# Gating and Regulation of Connexin Hemichannels

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $118,233

## Abstract

Connexin 43 (Cx43) in the heart is normally expressed at the intercalated disk where it commonly forms
junctional channels (gap junctions). Many cardiac diseases produce increased or aberrant expression of Cx43,
which results in lateralization of the protein in cardiomyocytes. Our group and others have provided evidence
that lateralized Cx43 forms unpaired hyperactive hemichannels (non-junctional channels) at the plasma
membrane. Excessive opening of these Cx43 hemichannels is associated with cell death during acute
ischemia and cardiac muscular dystrophy. Cell death is thought to result from the loss of electrochemical
gradients and small cytoplasmic metabolites through the large and modest selective aqueous pore of connexin
hemichannels. We and others have indirect evidence indicating that nitric oxide (NO) opens Cx43
hemichannels, promoting cellular dysfunction in the heart and brain. In addition, we have evidence that under
conditions that cause lateralization in cardiomyocytes, Cx43 is S-nitrosated. The molecular mechanisms that
cause Cx43 hemichannel opening by NO have not been elucidated, despite the importance this may have in
cardiac and other pathologies. We propose that a major contributor to the aberrant opening of undocked
hemichannels is Cx43 S-nitrosation. In this proposal, we will take advantage of our expertise in connexin
hemichannel biophysics to identify the mechanisms by which NO gates Cx43 hemichannels. Specific Aim 1 will
determine whether NO directly opens Cx43 hemichannels via S-nitrosation and identify residues involved.
Specific Aim 2 will identify the precise cytoplasmic domain interactions that mediate the effects of NO on Cx43
gating. Specific Aim 3 will determine whether S-nitrosated Cx43 hemichannels promote cell and tissue
damage. We plan to accomplish these specific aims using an integrative multidisciplinary approach that
combines electrophysiology, mutagenesis, fluorescence and NMR spectroscopy, mass spectrometry, and a
cardiac disease model. We expect that our work will contribute to the rational development of new
pharmacological strategies to target the specific connexin domains involved in aberrant hemichannel gating.
This will allow us to achieve specific therapeutic outcomes, for example, to decrease opening of hyperactive
hemichannels during myocardial infarction preventing arrhythmias and tissue damage.

## Key facts

- **NIH application ID:** 9948682
- **Project number:** 5R01GM099490-09
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Jorge Enrique Contreras
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $118,233
- **Award type:** 5
- **Project period:** 2011-07-01 → 2021-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948682

## Citation

> US National Institutes of Health, RePORTER application 9948682, Gating and Regulation of Connexin Hemichannels (5R01GM099490-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948682. Licensed CC0.

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