# A novel system for controlling dimeric receptor composition to discover unique heterodimer pharmacology

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $415,475

## Abstract

Metabotropic glutamate receptors (mGluRs) are class C G protein coupled receptors that function as dimers.
While mGluRs are known to form homodimers, more recent work has shown that they can also heterodimerize,
but not promiscuously. Because mGluRs exhibit widespread expression in the brain and regulate excitability
and plasticity, they have become candidates as druggable targets for a variety of pathologies. To date
however, excitement generated by preclinical data has not resulted in mGluR-targeting therapies in the clinic,
despite a wealth of available ligands with good selectivity targeting these receptors. Our recent work examining
mGluR2/4 heterodimers provides a possible explanation: ligands that are highly efficacious when targeting
homodimeric receptors are often without effect when the same receptor is expressed as a heterodimer with
another mGluR. Further complicating matters, these changes in pharmacological responses observed in
mGluR2/4 heterodimers are not generalizable to all mGluR heterodimers, or even all mGluR2 containing
heterodimers. Thus, to understand how any mGluR ligand will function in the brain, we must examine the
pharmacological responses of each possible heterodimer pair in isolation. But this is complicated because
every mGluR can also form homodimers, so any pair of expressed mGluR will have an unknown propensity to
homo- and heterodimerize. To solve this problem, we have designed a novel dimer composition control system
using a combination of ER retention sequences paired with orthogonal, split inteins, self-excising protein
sequences, that will allow expression of pure populations of nearly wild type mGluR dimers of known
composition. We plan to generate a comprehensive ligand vs. mGluR dimer atlas to be used to not only aid in
interpretation of experimental data but also to improve therapeutic strategies targeting mGluRs for a range of
pathologies. To accomplish these goals, we will pursue the following Specific Aims: 1, T To build and
characterize the full complement of tagged mGluRs using the split intein-ER retention strategy, 2, To
employ an adapted CODA-RET approach to obtain parallel heterodimer specific G protein recruitment data,
and 3, To systematically assess the pharmacological responses of each probable mGluR dimer pair to
selective agonists, competitive antagonists, PAMs and NAMs.

## Key facts

- **NIH application ID:** 10873281
- **Project number:** 5R01MH125849-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Paul J. Kammermeier
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $415,475
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873281

## Citation

> US National Institutes of Health, RePORTER application 10873281, A novel system for controlling dimeric receptor composition to discover unique heterodimer pharmacology (5R01MH125849-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873281. Licensed CC0.

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