# Mechanism of activation and modulation in human GABA(B) receptor

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $421,812

## Abstract

PROJECT SUMMARY
The inhibitory neurotransmitter GABA produces slow and prolonged inhibition in the brain through
activation of metabotropic GABAB receptors (GABABR). Defects in GABABR signaling have been
implicated in various neurological and mood disorders including spasticity, epilepsy, addiction and
anxiety. GABABR is a member of the class C G protein-coupled receptor (GPCR) family, which typically
functions as a dimer and possesses large extracellular domains. Fundamental questions remain
concerning the molecular mechanisms underlying activation and modulation of these class C receptors.
The GABABR is a heterodimer of GABAB1 and GABAB2 subunits and is modulated by the potassium
channel tetramerization domain-containing (KCTD) protein auxiliary subunits. In this proposal, we will
develop structural models for full-length GABABR, its auxiliary subunits and their complexes with G-
protein. Building on our structural models for both the extracellular and intracellular components of
human GABABR, we propose to determine the structural diversity of GABABR auxiliary subunits
KCTDs, and elucidate the interactions between KCTDs and G proteins (Aim 1), describe the molecular
association between GABABR and KCTD, and determine its impact on GABABR signaling (Aim 2), and
solve the structures of full-length GABABR in multiple functional states, characterizing the allosteric
interaction between the GABABR and G proteins (Aim 3). We will use an innovative strategy of
combining structural and functional analyses, including cryo-electron microscopy (EM) and nanodiscs.
Together, these studies will advance our understanding of the molecular basis of GABA action in the
brain, leading to the development of novel therapeutics for treating neurological diseases.

## Key facts

- **NIH application ID:** 9982345
- **Project number:** 5R01GM125801-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** QING R FAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,812
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982345

## Citation

> US National Institutes of Health, RePORTER application 9982345, Mechanism of activation and modulation in human GABA(B) receptor (5R01GM125801-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982345. Licensed CC0.

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