# Molecular mechanism of dimeric G protein-coupled receptor signaling

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $8,732

## Abstract

Summary
 Our research seeks to uncover the molecular mechanisms of activation and modulation of two dimeric
G protein-coupled receptors (GPCRs), human GABAB receptor and human calcium-sensing receptor (CaSR).
The GABAB receptor is ubiquitous in the central nervous system, responsible for mediating slow and prolonged
synaptic inhibition. Defects in GABAB receptor have been implicated in brain and behavioral disorders,
including spasticity, epilepsy, addiction, and anxiety. CaSR maintains a stable Ca2+ level in the blood.
Abnormal activities of the CaSR are associated with a vareity of Ca2+ homeostatic disorders including
potentially life threatening hypercalcemic conditions. Both receptors function as obligatory dimers and contain
large extracellular domains that are responsible for orthosteric ligand binding. Fundamental questions remain
regarding how an extracellular stimulus propagates a signal across the membrane through such a dimeric
GPCR system. Building on our structural models for the extracellular domains of each receptor, we plan to
determine full-length structures of these GPCRs, including their transmembrane domains, in multiple functional
states. For each receptor, we aim to address three main questions: (1) how the dimeric interactions control
receptor activation, (2) what the mode of coupling between each receptor and its cognitive G protein is, and (3)
how allosteric modulators and auxiliary proteins regulate receptor function. We will combine structural and
functional approaches to understand the molecular basis of ligand-induced activation in each receptor system.
Our findings will ultimately lead to the development of novel therapeutics for treating diseases associated with
the GABAB and CaSR.

## Key facts

- **NIH application ID:** 11099282
- **Project number:** 3R35GM141871-04S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** QING R FAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $8,732
- **Award type:** 3
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099282

## Citation

> US National Institutes of Health, RePORTER application 11099282, Molecular mechanism of dimeric G protein-coupled receptor signaling (3R35GM141871-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11099282. Licensed CC0.

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