Key result
Mice lacking EHD3 display reduced expression of CaV3.1 and CaV3.2, leading to loss of T-type Ca2+ current, heart rate variability, sinus pause, and atrioventricular conduction block.
EHD3 is essential for the functional targeting and expression of T-type Ca2+ channels in the atria, and its deficiency leads to cardiac rhythm and conduction disorders.
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.
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Curran et al. (2015) studied Cardiac rhythm and conduction disorders. EHD3 deficiency vs. Wild-type (implied) was evaluated on Expression and targeting of CaV3.1 and CaV3.2 and T-type-mediated Ca2+ current. Mice lacking EHD3 display reduced expression of CaV3.1 and CaV3.2, leading to loss of T-type Ca2+ current, heart rate variability, sinus pause, and atrioventricular conduction block.
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