# MiR-9 regulation of beta-catenin mediated alcohol tolerance and EtOH consumption

> **NIH NIH R01** · UNIVERSITY OF PUERTO RICO MED SCIENCES · 2024 · $337,500

## Abstract

PROJECT SUMMARY
miRNA regulation of Wnt/beta-catenin triggers BK channel alcohol tolerance and
facilitated consumption
Research has identified the large conductance voltage- and calcium-activated channel (BK) as
a key regulator of neuronal excitability genetically associated to behavioral alcohol tolerance in
invertebrates. Similarly in mammals, decreasing BK channel alcohol sensitivity by knocking out
its ß4 subunit leads to increased alcohol voluntary consumption in mice. Sensitivity to ethanol at
the molecular level is characterized by acute potentiation of channel activity. However, different
isoforms of the BK channel show variations in alcohol sensitivity and are differentially distributed
on the plasma membrane surface in response to prolonged exposure, also known as persistent
alcohol tolerance (PMT). miRNA targeting of alcohol-sensitive isoforms coupled with active
internalization of BK channels in response to ethanol are believed to be key in establishing
homeostatic adaptations that produce persistent changes within the striatum. These
mechanisms may operate independently, with the same end point of increasing the
representation of alcohol insensitive BK channels or interact to orchestrate and optimize these
persistent adaptive changes at the translational and trafficking level of regulation.
Results from our current project have identified the Wnt/β-catenin signaling pathway as a key
regulator of BK channel surface redistribution in response to 6hr ethanol exposure. We have
characterized this as a form of long-term neuronal plasticity, which requires protein synthesis
resulting in increased ß-catenin expression and persistence, past 24hr withdrawal. Activation of
ß-catenin signaling has been linked to miR-9 upregulation in human cancer cells, as well as,
miRNA expression in depression-resilient mice. Notably, miR-9 upregulated expression in the
striatum is a key event in PMT mediating acute EtOH desensitization of BK channels. Thus, the
overarching hypothesis of this proposal is that a single “binge-like” 6hr exposure persistently
alters BK channel surface distribution within the NAc via miRNA regulated Wnt/β-catenin
signaling, impacting subsequent alcohol consumption. We will use electrophysiology, molecular
biology, behavioral assays and imaging techniques to determine the role of Wnt/ß-catenin
signaling in both BK trafficking and miRNA regulation within the striatum with the goal of
identifying novel therapeutic targets involved in preventing the transition from initial to
compulsive drinking behavior.

## Key facts

- **NIH application ID:** 10923826
- **Project number:** 5R01AA027808-05
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MED SCIENCES
- **Principal Investigator:** CRISTINA M. VELAZQUEZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $337,500
- **Award type:** 5
- **Project period:** 2020-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923826

## Citation

> US National Institutes of Health, RePORTER application 10923826, MiR-9 regulation of beta-catenin mediated alcohol tolerance and EtOH consumption (5R01AA027808-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10923826. Licensed CC0.

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