title: Role of protein phosphatase inhibitor-1 in cardiac beta adrenergic pathway.
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. Ca2+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.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany. Electronic address: Silvio.Weber@tu-dresden.de.
authors.forename: Silvio
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Meyer-Roxlau
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, Dresden 01307, Germany. Electronic address: Ali.El-Armouche@tu-dresden.de.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009928:Organ Specificity; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011943:Receptors, Adrenergic, beta; C021042:protein phosphatase inhibitor-1
keywords: Beta adrenergic; Protein phosphatase inhibitor-1 (I-1); Reversible phosphorylation