Role of protein phosphatase inhibitor-1 in cardiac beta adrenergic pathway. (December 2016)

• Record Type: Journal Article
• Authors: Weber, Silvio; Meyer-Roxlau, Stefanie; El-Armouche, Ali
• Is Part Of: Journal of molecular and cellular cardiology. Volume 101(2016:Dec.)
• Page Start: 116
• Page End: 126
• Publication Date: 2016-12
• Subjects: Protein phosphatase inhibitor-1 (I-1) -- Reversible phosphorylation -- Beta adrenergic; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2016.09.007
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Phosphoproteomic studies have shown that about one third of all cardiac proteins are reversibly phosphorylated, affecting virtually every cellular signaling pathway. The reversibility of this process is orchestrated by the opposing enzymatic activity of kinases and phosphatases. Conversely, imbalances in subcellular protein phosphorylation patterns are a hallmark of many cardiovascular diseases including heart failure and cardiac arrhythmias. While numerous studies have revealed excessive beta-adrenergic signaling followed by deregulated kinase expression or activity as a major driver of the latter cardiac pathologies, far less is known about the beta-adrenergic regulation of their phosphatase counterparts. In fact, most of the limited knowledge stems from the detailed analysis of the endogenous inhibitor of the protein phosphatase 1 (I-1) in cellular and animal models. I-1 acts as a nodal point between adrenergic and putatively non-adrenergic cardiac signaling pathways and is able to influence widespread cellular functions of protein phosphatase 1 which are contributing to cardiac health and disease, e.g. Ca 2 + handling, sarcomere contractility and glucose metabolism. Finally, nearly all of these studies agree that I-1 is a promising drug target on the one hand but the outcome of its pharmacological regulation maybe extremely context-dependent on the other hand, thus warranting for careful interpretation of past and future experimental results. In this respect we will: 1) comprehensively review the current knowledge about structural, functional and regulatory properties of I-1 within the heart 2) highlight current working hypothesis and potential I-1 mediated disease mechanisms 3) discuss state-of-the-art knowledge and future prospects of a potential therapeutic strategy targeting I-1 by restoring the balance of cardiac protein phosphorylation. Highlights: I-1 is a major regulator of PP1-mediated reversible cardiac protein phosphorylation. I-1 takes a nodal position in the cardiac beta adrenergic pathway. I-1 seems to be an "internal break" for exaggerated chronic beta-adrenergic drive. I-1 might be a novel starting point to treat heart failure and cardiac arrhythmias.