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The proton-activated G protein\u2013coupled receptors (GPCRs) GPR4 (Gpr4), TDAG8 (Gpr65), and OGR1 (Gpr68) form a subfamily of proteins capable of triggering intracellular signaling in response to alterations in extracellular pH around physiological values, i.e., in the range between pH 7.5 and 6.5. Expression of these receptors is widespread for GPR4 and OGR1 with particularly high levels in endothelial cells and vascular smooth muscle cells, respectively, while expression of TDAG8 appears to be more restricted to the immune compartment. These receptors have been linked to several well-studied pH-dependent physiological activities including central control of respiration, renal adaption to changes in acid\u2013base status, secretion of insulin and peripheral responsiveness to insulin, mechanosensation, and cellular chemotaxis. Their role in pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), and tumor cell metabolism and invasiveness, is increasingly receiving more attention and makes these receptors novel and interesting targets for therapy. In this review, we cover the role of these receptors in physiological processes and will briefly discuss some implications for disease processes.<\/jats:p>","DOI":"10.1007\/s00424-022-02671-1","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T05:10:54Z","timestamp":1646457054000},"page":"487-504","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Physiological relevance of proton-activated GPCRs"],"prefix":"10.1007","volume":"474","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2805-3601","authenticated-orcid":false,"given":"Pedro H.","family":"Imenez Silva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-8898","authenticated-orcid":false,"given":"Carsten A.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,5]]},"reference":[{"key":"2671_CR1","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1053\/j.gastro.2014.12.030","volume":"148","author":"A Alonso","year":"2015","unstructured":"Alonso A, Dom\u00e8nech E, Juli\u00e0 A, Pan\u00e9s J, Garc\u00eda-S\u00e1nchez V, Mateu PN, Guti\u00e9rrez A, Gomoll\u00f3n F, Mendoza JL, Garcia-Planella E, Barreiro-de Acosta M, Mu\u00f1oz F, Vera M, Saro C, Esteve M, Andreu M, Chaparro M, Many\u00e9 J, Cabr\u00e9 E, L\u00f3pez-Lasanta M, Tortosa R, Gelp\u00ed JL, Garc\u00eda-Montero AC, Bertranpetit J, Absher D, Myers RM, Marsal S, Gisbert JP (2015) Identification of risk loci for Crohn\u2019s disease phenotypes using a genome-wide association study. 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CAW has received honoraria from Kyowa-Kirin, Salmon Pharma and Medice, and Advicenne outside of the work discussed here.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}