Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria
Year: 2015
Type: article
Abstract: Proper trafficking of membrane-bound ion channels and transporters is requisite for normal cardiac function. Endosome-based protein trafficking of membrane-bound ion channels and transporters in the heart is poorly understood, particularly in vivo . In fact, for select cardiac cell types such as atrial myocytes, virtually nothing is known regarding endosomal transport. We previously linked the C-terminal Eps15 homology domain-containing protein 3 (EHD3) with endosome-based protein trafficking in ventricular cardiomyocytes. Here we sought to define the roles and membrane protein targets for EHD3 in atria. We identify the voltage-gated T-type Ca 2+ channels (Ca V 3.1, Ca V 3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Ca v 3.1 and Ca V 3.2 in the atria. Furthermore, functional experiments identify a significant loss of T-type-mediated Ca 2+ current in EHD3-deficient atrial myocytes. Moreover, EHD3 associates with both Ca V 3.1 and Ca V 3.2 in co-immunoprecipitation experiments. T-type Ca 2+ channel function is critical for proper electrical conduction through the atria. Consistent with these roles, EHD3-deficient mice demonstrate heart rate variability, sinus pause, and atrioventricular conduction block. In summary, our findings identify Ca V 3.1 and Ca V 3.2 as substrates for EHD3-dependent protein trafficking in heart, provide in vivo data on endosome-based trafficking pathways in atria, and implicate EHD3 as a key player in the regulation of atrial myocyte excitability and cardiac conduction. Background: Endosome-based protein trafficking in the heart is poorly understood. Results: Functional targeting and expression of the T-type Ca 2+ channel (TTCC) in the atria requires the endosomal protein, EHD3. Conclusion: Impaired endosomal transport leads to cardiac rhythm and conduction disorders. Significance: Understanding endosome-based protein trafficking in the heart may provide new therapeutic targets for cardiovascular disease.
Source: Journal of Biological Chemistry
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G117152681, G1270675593, G1325811013, Molecular Control of EGF Receptor Down-Regulation, G2903589952, Role of spectrin/ankyrin-G complex in myocyte signaling and cardiac excitability, G3242543384, Role of ankyrin-B in human arrhythmia, G3498129444, G3977408364, G463917580, CaMKII-dependent regulation of cardiac excitability, G5469753910, G5853396361, G5915938994, G629954890, ErbB2 Downregulation Through HSP90 Inhibition, G8878039642, G9000041484, G9000109270, G9000154535, G9000162494, G9000210543
OpenAlex ID: W2069909801