# Quantitative analysis of metabotropic glutamate receptor activation and modulation

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $68,323

## 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 cholesterol and synthetic modulators of mGluR signaling affect protein
conformation and dynamics to 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:** 11065308
- **Project number:** 3R01GM140272-05S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Reza Vafabakhsh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $68,323
- **Award type:** 3
- **Project period:** 2020-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11065308

## Citation

> US National Institutes of Health, RePORTER application 11065308, Quantitative analysis of metabotropic glutamate receptor activation and modulation (3R01GM140272-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11065308. Licensed CC0.

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