# Molecular mechanism of dimeric G protein-coupled receptor signaling

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $171,476

## 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
(CaS) receptor. 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. CaS receptor
maintains a stable Ca2+ level in the blood. Abnormal activities of the CaS receptor 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 CaS receptors.

## Key facts

- **NIH application ID:** 10207012
- **Project number:** 1R35GM141871-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** QING R FAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $171,476
- **Award type:** 1
- **Project period:** 2021-04-02 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207012

## Citation

> US National Institutes of Health, RePORTER application 10207012, Molecular mechanism of dimeric G protein-coupled receptor signaling (1R35GM141871-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10207012. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*