# Characterization of Compartmentalized GPCR Signaling in Neurons

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $373,915

## Abstract

More than a third of all G protein-coupled receptors (GPCRs) are expressed in the brain, where they modulate
synaptic plasticity, memory and behavior, and also contribute to the pathophysiology of
neuropsychiatric disorders. Therefore, improved understanding of how GPCRs
several neurological and
operate in neurons is
fundamentally important to neuroscience, and will enable mechanism-based discovery of more selective and
efficient therapies for memory disorders and mental illness. In this proposal, we build on our transformative
finding that receptor activation on endosomal compartments underlies unique cellular responses. We propose
to explore the molecular consequences of endosomal receptor signaling in neurons, and to investigate how
neurons discriminate between distinct sites of local activation. We focus on the prototypical β2-adrenoceptor
(β2-AR), a recognized mediator of neuronal function, to test the hypothesis that the molecular composition of
signaling complexes present at endosomes is distinct from the plasma membrane resulting in unique neuronal
outcomes upon β2-AR activation. We will employ an interdisciplinary approach in human iPSC-derived neurons
to 1) delineate the consequences of compartmentalized β2-AR signaling on transcriptional reprogramming, 2)
elucidate the role of plasma membrane- and endosomal β2-ARs in translational regulation of gene expression,
and 3) determine how the endosome induces spatially biased GPCR responses. Successful completion of these
studies will illuminate how spatial GPCR regulation is established, and how it shapes critical neuronal outputs of
this pathway.

## Key facts

- **NIH application ID:** 10840365
- **Project number:** 5R01NS127847-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Nikoleta Georgieva Tsvetanova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,915
- **Award type:** 5
- **Project period:** 2022-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840365

## Citation

> US National Institutes of Health, RePORTER application 10840365, Characterization of Compartmentalized GPCR Signaling in Neurons (5R01NS127847-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10840365. Licensed CC0.

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