Proton-sensing GPCRs in health and disease

  • The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.

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Author:Marco SisignanoORCiDGND, Michael J. M. Fischer, Gerd GeisslingerORCiDGND
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/08/10
Date of first Publication:2021/08/10
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2021/09/22
Tag:G2A; GPCR; GPR4; OGR1; TDAG8; inflammation; neuropathic pain; pain; proton-sensing GPCR; tumor microenvironment
Issue:8, art. 2050
Page Number:19
First Page:1
Last Page:19
This work was supported by Grants SFB1039 A09 and Z01 of the Deutsche Forschungsgemeinschaft (German Research Foundation) and from the Fraunhofer Foundation Project: Neuropathic
Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD).
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0