The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K ATP channel surface expression: role in cardioprotection

The FASEB JournalVolume 32, Issue 3 p. 1613-1625 ResearchFree to Read The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection Hua Qian Yang, Hua Qian Yang Department of Pediatrics, New York University School of Medicine, New York, New York, USASearch for more papers by this authorKundan Jana, Kundan Jana Department of Pediatrics, New York University School of Medicine, New York, New York, USASearch for more papers by this authorMichael J. Rindler, Michael J. Rindler Department of Cell Biology, New York University School of Medicine, New York, New York, USASearch for more papers by this authorWilliam A. Coetzee, Corresponding Author William A. Coetzee william.coetzee@med.nyu.edu Department of Pediatrics, New York University School of Medicine, New York, New York, USA Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York, USA Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USACorrespondence: NYU School of Medicine, 450 E 29th St., ACLS 824, New York, NY 10016, USA. E-mail: william.coetzee@med.nyu.eduSearch for more papers by this author Hua Qian Yang, Hua Qian Yang Department of Pediatrics, New York University School of Medicine, New York, New York, USASearch for more papers by this authorKundan Jana, Kundan Jana Department of Pediatrics, New York University School of Medicine, New York, New York, USASearch for more papers by this authorMichael J. Rindler, Michael J. Rindler Department of Cell Biology, New York University School of Medicine, New York, New York, USASearch for more papers by this authorWilliam A. Coetzee, Corresponding Author William A. Coetzee william.coetzee@med.nyu.edu Department of Pediatrics, New York University School of Medicine, New York, New York, USA Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York, USA Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USACorrespondence: NYU School of Medicine, 450 E 29th St., ACLS 824, New York, NY 10016, USA. E-mail: william.coetzee@med.nyu.eduSearch for more papers by this author First published: 03 January 2018 https://doi.org/10.1096/fj.201700027RCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract ATP-sensitive K+ (KATP) 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 KATP 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 KATP channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate KATP 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 KATP channel trafficking to increase surface KATP 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 KATP channel surface expression. EHD2 did not directly affect KATP 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 KATP channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated KATP 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 KATP channel trafficking defects.—Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection. FASEB J. 32,1613-1625 (2018). www.fasebj.org Citing Literature Supporting Information Filename Description fsb2fj201700027r-sup-0001.docxapplication/docx, 1.6 MB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume32, Issue3March 2018Pages 1613-1625 RelatedInformation