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      Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein–Coupled Receptor OGR1 (GPR68)

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      Cellular and Molecular Gastroenterology and Hepatology
      Ovarian Cancer G-Protein–Coupled Receptor, Inflammation, Inflammatory Bowel Disease, TDAG8, GRP65, AICAR, 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, CD, Crohn's disease, ChIP, chromatin immunoprecipitation, FCS, fetal calf serum, GPR, G-protein–coupled receptor, HIF, hypoxia-inducible factor, HV, healthy volunteer, IBD, inflammatory bowel disease, IEC, intestinal epithelial cell, IFN, interferon, IL, interleukin, MM6, MonoMac 6, mRNA, messenger RNA, NF-κB, nuclear factor-κB, OGR1, ovarian cancer G-protein–coupled receptor 1 (GPR68), RT-qPCR, quantitative reverse-transcription polymerase chain reaction, SPARC, secreted protein acidic and rich in cysteine, TDAG8, T-cell death-associated gene 8 (GPR65), Th, T-helper, TNF, tumor necrosis factor, UC, ulcerative colitis, WT, wild type

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          Background & Aims

          A novel family of proton-sensing G-protein–coupled receptors, including ovarian cancer G-protein–coupled receptor 1 (OGR1) (GPR68) has been identified to play a role in pH homeostasis. Hypoxia is known to change tissue pH as a result of anaerobic glucose metabolism through the stabilization of hypoxia-inducible factor-1α. We investigated how hypoxia regulates the expression of OGR1 in the intestinal mucosa and associated cells.


          OGR1 expression in murine tumors, human colonic tissue, and myeloid cells was determined by quantitative reverse-transcription polymerase chain reaction. The influence of hypoxia on OGR1 expression was studied in monocytes/macrophages and intestinal mucosa of inflammatory bowel disease (IBD) patients. Changes in OGR1 expression in MonoMac6 (MM6) cells under hypoxia were determined upon stimulation with tumor necrosis factor (TNF), in the presence or absence of nuclear factor-κB (NF-κB) inhibitors. To study the molecular mechanisms involved, chromatin immunoprecipitation analysis of the OGR1 promoter was performed.


          OGR1 expression was significantly higher in tumor tissue compared with normal murine colon tissue. Hypoxia positively regulated the expression of OGR1 in MM6 cells, mouse peritoneal macrophages, primary human intestinal macrophages, and colonic tissue from IBD patients. In MM6 cells, hypoxia-enhanced TNF-induced OGR1 expression was reversed by inhibition of NF-κB. In addition to the effect of TNF and hypoxia, OGR1 expression was increased further at low pH. Chromatin immunoprecipitation analysis showed that HIF-1α, but not NF-κB, binds to the promoter of OGR1 under hypoxia.


          The enhancement of TNF- and hypoxia-induced OGR1 expression under low pH points to a positive feed-forward regulation of OGR1 activity in acidic conditions, and supports a role for OGR1 in the pathogenesis of IBD.

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          Most cited references44

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          Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity.

          Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in-vitro-differentiated Th17 cells and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso, and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones.
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            The effects of extracellular pH on immune function.

            A Lardner (2001)
            The effect of alterations in extracellular pH on cellular and humoral immune function is reviewed. Because acidic pH predominates at inflammatory loci and other sites of immune activity, most studies to date focus on the effect of acidic rather than alkaline pH. Investigations on polymorphonuclear leukocytes demonstrate mainly inhibition of chemotaxis, respiratory activity, and bactericidal capacity at reduced pH. Evidence of impaired lymphocyte cytotoxicity and proliferation at acidic pH is also beginning to emerge. Many of the clinical acidoses are accompanied similarly by immunodeficiency. Studies on macrophages and eosinophils are few and inconclusive. A small number of studies demonstrate acid-induced activation of complement proteins and the alternative complement pathway, plus increased antibody-binding to leukocytes at lowered pH. A differential effect of acidic pH on humoral and cellular immunity may, therefore, exist. Increasing recognition of the significance of extracellular pH in relation to immune function warrants further studies in this presently incomplete but rewarding field.
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              Proton-sensing G-protein-coupled receptors.

              Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.

                Author and article information

                Cell Mol Gastroenterol Hepatol
                Cell Mol Gastroenterol Hepatol
                Cellular and Molecular Gastroenterology and Hepatology
                25 June 2016
                November 2016
                25 June 2016
                : 2
                : 6
                : 796-810
                [1 ]Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
                [3 ]Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
                [5 ]Institute of Physiology, University Hospital Zurich, Zurich, Switzerland
                [2 ]Department of Pharmacology and Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBERehd), Faculty of Medicine, University of Valencia, Valencia, Spain
                [4 ]Novartis Institutes for Biomedical Research, Basel, Switzerland
                Author notes
                [] Correspondence Address correspondence to: Gerhard Rogler, MD, PhD, Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland. fax: +41-(0)44-255-9497.Division of Gastroenterology and HepatologyUniversity Hospital ZürichRämistrasse 1008091 ZürichSwitzerland gerhard.rogler@ 123456usz.ch

                Authors share co-first authorship.

                © 2016 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 4 January 2016
                : 17 June 2016
                Original Research

                ovarian cancer g-protein–coupled receptor,inflammation,inflammatory bowel disease,tdag8,grp65,aicar, 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside,cd, crohn's disease,chip, chromatin immunoprecipitation,fcs, fetal calf serum,gpr, g-protein–coupled receptor,hif, hypoxia-inducible factor,hv, healthy volunteer,ibd, inflammatory bowel disease,iec, intestinal epithelial cell,ifn, interferon,il, interleukin,mm6, monomac 6,mrna, messenger rna,nf-κb, nuclear factor-κb,ogr1, ovarian cancer g-protein–coupled receptor 1 (gpr68),rt-qpcr, quantitative reverse-transcription polymerase chain reaction,sparc, secreted protein acidic and rich in cysteine,tdag8, t-cell death-associated gene 8 (gpr65),th, t-helper,tnf, tumor necrosis factor,uc, ulcerative colitis,wt, wild type


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