title: The proton-activated G protein coupled receptor OGR1 acutely regulates the activity of epithelial proton transport proteins.
abstract: The Ovarian cancer G protein-coupled Receptor 1 (OGR1; GPR68) is proton-sensitive in the pH range of 6.8 - 7.8. However, its physiological function is not defined to date. OGR1 signals via inositol trisphosphate and intracellular calcium, albeit downstream events are unclear. To elucidate OGR1 function further, we transfected HEK293 cells with active OGR1 receptor or a mutant lacking 5 histidine residues (H5Phe-OGR1). An acute switch of extracellular pH from 8 to 7.1 (10 nmol/l vs 90 nmol/l protons) stimulated NHE and H(+)-ATPase activity in OGR1-transfected cells, but not in H5Phe-OGR1-transfected cells. ZnCl(2) and CuCl(2) that both inhibit OGR1 reduced the stimulatory effect. The activity was blocked by chelerythrine, whereas the ERK1/2 inhibitor PD 098059 had no inhibitory effect. OGR1 activation increased intracellular calcium in transfected HEK293 cells. We next isolated proximal tubules from kidneys of wild-type and OGR1-deficient mice and measured the effect of extracellular pH on NHE activity in vitro. Deletion of OGR1 affected the pH-dependent proton extrusion, however, in the opposite direction as expected from cell culture experiments. Upregulated expression of the pH-sensitive kinase Pyk2 in OGR1 KO mouse proximal tubule cells may compensate for the loss of OGR1. Thus, we present the first evidence that OGR1 modulates the activity of two major plasma membrane proton transport systems. OGR1 may be involved in the regulation of plasma membrane transport proteins and intra- and/or extracellular pH.
authors.affiliation: Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Chahira
authors.initials: C
authors.lastname: Benabbas
authors.forename: Solange
authors.initials: S
authors.lastname: Vidal
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.forename: Soline
authors.initials: S
authors.lastname: Bourgeois
authors.forename: Ana
authors.initials: A
authors.lastname: Velic
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Ludwig
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000494:pharmacology; D004789:Enzyme Activation; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014162:Transfection; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D053119:Benzophenanthridines; D002712:Chlorides; D005419:Flavonoids; C525539:GPR68 protein, mouse; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D017967:Zinc Compounds; C016837:zinc chloride; C016299:chelerythrine; D011494:Protein Kinases; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D006180:Proton-Translocating ATPases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium