# Conventional and unconventional GPCR-G protein coupling

> **NIH NIH R35** · AUGUSTA UNIVERSITY · 2024 · $385,000

## Abstract

PROJECT SUMMARY/ABSTRACT
G protein-coupled receptors (GPCRs) are important targets of hormones, neurotransmitters and approximately
one-third of FDA-approved drugs. These receptors signal by coupling to transducer proteins from four families
of heterotrimeric G proteins and a family of four arrestins. Recent structural and functional studies have defined
a conventional allosteric mechanism whereby ligand binding to receptors promotes activation of G proteins and
arrestins. However, there is extensive functional diversity across hundreds of GPCRs and sixteen G proteins,
and many examples of physiology and pharmacology do not conform to the conventional model. For example,
we have found significant variability in the mechanism whereby GPCRs select appropriate G proteins, and
some receptors that recognize unconventional G protein determinants for selectivity. We have also found some
receptors that paradoxically inhibit G protein signaling instead of the usual activation, a type of GPCR-G
protein coupling that is unproductive. Finally, we have found receptors that associate with G proteins prior to
ligand binding and on average release G proteins after activation, a type of inverse coupling that can explain
the unusal pharmacology of such receptors. A complete understanding of GPCR-mediated signaling will
require a better understanding of these unconventional GPCR-G protein coupling mechanisms. In addition, it
will be necessary to translate molecular studies carried out with overexpressed molecules in model cells to
endogenously-expressed GPCRs and G proteins in their native context, where expression levels, stoichiometry
and subcellular compartmentalization more closely match the in vivo situation. Accordingly, we will carry out
studies to map unconventional selectivity determinants, determine the prevalence and physiological
significance of unproductive and inverse GPCR-G protein coupling, and to better understand the
conformational dynamics of GPCRs in cell membranes, and how this conformational landscape changes as
receptors bind ligands and interact with transducer molecules.

## Key facts

- **NIH application ID:** 10820489
- **Project number:** 5R35GM145284-03
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Nevin Alan Lambert
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820489

## Citation

> US National Institutes of Health, RePORTER application 10820489, Conventional and unconventional GPCR-G protein coupling (5R35GM145284-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10820489. Licensed CC0.

---

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