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Newly Identified NO-Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

Pierre-Antoine Crassous1, Ping Shu1, Can Huang1

  • 1Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School-Rutgers, Newark, NJ.

Journal of the American Heart Association
|December 23, 2017
PubMed

Insights

Guanylyl cyclase (GC1) interacts with connexin 43 (Cx43) to maintain cardiac electrical function. This NO-GC1-Cx43 pathway protects against electrical disturbances during cardiac hypertrophy.

Area of Science:

  • Cardiovascular Biology
  • Cellular Signaling
  • Cardiac Electrophysiology

Background:

  • Guanylyl cyclase (GC1) is a heme-containing enzyme crucial for nitric oxide (NO) signaling, regulating cardiomyocyte contractility and protecting against cardiac hypertrophy.
  • The NO-GC1-cGMP pathway plays a protective role in the heart.
  • GC1's β1 subunit is found at the intercalated disc, interacting with connexin 43 (Cx43), a key component of gap junctions responsible for electrical propagation.

Purpose of the Study:

  • To investigate the functional association between GC1 and Cx43.
  • To determine the role of the GC1-Cx43 interaction in cardiac homeostasis and electrical function.

Main Methods:

  • Immunostaining and co-immunoprecipitation to confirm GC1 and Cx43 association.
  • Dye-spread assays in GCα1 knockout mice to assess gap junction function.
  • Angiotensin II treatment to induce cardiac hypertrophy and evaluate disruption of the GC1-Cx43 complex.
  • Electrocardiography (ECG) to assess ventricular electrical propagation.

Main Results:

  • GC1 and Cx43 were found to be associated at the intercalated disc.
  • GCα1 knockout mice exhibited reduced gap junction function and altered Cx43 membrane localization.
  • Angiotensin II treatment disrupted the GC1-Cx43 association, leading to Cx43 lateralization and decreased Cx43-containing gap junctions.
  • Reduced Cx43 phosphorylation at serine 365 was observed in hypertrophic models.
  • Impaired ventricular electrical propagation was evident in angiotensin II-treated GCα1 knockout mice.

Conclusions:

  • GC1 modulates Cx43 localization and gap junction function, offering partial protection against electrical dysfunction during cardiac hypertrophy.
  • Disruption of the NO-cGMP pathway is linked to cardiac electrical disturbances and abnormal Cx43 phosphorylation.
  • The identified NO/Cx43 signaling pathway represents a potential protective mechanism against stress-induced arrhythmias.
Abstract

Keywords:
Nitric oxidearrhythmiacGMPcardiac functioncardiovascular diseaseconnexin 43guanylyl cyclase

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