Journal article
EH Domain Proteins Regulate Cardiac Membrane Protein Targeting
Circulation research, Vol.107(1), pp.84-95
07/09/2010
DOI: 10.1161/CIRCRESAHA.110.216713
PMCID: PMC2901408
PMID: 20489164
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.
Details
- Title: Subtitle
- EH Domain Proteins Regulate Cardiac Membrane Protein Targeting
- Creators
- Hjalti Gudmundsson - University of IowaThomas J Hund - University of IowaPatrick J Wright - University of IowaCrystal F Kline - University of IowaJedidiah S Snyder - University of IowaLan Qian - University of IowaOlha M Koval - University of IowaShane R Cunha - University of IowaManju George - University of Nebraska Medical CenterMark A Rainey - University of Nebraska Medical CenterFarshid E Kashef - University of IowaWen Dun - Columbia UniversityPenelope A Boyden - Columbia UniversityMark E Anderson - University of IowaHamid Band - University of Nebraska Medical CenterPeter J Mohler - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.107(1), pp.84-95
- DOI
- 10.1161/CIRCRESAHA.110.216713
- PMID
- 20489164
- PMCID
- PMC2901408
- NLM abbreviation
- Circ Res
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 07/09/2010
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984200021802771
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