# Cell signaling by G protein-coupled receptors

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $530,880

## Abstract

Abstract
Mammalian G protein coupled receptors (GPCRs) mediate a vast array of biological responses and have been
implicated in numerous diseases. GPCRs are highly druggable and the target of about one-third of all FDA
approved drugs. Currently, all drugs targeting GPCRs have been developed to modulate signals transduced at
the plasma membrane. However, we and others have shown that GPCRs remain active inside the cell and signal
from endosomes. The orchestration of GPCR signaling from the plasma membrane and endosomes is essential
for achieving proper cellular responses, dysregulation of these pathways, through either aberrant increases or
decreases in signaling drives disease progression. Our laboratory has long focused on understanding the
regulatory mechanisms that control GPCR signaling. In recent projects funded by MIRA, we discovered that
ubiquitination of a subset of GPCRs drives p38 mitogen-activated protein kinase (MAPK) endosomal signaling
and vascular inflammation. The molecular mechanisms by which key regulators and mediators of ubiquitination
regulate GPCR-p38 endosomal signaling is not known and a gap in knowledge. In the next 5 years, our
laboratory will focus on understanding how two key deubiquitinases regulate GPCR-stimulated p38 signaling by
identifying key substrates and elucidating the mechanisms of regulation and function in vascular inflammation.
We also discovered that the α-arrestin arrestin-related domain containing protein-3 (ARRDC3) is an endosomal
multi-functional adaptor protein that controls GPCR signaling and trafficking via distinct mechanisms in projects
funded by MIRA. Unlike classical arrestins, virtually nothing is known about the mechanisms that regulate α-
arrestin activity and how α-arrestins govern mammalian GPCR function and a major gap in knowledge. In the
next 5 years, we will define the molecular mechanisms that control GPCR-stimulated ARRDC3 activity and
elucidate the mechanisms of regulation and function in cancer progression. We will integrate hypothesis-driven
and unbiased systems approaches to interrogate the mechanisms that control ubiquitin-driven GPCR endosomal
signaling and ARRDC3 activity and function utilizing innovative and cutting-edge technologies. A thorough
understanding of the spatial-temporal regulatory mechanisms that control GPCR signaling is critical for improving
the development of novel drugs targeting GPCRs.

## Key facts

- **NIH application ID:** 10839841
- **Project number:** 5R35GM127121-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Joann Trejo
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,880
- **Award type:** 5
- **Project period:** 2018-06-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839841

## Citation

> US National Institutes of Health, RePORTER application 10839841, Cell signaling by G protein-coupled receptors (5R35GM127121-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839841. Licensed CC0.

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