# Structure and Function of GABA-A Receptors

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $497,832

## Abstract

The GABA-A receptor is the most abundant inhibitory neurotransmitter receptor in the central nervous
system and is the target of myriad therapeutic compounds and drugs of abuse. Function of the nervous system
is governed by a balance of excitatory and inhibitory signaling; GABA-A receptor dysfunction results in
disorders of anxiety and excitotoxicity including epilepsy. The principal isoform of this pentameric ligand-gated
chloride channel is found on post-synaptic membranes in the brain. GABA (γ-aminobutyric acid) is the
endogenous neurotransmitter and agonist of this receptor. Benzodiazepines, like diazepam (Valium) and
midazolam (Versed), are positive allosteric modulators taken by 5% of the US for anxiety and insomnia.
Barbiturates like pentobarbital, anesthetics like isoflurane and propofol, neurosteroids, and ethanol are all
positive modulators acting through non-overlapping sites. This rich pharmacology derives from the complex
subunit assembly of the synaptic GABA-A receptor. The predominant synaptic isoform consists of two α1
subunits, two β2 subunits and one γ2 subunit. Here we propose to address a lack of structural information on
physiological GABA-A receptors using a direct approach. In three Specific Aims, we propose to elucidate the
structural mechanism of benzodiazepine potentiation of these receptors, perform complementary
electrophysiological experiments on the recombinant receptor, and in parallel characterize the structural
principles underlying modulation by barbiturates, anesthetics and neurosteroids. The two structural Aims are
independent and will yield fundamentally new and distinct structural information for the principal GABA-A
receptor type in the central nervous system in complex with extracellular and transmembrane-site ligands. The
functional Aim complements the structural work to define determinants for benzodiazepine binding, efficacy
and allosteric signaling. The sum of structures and function will illuminate principles defining heteromer
assembly and ligand recognition and will elucidate how drug binding changes molecular behavior, with broad
relevance across the Cys-loop receptor superfamily.

## Key facts

- **NIH application ID:** 10066338
- **Project number:** 5R01DA047325-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ryan E Hibbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $497,832
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066338

## Citation

> US National Institutes of Health, RePORTER application 10066338, Structure and Function of GABA-A Receptors (5R01DA047325-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066338. Licensed CC0.

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