Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

Authors

Lan Cheng, Thomas Jefferson UniversityFollow
Moza Al-Owais, University of Leeds
Manuel Covarrubias, Thomas Jefferson UniversityFollow
Walter J. Koch, Temple University
David R. Manning, University of Pennsylvania
Chris Peers, University of Leeds
Natalia A Riobo-Del Galdo, Thomas Jefferson University; Temple UniversityFollow

Document Type

Article

Publication Date

7-13-2018

Comments

This research was originally published in Journal of Biological Chemistry. Cheng, L., Al-Owais, M., Covarrubias, M. L., Koch, W. J., Manning, D. R., Peers, C., & Riobo-Del Galdo, N. A.. Coupling of smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration. Journal of Biological Chemistry. 2018; 293:11022-11032. © the American Society for Biochemistry and Molecular Biology.

The published version is available at https://doi.org/10.1074/jbc.RA118.001989. Copyright © Cheng et al.

Abstract

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric G_i proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) 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 G_iCT/TTA mice, in which G_i signaling is impaired, suggesting that the effect of SMO is mediated by G_i 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 down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT 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, noncanonical Hh signaling mediated by G_i proteins regulates K⁺ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al.

Recommended Citation

Cheng, Lan; Al-Owais, Moza; Covarrubias, Manuel; Koch, Walter J.; Manning, David R.; Peers, Chris; and Riobo-Del Galdo, Natalia A, "Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K" (2018). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 138.
https://jdc.jefferson.edu/bmpfp/138

PubMed ID

29802197

Language

English