Eps15 homology domain-containing protein 3 regulates cardiac T-type Ca<sup>2+</sup> channel targeting and function in the atria

Jerry Curran, Hassan Musa, Crystal F. Kline, Michael A. Makara, Sean C. Little, John D. Higgins, Thomas J. Hund, Hamid Band, Peter J. Mohler

Research output: Contribution to journalArticle

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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<sup>2+</sup> channels (Ca<inf>V</inf>3.1, Ca<inf>V</inf>3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Ca<inf>v</inf>3.1 and Ca<inf>V</inf>3.2 in the atria. Furthermore, functional experiments identify a significant loss of T-type-mediated Ca<sup>2+</sup> current in EHD3-deficient atrial myocytes. Moreover, EHD3 associates with both Ca<inf>V</inf>3.1 and Ca<inf>V</inf>3.2 in co-immunoprecipitation experiments. T-type Ca<sup>2+</sup> 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<inf>V</inf>3.1 and Ca<inf>V</inf>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.

Original languageEnglish (US)
Pages (from-to)12210-12221
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number19
DOIs
StatePublished - May 8 2015

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Proteins
Endosomes
Protein Transport
Ion Channels
Cardiac Myocytes
Muscle Cells
Protein Domains
Membranes
Atrioventricular Block
Immunoprecipitation
Membrane Proteins
Substrates
Heart Rate
Experiments
Display devices
Electric potential

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Curran, J., Musa, H., Kline, C. F., Makara, M. A., Little, S. C., Higgins, J. D., ... Mohler, P. J. (2015). Eps15 homology domain-containing protein 3 regulates cardiac T-type Ca<sup>2+</sup> channel targeting and function in the atria. Journal of Biological Chemistry, 290(19), 12210-12221. https://doi.org/10.1074/jbc.M115.646893

Eps15 homology domain-containing protein 3 regulates cardiac T-type Ca<sup>2+</sup> channel targeting and function in the atria. / Curran, Jerry; Musa, Hassan; Kline, Crystal F.; Makara, Michael A.; Little, Sean C.; Higgins, John D.; Hund, Thomas J.; Band, Hamid; Mohler, Peter J.

In: Journal of Biological Chemistry, Vol. 290, No. 19, 08.05.2015, p. 12210-12221.

Research output: Contribution to journalArticle

Curran, Jerry ; Musa, Hassan ; Kline, Crystal F. ; Makara, Michael A. ; Little, Sean C. ; Higgins, John D. ; Hund, Thomas J. ; Band, Hamid ; Mohler, Peter J. / Eps15 homology domain-containing protein 3 regulates cardiac T-type Ca<sup>2+</sup> channel targeting and function in the atria. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 19. pp. 12210-12221.
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AU - Little, Sean C.

AU - Higgins, John D.

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