# Structural and Allosteric Mechanisms of mGluR Activation

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $42,486

## Abstract

ABSTRACT
In the nervous system, G protein coupled receptors (GPCRs) serve to detect the precise spatial and temporal
pattern of neurotransmitter release to modulate synaptic transmission. The metabotropic glutamate receptors
(mGluRs) are family C GPCRs that sense the excitatory neurotransmitter glutamate. mGluRs are constitutive
dimers with a large extracellular ligand binding domain which is connected to a seven-helix transmembrane
domain via an intermediate cysteine-rich linker. There are eight mGluR subtypes, which are expressed in
overlapping regions of the brain and play distinct roles at the synapse. Additionally, mGluRs readily form
heterodimers, increasing the molecular diversity and functional complexity of this system. Recent breakthroughs
in cryogenic electron microscopy (cryo-EM) have led to full-length structures of mGluRs, providing an improved
understanding of the overall architecture of this receptor. However, these structures raise further questions
regarding the dynamic rearrangements that occur upon activation. While the extracellular domain is known to
undergo glutamate-induced rearrangements, how these conformational changes are coupled to yield activation
and G protein recruitment at the TMD remains to be defined. Additionally, how this coupling is tuned across
mGluR homo- and heterodimer subtypes to produce the observed differences in activation properties is
unknown. The group II mGluRs are ideal candidates for addressing these questions and are the focus of this
proposal. Group II mGluRs consist of mGluR2 and mGluR3, which have the highest sequence homology of all
mGluRs, yet still show distinct glutamate affinity, kinetics, and basal activity. Furthermore, mGluR2 and mGluR3
readily heterodimerize in the brain. In this proposal, I will use a combination of cryo-EM structural analysis and
functional assays in addition to subtype specific pharmacological compounds. Using these tools, I will probe the
conformational dynamics of group II mGluRs, with a focus on the allosteric mechanisms that couple ligand
binding to transmembrane domain activation. Together, this work will provide a high-resolution picture of
activation for mGluR homo- and heterodimers.

## Key facts

- **NIH application ID:** 10798168
- **Project number:** 5F31NS129320-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alexa Strauss
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,486
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-01-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798168

## Citation

> US National Institutes of Health, RePORTER application 10798168, Structural and Allosteric Mechanisms of mGluR Activation (5F31NS129320-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10798168. Licensed CC0.

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