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      Palmitoylation: A Fatty Regulator of Myocardial Electrophysiology

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          Regulation of cardiac physiology is well known to occur through the action of kinases that reversibly phosphorylate ion channels, calcium handling machinery, and signaling effectors. However, it is becoming increasingly apparent that palmitoylation or S-acylation, the post-translational modification of cysteines with saturated fatty acids, plays instrumental roles in regulating the localization, activity, stability, sorting, and function of numerous proteins, including proteins known to have essential functions in cardiomyocytes. However, the impact of this modification on cardiac physiology requires further investigation. S-acylation is catalyzed by the zDHHC family of S-acyl transferases that localize to intracellular organelle membranes or the sarcolemma. Recent work has begun to uncover functions of S-acylation in the heart, particularly in the regulation of cardiac electrophysiology, including modification of the sodium-calcium exchanger, phospholemman and the cardiac sodium pump, as well as the voltage-gated sodium channel. Elucidating the regulatory functions of zDHHC enzymes in cardiomyocytes and determination of how S-acylation is altered in the diseased heart will shed light on how these modifications participate in cardiac pathogenesis and potentially identify novel targets for the treatment of cardiovascular disease. Indeed, proteins with critical signaling roles in the heart are also S-acylated, including receptors and G-proteins, yet the dynamics and functions of these modifications in myocardial physiology have not been interrogated. Here, we will review what is known about zDHHC enzymes and substrate S-acylation in myocardial physiology and highlight future areas of investigation that will uncover novel functions of S-acylation in cardiac homeostasis and pathophysiology.

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          Most cited references 106

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          Heterotrimeric G protein activation by G-protein-coupled receptors.

          Heterotrimeric G proteins have a crucial role as molecular switches in signal transduction pathways mediated by G-protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP-GDP exchange on the G protein alpha-subunit. The complex series of interactions and conformational changes that connect agonist binding to G protein activation raise various interesting questions about the structure, biomechanics, kinetics and specificity of signal transduction across the plasma membrane.
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            Protein palmitoylation in neuronal development and synaptic plasticity.

            Protein palmitoylation, a classical and common lipid modification, regulates diverse aspects of neuronal protein trafficking and function. The reversible nature of palmitoylation provides a potential general mechanism for protein shuttling between intracellular compartments. The recent discovery of palmitoylating enzymes--a large DHHC (Asp-His-His-Cys) protein family--and the development of new proteomic and imaging methods have accelerated palmitoylation analysis. It is becoming clear that individual DHHC enzymes generate and maintain the specialized compartmentalization of substrates in polarized neurons. Here, we discuss the regulatory mechanisms for dynamic protein palmitoylation and the emerging roles of protein palmitoylation in various aspects of pathophysiology, including neuronal development and synaptic plasticity.
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              Phospholamban: a crucial regulator of cardiac contractility.

              Heart failure is a major cause of death and disability. Impairments in blood circulation that accompany heart failure can be traced, in part, to alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are induced by its interactions with phospholamban, a reversible inhibitor. If phospholamban becomes superinhibitory or chronically inhibitory, contractility is diminished, inducing dilated cardiomyopathy in mice and humans. In mice, phospholamban seems to encumber an otherwise healthy heart, but humans with a phospholamban-null genotype develop early-onset dilated cardiomyopathy.

                Author and article information

                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                19 February 2020
                : 11
                1Department of Pharmacology, University of Michigan , Ann Arbor, MI, United States
                2Department of Psychiatry, University of Michigan , Ann Arbor, MI, United States
                3Department of Internal Medicine, University of Michigan , Ann Arbor, MI, United States
                Author notes

                Edited by: Sachio Morimoto, International University of Health and Welfare (IUHW), Japan

                Reviewed by: Luke Chamberlain, University of Strathclyde, United Kingdom; Darren Boehning, Cooper Medical School of Rowan University, United States

                *Correspondence: Matthew J. Brody, majbrody@

                This article was submitted to Striated Muscle Physiology, a section of the journal Frontiers in Physiology

                Copyright © 2020 Essandoh, Philippe, Jenkins and Brody.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 127, Pages: 11, Words: 0
                Funded by: National Institutes of Health 10.13039/100000002


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