# Role of S-nitrosylated Cx43 in normal cardiac contractility

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $252,079

## Abstract

Modulation of cardiac function by sympathetic activity, which occurs during exercise and
emotional excitement, is thought to promote an augmentation of cell-to-cell electrical coupling in
the heart. This is necessary to increase the strength of cardiac muscle contraction. Electrical
coupling in the heart is mediated by specialized structures at the intercalated discs of
cardiomyocytes, referred to as gap junction channels (GJCs). These are intercellular channels
formed by connexin proteins, with connexin 43 (Cx43) being the most abundant in the heart. While
is known that Cx43 GJCs are vital to sustain the propagation of electrical impulses and
coordinated heart contraction, the mechanisms by which cardiac GJC coupling is regulated
remains poorly understood. It has recently been proposed that β-adrenergic stimulation, which is
used to mimic sympathetic activity, induces nitric oxide (NO) production and S-nitrosylation of
cardiac proteins and this may account for one third of the inotropic effects in the heart. In this
context, we found Cx43 at the intercalated disk is heavily S-nitrosylated upon β-adrenergic
stimulation. In addition, we found that NO increases coupling mediated by Cx43 GJCs in a
heterologous expression system. Accordingly, we hypothesize that S-nitrosylated Cx43 GJCs
enhances electrical coupling between cardiomyocytes, which is critical for concerted contractility.
To test our hypothesis, we identified the S-nitrosylated site and created a knockin mouse line
where this site (C271) was replaced by a serine, and which we will use to assess cardiac function
in vivo. In addition, we will perform biophysical studies to unveil the molecular mechanisms by
which NO induce increased GJC coupling in the cardiomyocytes. The proposed research is
innovative, as it is designed to reveal novel biophysical properties of S-nitrosylated Cx43 GJCs
and provide mechanistic understanding on cardiac conduction and contractility.

## Key facts

- **NIH application ID:** 10466683
- **Project number:** 1R21HL163930-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Jorge Enrique Contreras
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $252,079
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466683

## Citation

> US National Institutes of Health, RePORTER application 10466683, Role of S-nitrosylated Cx43 in normal cardiac contractility (1R21HL163930-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466683. Licensed CC0.

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