# Molecular Mechanisms of Synaptic G Protein-Coupled Receptors

> **NIH NIH R35** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $419,066

## Abstract

Project Summary
 In many biological systems G protein-coupled receptors (GPCRs) provide a crucial molecular link between the dynamics
of the extracellular environment and the associated intracellular signaling response. In the nervous system, GPCRs serve as
detectors of precise patterns of neurotransmitter release and are able to, in turn, modulate neuronal excitability and synaptic
transmission. Of particular importance are the class C metabotropic glutamate (mGluR) and GABA receptors (GABABR), which
respond to the major excitatory and inhibitory neurotransmitters, respectively, and serve as drug targets for neurological and
psychiatric disorders. Unfortunately, our understanding of their underlying molecular mechanisms of signaling remain limited
due to a lack of methods for the direct measurement and manipulation of their activity with high specificity and spatial and
temporal precision. Furthermore, the biophysical activation mechanism of class C GPCRs is particularly challenging to decipher
because unlike class A GPCRs, such as rhodopsin or ß-adrenergic receptors, they contain large, extracellular ligand binding
domains (LBDs) that multimerize and couple, via a poorly understood mechanism, to a transmembrane domain (TMD).
 Our recent work has established new optical methods for directly measuring mGluR assembly and conformational
dynamics at the single molecule level and has also produced an optogenetic method to manipulate receptors with subtype
selectivity and high spatiotemporal precision using photoswitchable tethered ligands. These breakthroughs have advanced our
understanding of how mGluRs dimerize and the initial molecular motions that lead to cooperative receptor activation, but many
fundamental questions remain. In research area 1 we will dissect the activation mechanism of mGluRs and GABABRs in
a quantitative, interdisciplinary way using optical approaches, including single molecule Forster resonance energy
transfer (FRET) to measure conformational dynamics, in conjunction with functional reporters and detailed structural
analysis. The long-term goal is to understand, biophysically, how allosteric inter-domain and inter-subunit coupling interactions
permit orthosteric and allosteric ligand binding to produce G protein activation. This work will give major insight into the
fundamental activation processes of a large class of membrane receptors and should provide a deeper understanding of their
molecular pharmacology. In research area 2 we will improve and harness the power of optical sensors of activation and
optogenetic control of receptors to probe the kinetics of different mGluR subtypes at the level of activation, signaling,
and desensitization and to dissect their spatiotemporal signaling profiles at hippocampal synapses. In the long term
we plan to use this information to probe the mechanism of induction of long-term depression by pre-synaptic, post-synaptic,
and glial mGluR populations. This work will provide a dynamic pictur...

## Key facts

- **NIH application ID:** 10166865
- **Project number:** 5R35GM124731-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Joshua Levitz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,066
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166865

## Citation

> US National Institutes of Health, RePORTER application 10166865, Molecular Mechanisms of Synaptic G Protein-Coupled Receptors (5R35GM124731-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10166865. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*