# Structure and mechanism of extrasynaptic GABAA receptors

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $34,056

## Abstract

Project Summary:
 Type A γ-aminobutyric acid receptors (GABAA) are pentameric ligand-gated ion channels found
abundantly in the central nervous system. The binding of GABA, the major brain inhibitory neurotransmitter, to
GABAA receptors, accounts for ~30% of the fast synaptic signaling in the brain. These receptors are important
for sensory and motor processing, central autonomic control, and cognition. While much of the research in
GABAA receptor structure and function has focused on the subunit assemblies found at synapses, a tremendous
diversity of pharmacologically important GABAA receptor subtypes are found outside of synapses. The goal of
this proposal is to determine and validate high-resolution structures of extrasynaptic GABAA receptors bound to
distinct drug classes of relevance to neurological disorders, anesthesia, addiction and drug abuse. These
receptors are potentiated by mildly intoxicating concentrations of ethanol, have high affinity for neurosteroids
and are targets of anesthetics, analgesics, and anticonvulsant drugs. In two Aims, I propose to optimize
conditions for expression and purification of defined heteromeric GABAA receptor assemblies, refine sample
preparation for cryo-electron microscopy, collect and process single particle cryo-EM datasets, and build and
refine atomic models of receptor-drug complexes. High-resolution structural information for physiologically
important but understudied subunit assemblies, in complex with allosteric and orthosteric-site ligands will broadly
inform on principles of ligand recognition and subunit assembly.
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## Key facts

- **NIH application ID:** 9991645
- **Project number:** 1F31DA051176-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Dagimhiwat Legesse
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,056
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991645

## Citation

> US National Institutes of Health, RePORTER application 9991645, Structure and mechanism of extrasynaptic GABAA receptors (1F31DA051176-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9991645. Licensed CC0.

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