# Structure and Function of GABA-A receptors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $723,802

## Abstract

Abstract
 GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and targets of
important therapeutics and drugs of abuse. Given their susceptibility to diverse therapeutic and abused
compounds and their involvement in anxiety disorders, excitotoxicity, and epilepsy, a comprehensive
understanding of this receptor is imperative. In this competing renewal application, we build upon our initial
elucidation of structures of the α1β2γ2 GABAA receptor subtype. Specific projects span structural
pharmacology, the mechanisms underlying ion channel gating, and studies of receptors in healthy and
diseased brain tissue. Our proposed efforts in structural pharmacology focus on unexplored drug classes
including allosteric modulators used in the clinic and prominently abused drugs. We propose to first identify
binding sites, then interrogate mechanisms of potentiation through a combination of functional assays and
computational approaches. Concurrently, we propose to address a significant gap in our understanding of
GABAA receptor signaling, the structure-based mechanism for channel gating. Employing time-resolved cryo-
EM techniques coupled with molecular dynamics, our aim is to capture the activated state, mapping transitions
among resting, activated, and desensitized states. To better understand the assemblies of GABAA receptors
found in their native environments, we propose to develop approaches for mapping subunit arrangements in
receptors in brain tissue. We propose to examine distinct brain regions to provide insights relevant to targeted
therapeutic interventions. This comprehensive, multidisciplinary approach integrates structural biology,
electrophysiology, and computational analyses, yielding an expanded understanding of GABAA receptors
relevant to basic signaling mechanisms, drug abuse, and drug development.

## Key facts

- **NIH application ID:** 10997244
- **Project number:** 2R01DA047325-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ryan E Hibbs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $723,802
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997244

## Citation

> US National Institutes of Health, RePORTER application 10997244, Structure and Function of GABA-A receptors (2R01DA047325-07). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10997244. Licensed CC0.

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