# MicroRNA permeability of connexin mutants related to genetic disease

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $340,931

## Abstract

Project Summary/Abstract
 Gap junctions are essential to normal tissue physiology, providing a direct intercellular pathway for cell to
cell signaling and impulse conduction. Mutations in the genes of their subunit protein (connexins) have been
linked to a number of human diseases. For instance, mutations in connexin40 (Cx40) have been associated
with atrial fibrillation and other arrhythmias. Three Cx40 mutations (A96S, M163V and G38D) that correlate
with atrial fibrillation have been previously shown to retain the ability to form conductive gap junction channels
in vitro. Our recent publication demonstrates that two of the three have the same unitary conductance and
voltage dependent behaviors as wild-type Cx40, while the third one has a significantly higher unitary
conductance. All three mutants have altered permeability characteristics relative to wild-type channels. An
increasing amount of evidence today indicates the important role of microRNAs in the pathogenesis and
development of heart diseases. The data suggest another and as of yet untested possibility; these connexin
mutants might affect cardiac conduction and pacing via altered permeability to microRNAs within the
myocardium, which themselves target specific membrane K+ channels, IK1 (KCNJ2/Kir2.1) and IKr (HERG), that
participate in conduction and pacemaking activities. It was recently reported that the microRNA miR-26
regulates IK1 expression and is down regulated in atrial fibrillation. miR-212 has also been shown to affect IK1
expression, whereas IKr expression is affected by miR-133.
 In this proposed study we will test if pacemaker activity can be modulated by connexin permeability to
microRNAs/siRNAs that in turn regulate gene expression of specific membrane channels associated with
pacemaker-like activity. In Aim 1 we will determine the permeability of gap junction channels formed by
disease-linked mutations in Cx40 to miR-26, miR-212, miR-133, and siRNAs specific to IK1 and IKr,
respectively, while simultaneously monitoring junctional conductance and cell to cell flux of
microRNAs/siRNAs. In Aim 2 we will use a two-cell pacemaker model (a heterologous pair comprised of a
source cell and a cardiac myocyte) to explore effects on pacemaker activity, by cellularly delivering microRNAs
and siRNAs that target IK1 and IKr. Thereafter, in Aim3, we will analyze these results using our dynamic clamp
model in order to add and subtract relevant currents associated with pacemaker activity to/from a single cell, a
coupled pair, or two uncoupled cells paired electronically.
 In this proposed study, using a cellular biophysical approach, we seek to define if the permeability of gap
junction channels might be an essential component in a process of dynamic gene expression that ultimately
affects cellular and tissue functions in normal physiology and disease states.

## Key facts

- **NIH application ID:** 9921428
- **Project number:** 5R01GM088181-09
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Virginijus Valiunas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,931
- **Award type:** 5
- **Project period:** 2011-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921428

## Citation

> US National Institutes of Health, RePORTER application 9921428, MicroRNA permeability of connexin mutants related to genetic disease (5R01GM088181-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9921428. Licensed CC0.

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