# Elucidating transsynaptic regulation of metabotropic glutamate receptors

> **NIH NIH F32** · UNIVERSITY OF FLORIDA · 2024 · $73,828

## Abstract

Project Summary / Abstract
 It has recently been discovered that G-protein coupled receptors (GPCR) can be regulated by
extracellular interactions. The mechanisms behind this phenomenon remain poorly understood. One such
interaction is the trans-synaptic connection between presynaptic group III metabotropic glutamate receptors
(mGluR) and postsynaptic cell-adhesion molecules of the extracellular leucine-rich repeat and fibronectin type
III domain-containing (ELFN) family. Group III mGluRs sense glutamate release and inhibit further release in a
negative feedback mechanism. A great body of evidence points to the essential role of synaptic glutamate
homeostasis in a range of cognitive and motor functions with dysregulation leading to movement disorders and
epilepsy. Binding and stabilization of mGluRs by trans-synaptic interactions with ELFN proteins is critical for
regulating glutamate homeostasis. Loss of ELFN proteins in mice tremendously augments glutamate release
and results in seizures and hyperactivity. Understanding how these proteins interact in the synaptic environment
will provide valuable insight into how neurons maintain control over glutamate levels in the synapse and has
implications for physiology and disease. Importantly, both mGluRs and ELFN proteins have been shown to form
homo- and hetero-dimers. This proposal aims to test the hypothesis that apart from positioning and stabilizing
group III mGluRs at the synapses, ELFN proteins act to allosterically modulate mGluR activity in part by
influencing the dimerization dynamics of mGluR subunits. To test this hypothesis, I will build a structural model
of the ELFN-mGluR interaction using crosslinking coupled with mass spectrometry, hydrogen/deuterium
exchange, and cryo-electron microscopy to understand what binding determinants govern the ELFN-mGluR
binding interaction. Additionally, I will investigate the mechanisms of mGluR allosteric modulation by ELFN
proteins using a variety of cell-based signaling assays. Together, these experiments will provide a clear
foundation for understanding how the brain maintains glutamate homeostasis inside the synapse.

## Key facts

- **NIH application ID:** 10695928
- **Project number:** 5F32NS124758-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** William Grant LUDLAM
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 5
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695928

## Citation

> US National Institutes of Health, RePORTER application 10695928, Elucidating transsynaptic regulation of metabotropic glutamate receptors (5F32NS124758-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695928. Licensed CC0.

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