Cheng, L, Al-Owais, MM, Covarrubias, M et al. (4 more authors) (2018) Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs the cardiac action potential duration. Journal of Biological Chemistry, 293 (28). pp. 11022-11032. ISSN 0021-9258
Abstract
Smoothened (SMO), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with Sonic Hedgehog (SHH) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K⁺ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a downregulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from wild type but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, non-canonical Hh signaling mediated by Gi proteins regulates K⁺ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This research was originally published in the Journal of Biological Chemistry. Lan Cheng, Moza M. Al-Owais, Manuel Covarrubias, Walter J. Koch, David R. Manning, Chris Peers, and Natalia Riobo-Del Galdo. Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs the cardiac action potential duration. J. Biol. Chem. 2018, Vol 293 (28), pp 11022-11032. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Smoothened; Hedgehog; G proteins; Kv channels; arrhythmias; action potential |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number National Institute of Health - NIH (PHS) 562836/10041422/17219 |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Jun 2018 11:27 |
Last Modified: | 01 Jul 2019 11:24 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.RA118.001989 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131609 |