# Direct assessment of GPCR-transducer coupling and G protein subtype bias

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $338,800

## 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. It is now recognized that individual GPCRs produce
complex signaling responses by interacting with several different transducer subtypes, i.e. that signaling is
“pluridimensional”. The broad selectivity of a given GPCR for different transducer proteins defines it's ability to
influence cellular behavior, therefore it is important to know which tranducers can be activated by each
receptor. This information can be surprisingly difficult to obtain, in large part because transducer coupling is
most often inferred indirectly using assays that monitor events that are well downstream from receptors, such
as accumulation of second messengers. It is also understood that certain activating ligands (agonists) can
specifically promote GPCR coupling to some transducers at the expense of others, a phenomenon most often
referred to as “biased agonism”. Biased agonists are especially promising candidates for drug development,
and have rapidly advanced into the clinical setting, because they are able to produce therapeutic responses
without also producing adverse effects. Almost all biased agonists discovered to date select between G
proteins and arrestins as classes, and there are very few ligands that are thought to select between different G
protein subtypes. Again, a critical roadblock to discovery and development of G protein subtype-selective
drugs is the reliance on downstream signaling assays, which lack the necessary sensitivity to detect subtle
ligand bias and are susceptible to signal crosstalk. We will address these problems using a combination of
advanced optical tools that allow direct assessment of receptor-transducer coupling. Specifically, we will use
improved cellular and cell-free assays based on engineered mini G (mG) proteins to: 1) comprehensively
profile GPCR transducer coupling for >200 non-sensory GPCRs, and 2) characterize and discover new G
protein subtype-selective ligands. These studies will generate and test hypotheses that are central to
pluridimensional signaling, will make a powerful new set of sensitive transducer assays available to the
scientific community, and will advance understanding of G protein subtype-biased ligands as potential
therapeutic agents.

## Key facts

- **NIH application ID:** 10239055
- **Project number:** 5R01GM130142-04
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Nevin Alan Lambert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,800
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239055

## Citation

> US National Institutes of Health, RePORTER application 10239055, Direct assessment of GPCR-transducer coupling and G protein subtype bias (5R01GM130142-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10239055. Licensed CC0.

---

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