# Functional and Mechanistic Dissection of GPCR Endosomal Signaling Dynamics

> **NIH NIH F31** · DUKE UNIVERSITY · 2022 · $37,665

## Abstract

Abstract
G protein-coupled receptors (GPCRs), which compose the largest class of drug targets, are critical signaling
proteins that translate extracellular stimuli to mediate human physiology. As such, understanding GPCR
signaling cascades will provide insight into the molecular mechanisms underlying these complex physiological
processes, their perturbation in disease, and inform our ability to design more efficient therapeutics. In recent
years, my lab and others have made a paradigm-shifting discovery that GPCRs can be activated after drug-
induced internalization from the plasma membrane into endosomal compartments. However, one essential
variable that remains unexplored is how the temporal dynamics of GPCR endosomal cAMP activity impact
downstream signaling. In the current proposal, I will dissect the influence of the duration of GPCR activation in
endosomes on downstream signaling, identify novel protein complexes that regulate receptor spatiotemporal
signaling dynamics, and apply this knowledge to a physiologically relevant system—hippocampal neurons. By
combining functional genomics, proteomics, and optogenetics, this proposal aims to provide a comprehensive
understanding of how the temporal dynamics of GPCR signaling in endosomes regulates biological functions.
This work is essential to comprehending the mechanisms of GPCR signaling and identifying novel signaling
pathways, providing new targets for pharmacologic therapies.

## Key facts

- **NIH application ID:** 10368945
- **Project number:** 5F31NS120567-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Blair Willette
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,665
- **Award type:** 5
- **Project period:** 2021-03-01 → 2023-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368945

## Citation

> US National Institutes of Health, RePORTER application 10368945, Functional and Mechanistic Dissection of GPCR Endosomal Signaling Dynamics (5F31NS120567-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10368945. Licensed CC0.

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