# Ethanol actions on slo channels from arteries vs. brain.

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $507,693

## Abstract

Alcohol-induced blackouts (AIB), a form of amnesia linked to dysfunction of the hippocampal CA1 region, often
occur upon moderate-heavy, acute ethanol consumption disregarding age, drinking history, biological sex,
gender or education. Despite their high prevalence and detrimental impact on individuals, families and society,
biomedical research has largely failed to identify the molecular targets underlying AIB and, more important, to
develop pharmacotherapeutic approaches to counteract them. We will cover these gaps in knowledge by
departing from all previous work, which focused on AIB-induced disruption of mechanisms operating at the
hippocampal neurons themselves, to advance a vascular theory of AIB that is centered on the β1 subunit of ion
channels of BK type that is highly expressed in cerebrovascular smooth muscle. Thus, we will test this
overarching hypothesis: at concentrations reached in the brain during AIB, specific amino acids (e.g., S160) in
BK β1 mediate alcohol-induced BK channel inhibition and, eventually, cerebral artery constriction thus leading
to AIB, all these actions being counteracted by selective, novel β1 transmembrane region 2 (TM2)-targeting
agents that activate BK channels. We will address three conceptually related, yet independently testable
specific aims (SA): SA1 (molecular-cellular resolution) will identify the central role of β1 S160 in mediating
ethanol inhibition of BK channels and its reversion by novel β1 TM2-targeting agents whether drug actions are
studied using recombinant BK proteins expressed in heterologous, isolated membranes or in the native cell.
SA2 (tissue-organ resolution) will identify the role of β1 TM2 specific amino acids in ethanol actions of middle
cerebral artery constriction, both in vitro and in vivo, and the reversion of ethanol actions by the β1 TM2-
targeting agents. SA3 (organismal resolution) will address the impact of β1 TM2 specific amino acids in a
mouse model of AIB and demonstrate AIB reversion by β1 TM2-targeting agents. Testing of the three SAs will
be accomplished by combining computational modeling, nano differential scanning fluorimetry (nanoDSF),
point mutagenesis, robotic/manual patch-clamp, electroporation of vascular myocytes and middle cerebral
artery with recombinant DNAs, engineered mice (“knockouts” and “knockins”), middle cerebral artery in vitro
and in vivo (cranial window) diameter determinations, selective pharmacology, and simultaneous evaluation of
CA1 vessels, blood flow and neuron activity in freely behaving mice subject to AIB, all supported by our papers
or preliminary data.

## Key facts

- **NIH application ID:** 10517177
- **Project number:** 2R01AA011560-22
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Alex Dopico
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $507,693
- **Award type:** 2
- **Project period:** 1999-01-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517177

## Citation

> US National Institutes of Health, RePORTER application 10517177, Ethanol actions on slo channels from arteries vs. brain. (2R01AA011560-22). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10517177. Licensed CC0.

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