 in healthy and diseased heart

Abstract Reversible phosphorylation of ion channels and calcium-handling proteins provides precise post-translational regulation of cardiac excitation and contractility. Serine/threonine phosphatases govern dephosphorylation of the majority of cardiac proteins. Accordingly, dysfunction of this regulation contributes to the development and progression of heart failure and atrial fibrillation. On the molecular level, these changes include alterations in the expression level and phosphorylation status of Ca2+ handling and excitation-contraction coupling proteins provoked by dysregulation of phosphatases. The serine/threonine protein phosphatase PP1 is one a major player in the regulation of cardiac excitation-contraction coupling. PP1 essentially impacts on cardiac physiology and pathophysiology via interactions with cardiac ion channels Cav1.2, NKA, NCX and KCNQ1, sarcoplasmic reticulum-bound Ca2+ handling proteins such as RyR2, SERCA and PLB as well as proteins of the contractile proteins MLC2, TNI and MyBP-C. PP1 itself but also PP1-regulatory proteins like inhibitor-1, inhibitor-2 and heat-shock protein 20 are dysregulated in cardiac disease. Therefore, they represent interesting targets to gain more insights in heart pathophysiology and to identify new treatment strategies for patients with heart failure or atrial fibrillation. We describe the genetic and holoenzymatic structure of PP1 and review its role in the heart and cardiac disease. Finally, we highlight the importance of the PP1 regulatory proteins for disease manifestation, provide an overview of genetic models to study the role of PP1 for the development of heart failure and atrial fibrillation and discuss possibilities of pharmacological interventions.