Key result
EHD2 positively regulates cardiac sarcolemmal KATP channel surface expression by stabilizing caveolae, and its dominant-negative mutant abolishes the cardioprotective effect of ischemic preconditioning.
EHD2 is a novel positive regulator of K ATP channel surface expression and may serve as a potential pharmacologic target for cardioprotection during ischemia.
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May position EHD2 as a target for ischemic cardioprotection; hypothesis-generating in animal models, human validation needed.
ATP‐sensitive K + (K ATP ) channels uniquely link cellular energy metabolism to membrane excitability and are exρressed in diverse cell tyρes that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface exρression of K ATP channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up‐regulation of K ATP channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate K ATP channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and ρatch clamping to demonstrate that Eps15 homology domain‐containing protein 2 (EHD2) is a novel positive regulator of K ATP channel trafficking to increase surface K ATP channel density. EHD2 had no effect on cardiac Na + channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family—EHD1, EHD3, and EHD4—had no effect on K ATP channel surface expression. EHD2 did not directly affect K ATP channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing K ATP channel‐ containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated K ATP channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be car‐ dioprotective as a dominant‐negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our find‐ ings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with K ATP channel trafficking defects. — Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K ATP channel surface expression: role in cardioprotection. FASEB J. 32,1613 ‐1625 (2018). www.fasebj.org
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Yang et al. (2017) studied Cardiac ischemia. EHD2 expression vs. Control (empty vector or mCherry) was evaluated on KATP channel surface expression and current density. EHD2 positively regulates cardiac sarcolemmal KATP channel surface expression by stabilizing caveolae, and its dominant-negative mutant abolishes the cardioprotective effect of ischemic preconditioning.
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