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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ziolo, Mark T; Mohler, Peter J (2015) Defining the role of oxidative stress in atrial fibrillation and diabetes. J Cardiovasc Electrophysiol 26:223-5
Curran, Jerry; Makara, Michael A; Little, Sean C et al. (2014) EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology. Circ Res 115:68-78
Barry, Joshua; Gu, Yuanzheng; Jukkola, Peter et al. (2014) Ankyrin-G directly binds to kinesin-1 to transport voltage-gated Na+ channels into axons. Dev Cell 28:117-31
Makara, Michael A; Curran, Jerry; Little, Sean C et al. (2014) Ankyrin-G coordinates intercalated disc signaling platform to regulate cardiac excitability in vivo. Circ Res 115:929-38
Bonilla, Ingrid M; Long 3rd, Victor P; Vargas-Pinto, Pedro et al. (2014) Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure. PLoS One 9:e108824
Kline, Crystal F; Mohler, Peter J (2014) Defective interactions of protein partner with ion channels and transporters as alternative mechanisms of membrane channelopathies. Biochim Biophys Acta 1838:723-30
Chang, Kae-Jiun; Zollinger, Daniel R; Susuki, Keiichiro et al. (2014) Glial ankyrins facilitate paranodal axoglial junction assembly. Nat Neurosci 17:1673-81
Lou, Qing; Hansen, Brian J; Fedorenko, Olga et al. (2014) Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping. Circulation 130:315-24
Vreeker, Arnold; van Stuijvenberg, Leonie; Hund, Thomas J et al. (2014) Assembly of the cardiac intercalated disk during pre- and postnatal development of the human heart. PLoS One 9:e94722
Hund, Thomas J; Snyder, Jedidiah S; Wu, Xiangqiong et al. (2014) ?(IV)-Spectrin regulates TREK-1 membrane targeting in the heart. Cardiovasc Res 102:166-75

Showing the most recent 10 out of 14 publications