Membrane excitability and excitation-contraction (EC) coupling in the healthy heart rely upon the proper expression, trafficking, and retention of integral membrane proteins (ion channels, transporters, receptors). All play key roles in governing cardiac contraction and short and long term adaptations to physiological and pathophysiological stimuli. The profile of expressed proteins is dynamic, being tightly synchronized to assure the proper responses to stress1. This is highlighted by a decade of research linking dysfunction in membrane protein trafficking with heart disease. Yet, despite its obvious importance, little is known regarding even the identity of the molecular mechanisms underlying the targeting of integral membrane proteins in the context of the heart. The focus of this multiple PI proposal, is to identify new pathways for membrane protein targeting and regulation in heart with the goal of defining novel mechanisms for the regulation of cardiac membrane excitability as well as its dysregulation in disease. While not well studied in any organ system, Eps15 homology domain-containing (EHD) gene products (EHD1-4) are intracellular proteins that appear to be key regulators of membrane protein trafficking. Previously uncharacterized in the heart, our group (Boyden &Mohler) recently provided evidence that this protein family likely plays indispensible roles in protein trafficking in cardia muscle. Notably, we uncovered a vital role for one of these endosomal proteins, EHD3, in the membrane trafficking of the Na/Ca exchanger (NCX) in heart5. Moreover, we showed that EHD proteins are differentially regulated in large animal models of human cardiovascular disease, suggesting that EHD proteins may play a critical role in the remodeling of membrane proteins following myocardial infarction (post MI). Our initial findings predict a role for EHD proteins in membrane protein trafficking in the healthy and diseased heart. Our overall hypothesis is that EHD proteins are indispensable components in the proper trafficking of integral membrane proteins involved in cardiac excitability and EC coupling, and are involved in the remodeling of the heart over a wide variety of cardiac pathologies. The goal of this proposal is to directly test the role of EHD3 and EHD3 in cardiac structural and electrical activity using innovative in vivo models of EHD protein deficiency.
Normal function of ion channels/transporters requires defined biophysical properties as well as precise expression, organization, and regulation in defined membrane domains. EHD proteins are a recently identified family of proteins in heart and appear to be critical regulators of membrane protein targeting in heart and regulation of cardiac excitability in health and disease. Our new studies will provide insight on key upstream and downstream roles of EHD proteins in diverse excitable myocytes at baseline and in cardiovascular disease using a host of animal models.
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|Yoo, Shin; Aistrup, Gary; Shiferaw, Yohannes et al. (2018) Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure. JCI Insight 3:|
|He, Beixin Julie; Boyden, Penelope; Scheinman, Melvin (2018) Ventricular arrhythmias involving the His-Purkinje system in the structurally abnormal heart. Pacing Clin Electrophysiol 41:1051-1059|
|Boyden, Penelope A; Smith, Godfrey L (2018) Ca2+ leak-What is it? Why should we care? Can it be managed? Heart Rhythm 15:607-614|
|Makara, Michael A; Curran, Jerry; Lubbers, Ellen R et al. (2018) Novel Mechanistic Roles for Ankyrin-G in Cardiac Remodeling and Heart Failure. JACC Basic Transl Sci 3:675-689|
|Li, Ning; Hansen, Brian J; Csepe, Thomas A et al. (2017) Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure. Sci Transl Med 9:|
|Mohler, Peter J; Hund, Thomas J (2017) Novel Pathways for Regulation of Sinoatrial Node Plasticity and Heart Rate. Circ Res 121:1027-1028|
|Koenig, Sara N; Mohler, Peter J (2017) The evolving role of ankyrin-B in cardiovascular disease. Heart Rhythm 14:1884-1889|
|Boyden, Penelope A; Mohler, Peter J (2017) Treat the Patient, Not Just the Cell! Circ Res 120:1390-1392|
|Huq, A J; Pertile, M D; Davis, A M et al. (2017) A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. Heart Lung Circ 26:612-618|
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