# Quantitative analysis of metabotropic glutamate receptor activation and modulation

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $320,796

## Abstract

Project Summary
G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in human and have
emerged as the largest family of drug targets with more than 35% of all drugs on the market functioning
through GPCRs. Despite their desirability, to date, many GPCR families remain undrugged, partly due to lack
of mechanistic knowledge about their activation and modulation. Metabotropic glutamate receptors (mGluRs)
are members of class C GPCRs and are critical modulators of glutamate signaling. Due to their widespread
expression in tissue and their central role they are among the most promising drug targets for the neurological
disorders such as fragile X syndrome, epilepsy, anxiety, schizophrenia as well as some cancers. Advances in
protein engineering and functional, structural and computational methods in the past twenty years have
provided insights into the architecture, signaling and expression patterns of mGluRs. However, a general
model of how ligands change the shape of mGluRs and how this conformational change is relayed across the
membrane and over 12 nm to activate specific signaling pathways is poorly understood. In this research we will
develop a novel technology that will allow us to watch a single mGluR protein while functioning in
physiological conditions, in real time. This will allow us to quantify the motions of different domains of the
receptor that are involved in signaling. Next, we will employ this approach to study how
synthetic
modulators
of
mGluR
signaling
affect
protein
conformation
and
dynamics
to
cholesterol and
affect receptor
signaling. This is a multi-disciplinary proposal where state-of-the-art in vitro single-molecule FRET (smFRET)
spectroscopy is complemented by live-cell imaging, protein engineering and biophysical and biochemical
methods. Once accomplished, the proposed research could provide a critical step towards rational design of
efficient drugs with fewer undesirable side effects. Furthermore, these studies will provide a general roadmap
for quantitative high-resolution structure-function studies of mammalian membrane proteins.

## Key facts

- **NIH application ID:** 10100895
- **Project number:** 1R01GM140272-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Reza Vafabakhsh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $320,796
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10100895

## Citation

> US National Institutes of Health, RePORTER application 10100895, Quantitative analysis of metabotropic glutamate receptor activation and modulation (1R01GM140272-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10100895. Licensed CC0.

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