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Quantifying Agonist Activity at G Protein-coupled Receptors

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The Adhesion G Protein-Coupled Receptor GPR97/ADGRG3 Is Expressed in Human Granulocytes and Triggers Antimicrobial

Cheng-Chih Hsiao¹, Tai-Ying Chu², Chia-Jung Wu²

¹Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Frontiers in Immunology

|December 19, 2018

Insights

The GPR97 receptor is present in human granulocytes and regulates their antimicrobial activity. Activating GPR97 enhances neutrophil responses against bacteria, suggesting a key role in innate immunity.

Area of Science:

Immunology
Cell Biology
Molecular Biology

Background:

Adhesion G protein-coupled receptors (aGPCRs) are involved in polymorphonuclear cell (PMN) functions.
Previous studies suggested GPR97 expression in granulocytes.

Purpose of the Study:

To investigate the cellular distribution, molecular structure, signal transduction, and biological function of GPR97 in human PMNs.
To elucidate the role of GPR97 in regulating granulocyte antimicrobial activity.

Main Methods:

RNA sequencing and mass spectrometry for gene and protein expression analysis.
Generation of a GPR97-specific monoclonal antibody for detection of endogenous receptor.
Functional assays measuring reactive oxygen species production, proteolytic enzyme activity, bacterial uptake, and killing.
Analysis of signaling pathways including MAPK, IκBα phosphorylation, and cAMP levels.

Main Results:

ADGRG3/GPR97 is highly expressed in granulocyte precursors and differentiated granulocytes (neutrophils, eosinophils, basophils).
Endogenous GPR97 is a proteolytically processed, N-glycosylated receptor found in tissue-infiltrating PMNs and upregulated during inflammation.
GPR97 ligation enhanced neutrophil reactive oxygen species production, proteolytic activity, bacterial uptake, and killing.
GPR97 activation modulated signaling pathways, including a potential switch in G protein coupling and activation of downstream effectors like NF-κB.

Conclusions:

GPR97 is specifically expressed in human granulocytes and plays a crucial role in regulating their antimicrobial functions.
GPR97 activation enhances key neutrophil effector mechanisms essential for combating bacterial infections.

Read full analysis

Abstract:

The adhesion family of G protein-coupled receptors (aGPCRs) comprises 33 members in human, several of which are distinctly expressed and functionally involved in polymorphonuclear cells (PMNs). As former work indicated the possible presence of the aGPCR GPR97 in granulocytes, we studied its cellular distribution, molecular structure, signal transduction, and biological function in PMNs. RNA sequencing and mass-spectrometry revealed abundant RNA and protein expression of ADGRG3/GPR97 in granulocyte precursors and terminally differentiated neutrophilic, eosinophilic, and basophilic granulocytes. Using a newly generated GPR97-specific monoclonal antibody, we confirmed that endogenous GPR97 is a proteolytically processed, dichotomous, N-glycosylated receptor. GPR97 was detected in tissue-infiltrating PMNs and upregulated during systemic inflammation. Antibody ligation of GPR97 increased neutrophil reactive oxygen species production and proteolytic enzyme activity, which is accompanied by an increase in mitogen-activated protein kinases and IκBα phosphorylation. In-depth analysis of the GPR97 signaling cascade revealed a possible switch from basal Gαs/cAMP-mediated signal transduction to a Gαi-induced reduction in cAMP levels upon mutation-induced activation of the receptor, in combination with an increase in downstream effectors of Gβγ, such as SRE and NF-κB. Finally, ligation of GPR97 increased the bacteria uptake and killing activity of neutrophils. We conclude that the specific presence of GPR97 regulates antimicrobial activity in human granulocytes.

Keywords:

G-protein signaling adhesion GPCR antimicrobial activity granulocytes inflammation monoclonal antibody

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