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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL114383-02
Application #
8710332
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2016) Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. Circulation 134:486-98
Mohler, Peter J; Abriel, Hugues (2016) Complexity of cardiac ion channel macromolecular complexes. Cardiovasc Res 110:163-4
Hund, Thomas J; Mohler, Peter J (2016) Atrial-specific pathways for control of intracellular signaling and myocyte function. J Clin Invest 126:3731-3734
Boyden, Penelope A; Dun, Wen; Robinson, Richard B (2016) Cardiac Purkinje fibers and arrhythmias; The GK Moe Award Lecture 2015. Heart Rhythm 13:1172-81
Adelman, Sara; Daoud, Georges; Mohler, Peter J (2016) Strategies for Risk Analysis and Disease Classification in Atrial Fibrillation. J Cardiovasc Electrophysiol :
Unudurthi, Sathya D; Wu, Xiangqiong; Qian, Lan et al. (2016) Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability. J Am Heart Assoc 5:e002865
Roof, S R; Boslett, J; Russell, D et al. (2016) Insulin-like growth factor 1 prevents diastolic and systolic dysfunction associated with cardiomyopathy and preserves adrenergic sensitivity. Acta Physiol (Oxf) 216:421-34
Huq, A J; Pertile, M D; Davis, A M et al. (2016) A Novel Mechanism for Human Cardiac Ankyrin-B Syndrome due to Reciprocal Chromosomal Translocation. Heart Lung Circ :
Csepe, Thomas A; Zhao, Jichao; Hansen, Brian J et al. (2016) Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways. Prog Biophys Mol Biol 120:164-78
Sturm, Amy C; Kline, Crystal F; Glynn, Patric et al. (2015) Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy. J Am Heart Assoc 4:

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