# Molecular mechanisms of proton-sensing in CO2-dependent breathing

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $38,785

## Abstract

Abstract
GPR4 is a G-protein coupled receptor required for CO2-dependent breathing. In the brainstem, rising CO2
levels cause a decrease in pH that activates GPR4. Genetic knockout of GPR4 results in two pathological
phenotypes - reduced CO2-dependent breathing and frequent apneas, which are both rescued by specific
re-expression of GPR4 in the brainstem. This establishes a link between inactivation of GPR4 and symptoms
for severe breathing disorders including congenital central hypoventilation syndrome (CCHS) and central sleep
apnea (CSA). However we do not know how GPR4 senses pH, and we do not know how existing small
molecules modulate GPR4. Through this proposal, I will determine the molecular mechanism of GPR4
activation to provide insights into the regulation of CO2-dependent breathing and to enable the development of
small molecules that activate GPR4. In Aim 1, I will determine the molecular details of how protons activate
GPR4. In Aim 2, I will decipher how current antagonists bind and inactive GPR4. To accomplish these aims, I
will combine the techniques of biochemistry, structural biology (cryogenic electron microscopy), and
pharmacology (mutagenesis and signaling assays). These studies will provide mechanistic insight into the
regulation of GPR4 activity through protons and small molecules. This will expand our fundamental
understanding of how protons drive CO2-dependent breathing, and this will enable the future development of
small molecules that activate GPR4, which could be novel therapeutics for CCHS and CSA.

## Key facts

- **NIH application ID:** 10466557
- **Project number:** 1F31HL164045-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Nick Hoppe
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,785
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466557

## Citation

> US National Institutes of Health, RePORTER application 10466557, Molecular mechanisms of proton-sensing in CO2-dependent breathing (1F31HL164045-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10466557. Licensed CC0.

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