Abstract

SMO (Smoothened), 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 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 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 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 Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias.

Highlights

  • SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes

  • 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

  • Our results demonstrate that SMO/Gi coupling selectively reduces outward repolarizing Kϩ currents mediated by Kv channels, increases the action potential (AP) duration and induces ventricular arrhythmias

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Summary

Smoothened activity regulates cardiac Kv channels

Because Gi proteins regulate a large number of ionic channels that shape the action potential through inhibition of adenylyl cyclase/PKA by G␣i subunits, our previous findings suggested that noncanonical Hh signaling could have important repercussions in cardiac physiology. We sought to investigate whether SMO/Gi coupling could regulate cardiac electrophysiology. Our results demonstrate that SMO/Gi coupling selectively reduces outward repolarizing Kϩ currents mediated by Kv channels, increases the action potential (AP) duration and induces ventricular arrhythmias

Results
Discussion
Experimental procedures
Isolation of adult mouse cardiomyocytes
Isolation of guinea pig myocytes
Hedgehog pathway agonists and antagonists
Mouse cardiomyocyte electrophysiological recordings
Western blotting
Full Text
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