# Defining the Role of of Noncanonical GPCR Signalling in Pulmonary Hypertension

> **NIH NIH F31** · DUKE UNIVERSITY · 2022 · $37,691

## Abstract

ABSTRACT
Pulmonary hypertension (PH) is characterized by endothelial dysfunction, irregular vascular remodeling and
consistent vasoconstriction leading to eventual fatal right heart failure despite current medical therapies. The
most common drug targets in PH are G protein coupled receptors (GPCRs), which are a target for almost a
third of all FDA-approved drugs. Although these receptors have been studied intensely for over 40 years,
several aspects of GPCR signaling remain poorly understood. Canonically, it has been well established that
these receptors are able to signal through both heterotrimeric G proteins and β-arrestins (βarrs). These events
were thought to be largely separable given that G proteins primarily initiate downstream signaling while βarrs
can signal and regulate receptor desensitization and trafficking. Recent studies have suggested evidence
for a combined role of G protein and βarr in GPCRs signaling through the formation of signaling
“megaplexes” and the impairment of βarr-based signaling in the absence of functional G proteins. However,
there remains a significant knowledge gap surrounding the significance of G protein and βarr coordinated
signaling. Our long term aim is to understand the signaling mechanisms of GPCRs to provide better insight for
the development of novel therapeutics for PH. In our recent studies, we have directly assessed whether G
proteins and βarrs can interact across a panel receptors and were surprised to find that all receptors tested
could form a complex between the inhibitory G protein (Gαi) and βarr, including the type 1 angiotensin II
receptor (AT1R) and atypical chemokine receptor 3 (ACKR3, also known as CXCR7), which are both potential
drug targets in PH. We further found that these complexes could interact with secondary effectors, most
notably extracellular signal-regulated kinase (ERK). These results suggested a conserved, non-canonical
role for Gαi:βarr signaling across GPCRs. Our overarching goal is to define the mechanism in which
Gαi:βarr form complexes and understand their impact on physiology. We hypothesize that Gαi:βarr complex
formation require a discrete set of motifs present in Gαi, βarrs and GPCRs and that these complexes regulate
endothelial function in PH. To test this hypothesis, first I will determine the specific sequence motifs in Gαi, βarr
and the receptor that are required to form Gαi:βarr complex. Second, I will determine the signalling pathways
that are regulated by Gαi:βarr interaction using APEX proximity labeling and novel “complex BRET” assays.
Third, I will determine the impact of Gai:βarr within PH patient endothelial cells by targeting Gαi and βarr
signaling and testing their effects on endothelial function. This study strives to understand an emerging
paradigm in GPCR signalling in which Gαi and βarr work together to orchestrate unique downstream signalling.
Completion of these aims will provide novel insights for cell signalling, development of new pharmacologic...

## Key facts

- **NIH application ID:** 10544136
- **Project number:** 5F31HL152656-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Claudia Y Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,691
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10544136

## Citation

> US National Institutes of Health, RePORTER application 10544136, Defining the Role of of Noncanonical GPCR Signalling in Pulmonary Hypertension (5F31HL152656-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10544136. Licensed CC0.

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