# Mechanisms by which phosphorylation and protein partners regulate Cx45

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $413,290

## Abstract

Connexins are integral membrane proteins that oligomerize to form gap junction channels. Gap
junctions composed of Cx43 mediate electrical coupling and impulse propagation in the normal
working myocardium. In the failing heart, Cx43 remodeling (decreased expression, loss at
intercalated discs, increased presence at lateral membranes) contributes to ventricular arrhythmias.
However, the failing heart also aberrantly upregulates expression of Cx45 in ventricles, where it is
normally at very low levels. This greatly enhances the propensity for arrhythmias, logically due to the
low conductance and high voltage-sensitivity of Cx45 channels relative to Cx43. Crucially, the
deleterious effect of Cx45 at the intercalated discs is likely amplified by the propensity of Cx45 to
form heteromeric channels with Cx43, in which it has a dominant effect on the function of the
resulting channels. Unfortunately, little is known about the mechanisms that drive Cx45 presence at
intercalated discs or about the determinants of the functional properties of Cx45 that make its
presence at ventricular intercalated discs dangerous. Studies proposed in Specific Aims 1 and 2
address novel mechanisms by which phosphorylation of the Cx45 carboxyl terminal (Cx45CT)
domain modulates Cx45 protein partner interactions to increase or decrease gap junction
intercellular communication in vitro and in vivo (and the differences from effects on Cx43). Specific
Aim 3 focuses on determining how a recently discovered high-affinity protein-protein interaction of
the Cx45CT, dimerization, affects the channel functional properties. The significance of this proposal
is that discovery of how phosphorylations and interactions of the CT domain can be modulated
would enable strategies to ameliorate pathological alterations of connexins the failing heart and
elsewhere.

## Key facts

- **NIH application ID:** 10240634
- **Project number:** 5R01GM131092-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Andrew L Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,290
- **Award type:** 5
- **Project period:** 2019-09-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240634

## Citation

> US National Institutes of Health, RePORTER application 10240634, Mechanisms by which phosphorylation and protein partners regulate Cx45 (5R01GM131092-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10240634. Licensed CC0.

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