# Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling

> **NIH NIH SC2** · CALIFORNIA STATE UNIVERSITY NORTHRIDGE · 2020 · $145,000

## Abstract

Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled
 Receptor Signaling
Abstract
G protein-coupled receptors (GPCRs) are integral membrane proteins that directly couple with
their signaling partners like G proteins, GPCR kinases (GRKs), and arrestins, in response to
extracellular signals and can trigger multiple intracellular signaling cascades that control a range
of vital biological processes. Cells have evolved GPCR-mediated signaling mechanisms, where
ligands and receptors play unique functional roles. Each receptor has evolved to activate mainly
one subfamily of G proteins, which triggers a specific set of signaling cascades. A ligand is more
powerful as it can activate multiple receptor subtypes, which in turn activate multiple set of
signaling cascades that causes far reaching cellular effects than a receptor alone. The common
feature of ligand and receptor function is the ligand-induced innate G protein specificity of the
receptors. This proposal is aimed at probing the G protein specificity of receptor subtypes
activated by the same ligand (using muscarinic acetylcholine receptors and dopamine receptors
as examples), by the development of computational biophysical methods that will explore
thermodynamic and kinetic factors behind the observed G protein selectivities. The methods will
provide a structural basis for G protein specificity in dopamine D1 and D2 receptors, which will be
used to design receptor mutants with G protein specificity different from that of the wild-type
receptors. The methods will be validated by cell based biochemical assays using these mutant
receptors and in part by reproducing previously observed switches in G protein selectivity of
muscarinic receptor mutants. This mechanistic understanding will have broader implications for
many GPCR subfamilies and will lay the foundation for drugs targeting specific therapeutically
beneficial receptor – G protein interactions to reduce on-target and off-target side-effects.

## Key facts

- **NIH application ID:** 9855598
- **Project number:** 1SC2GM130480-01A1
- **Recipient organization:** CALIFORNIA STATE UNIVERSITY NORTHRIDGE
- **Principal Investigator:** Ravinder Abrol
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $145,000
- **Award type:** 1
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855598

## Citation

> US National Institutes of Health, RePORTER application 9855598, Probing the Structural Basis of Innate G Protein Specificity in G Protein-Coupled Receptor Signaling (1SC2GM130480-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9855598. Licensed CC0.

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