EH domain proteins regulate cardiac membrane protein targeting

Hjalti Gudmundsson, Thomas J. Hund, Patrick J. Wright, Crystal F. Kline, Jedidiah S. Snyder, Lan Qian, Olha M. Koval, Shane R. Cunha, Manju George, Mark A. Rainey, Farshid E. Kashef, Wen Dun, Penelope A. Boyden, Mark E. Anderson, Hamid Band, Peter J. Mohler

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Rationale: Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes. Objective: We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes. Methods and Results: We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain-containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart. Conclusions: Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model.

Original languageEnglish (US)
Pages (from-to)84-95
Number of pages12
JournalCirculation Research
Volume107
Issue number1
DOIs
StatePublished - Jul 9 2010

Fingerprint

Ankyrins
Protein Transport
Membrane Proteins
Cardiac Myocytes
Membranes
Proteins
Endosomes
Recycling
Ion Channels
Muscle Cells
Protein Domains
Heart Diseases
Cardiovascular Diseases
Animal Models
Myocardial Infarction
Health
Research

Keywords

  • Ankyrin
  • Arrhythmia
  • Cytoskeleton
  • EHD proteins
  • Ion channel
  • Trafficking

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gudmundsson, H., Hund, T. J., Wright, P. J., Kline, C. F., Snyder, J. S., Qian, L., ... Mohler, P. J. (2010). EH domain proteins regulate cardiac membrane protein targeting. Circulation Research, 107(1), 84-95. https://doi.org/10.1161/CIRCRESAHA.110.216713

EH domain proteins regulate cardiac membrane protein targeting. / Gudmundsson, Hjalti; Hund, Thomas J.; Wright, Patrick J.; Kline, Crystal F.; Snyder, Jedidiah S.; Qian, Lan; Koval, Olha M.; Cunha, Shane R.; George, Manju; Rainey, Mark A.; Kashef, Farshid E.; Dun, Wen; Boyden, Penelope A.; Anderson, Mark E.; Band, Hamid; Mohler, Peter J.

In: Circulation Research, Vol. 107, No. 1, 09.07.2010, p. 84-95.

Research output: Contribution to journalArticle

Gudmundsson, H, Hund, TJ, Wright, PJ, Kline, CF, Snyder, JS, Qian, L, Koval, OM, Cunha, SR, George, M, Rainey, MA, Kashef, FE, Dun, W, Boyden, PA, Anderson, ME, Band, H & Mohler, PJ 2010, 'EH domain proteins regulate cardiac membrane protein targeting', Circulation Research, vol. 107, no. 1, pp. 84-95. https://doi.org/10.1161/CIRCRESAHA.110.216713
Gudmundsson H, Hund TJ, Wright PJ, Kline CF, Snyder JS, Qian L et al. EH domain proteins regulate cardiac membrane protein targeting. Circulation Research. 2010 Jul 9;107(1):84-95. https://doi.org/10.1161/CIRCRESAHA.110.216713
Gudmundsson, Hjalti ; Hund, Thomas J. ; Wright, Patrick J. ; Kline, Crystal F. ; Snyder, Jedidiah S. ; Qian, Lan ; Koval, Olha M. ; Cunha, Shane R. ; George, Manju ; Rainey, Mark A. ; Kashef, Farshid E. ; Dun, Wen ; Boyden, Penelope A. ; Anderson, Mark E. ; Band, Hamid ; Mohler, Peter J. / EH domain proteins regulate cardiac membrane protein targeting. In: Circulation Research. 2010 ; Vol. 107, No. 1. pp. 84-95.
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