EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology

Jerry Curran, Michael A. Makara, Sean C. Little, Hassan Musa, Bin Liu, Xiangqiong Wu, Iuliia Polina, Joseph S. Alecusan, Patrick Wright, Jingdong Li, George E. Billman, Penelope A. Boyden, Sandor Gyorke, Hamid Band, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Rationale: Cardiac function is dependent on the coordinate activities of membrane ion channels, transporters, pumps, and hormone receptors to tune the membrane electrochemical gradient dynamically in response to acute and chronic stress. Although our knowledge of membrane proteins has rapidly advanced during the past decade, our understanding of the subcellular pathways governing the trafficking and localization of integral membrane proteins is limited and essentially unstudied in vivo. In the heart, to our knowledge, there are no in vivo mechanistic studies that directly link endosome-based machinery with cardiac physiology. Objective: To define the in vivo roles of endosome-based cellular machinery for cardiac membrane protein trafficking, myocyte excitability, and cardiac physiology. Methods and Results: We identify the endosome-based Eps15 homology domain 3 (EHD3) pathway as essential for cardiac physiology. EHD3-deficient hearts display structural and functional defects including bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation. Mechanistically, EHD3 is critical for membrane protein trafficking, because EHD3-deficient myocytes display reduced expression/localization of Na/Ca exchanger and L-type Ca channel type 1.2 with a parallel reduction in Na/Ca exchanger-mediated membrane current and Ca v1.2-mediated membrane current. Functionally, EHD3-deficient myocytes show increased sarcoplasmic reticulum [Ca], increased spark frequency, and reduced expression/localization of ankyrin-B, a binding partner for EHD3 and Na/Ca exchanger. Finally, we show that in vivo EHD3-deficient defects are attributable to cardiac-specific roles of EHD3 because mice with cardiac-selective EHD3 deficiency demonstrate both structural and electric phenotypes. Conclusions: These data provide new insight into the critical role of endosome-based pathways in membrane protein targeting and cardiac physiology. EHD3 is a critical component of protein trafficking in heart and is essential for the proper membrane targeting of select cellular proteins that maintain excitability.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalCirculation Research
Volume115
Issue number1
DOIs
StatePublished - Jun 20 2014

Keywords

  • Ehd3 protein
  • ankyrins
  • cell biology
  • electrophysiology
  • ion channels
  • mice
  • protein transport

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Curran, J., Makara, M. A., Little, S. C., Musa, H., Liu, B., Wu, X., Polina, I., Alecusan, J. S., Wright, P., Li, J., Billman, G. E., Boyden, P. A., Gyorke, S., Band, H., Hund, T. J., & Mohler, P. J. (2014). EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology. Circulation Research, 115(1), 68-78. https://doi.org/10.1161/CIRCRESAHA.115.304149