title: Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria.
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 (CaV3.1, CaV3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Cav3.1 and CaV3.2 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 CaV3.1 and CaV3.2 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 CaV3.1 and CaV3.2 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.
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology, jerry.curran@osumc.edu.
authors.forename: Jerry
authors.initials: J
authors.lastname: Curran
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology.
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology.
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Makara
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Little
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology.
authors.forename: John D
authors.initials: JD
authors.lastname: Higgins
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, Biomedical Engineering,The Ohio State University Wexner Medical Center, Columbus, Ohio 43210 and.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: The Eppley Institute and UNMC-Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.affiliation: From the Dorothy M. Davis Heart and Lung Research Institute, the Departments of Physiology and Cell Biology, Medicine, and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D000483:Alleles; D000818:Animals; D002118:Calcium / Q000737:chemistry; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D004562:Electrocardiography; D011992:Endosomes / Q000378:metabolism*; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000378:metabolism*; D006339:Heart Rate; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000166:cytology; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; D020747:Calcium Channels, T-Type; D002352:Carrier Proteins; C470993:Ehd3 protein, mouse; D002118:Calcium
keywords: ankyrin; arrhythmia; cytoskeleton; endosome; heart; ion channel; membrane trafficking
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