Disease relevance of GPR68

• We describe the cloning of a novel G protein-coupled receptor, termed ovarian cancer G protein-coupled receptor 1 (OGR1), from an ovarian cancer cell line that maps to chromosome 14q31 [1].
• 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 [2].

High impact information on GPR68

• The specific binding of SPC to OGR1 also activates p42/44 mitogen-activated protein kinases (MAP kinases) and inhibits cell proliferation [3].
• In accordance with previously published reports, OGR1 was found to evoke strong pH-dependent responses as measured by inositol phosphate accumulation [4].
• Taken together, these data indicate that OGR1 is expressed early during osteoclastogenesis both in vivo and in vitro and plays a role in osteoclast differentiation [5].
• Specific inhibition of OGR1 by anti-OGR1 antibody and by small inhibitory RNA inhibited RANKL-induced differentiation of both mouse bone marrow mononuclear cells and RAW cells in vitro, as evidenced by a decrease in tartrate-resistant acid phosphatase-positive osteoclasts [5].
• Unexpectedly, the acid-induced cAMP accumulation was also largely inhibited by OGR1 siRNA but only slightly by GPR4 siRNA [6].

Biological context of GPR68

• Among G protein-coupled receptors, GPR4 shares highest sequence homology with OGR1 (51%) [7].
• Identification of human OGR1, a novel G protein-coupled receptor that maps to chromosome 14 [1].
• The predicted open reading frame of OGR1 encodes a protein of 365 amino acids [1].
• GPR12A and GPR6C.1 are 46.1% identical in amino acid sequence, but are less than 33% identical to any other known receptors [8].
• Screening of a human lung cDNA library with GPR12A as a probe also identified a closely-related cDNA (GPR6C.1) that has been previously reported as GPR4 [13] [8].

Anatomical context of GPR68

• Prostaglandin I(2) production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cells [6].
• Utilizing RT-PCR, flow cytometry and immunoblot analyses, we show for the first time that ovarian cancer G protein-coupled receptor 1, the receptor for SPC, is expressed in IL-2-, IL-12- and IL-15-activated but not in resting CD16-, resting CD16+ or IFN-alpha-activated NK cells [9].
• OGR1 is expressed as a single 3.0-kb transcript in several tissues, including spleen, testis, small intestine, peripheral blood leukocytes, brain, heart, lung, placenta, and kidney, with no detectable OGR1 expression in thymus, prostate, ovary, colon, liver, skeletal muscle, or pancreas [1].
• Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes [2].

Associations of GPR68 with chemical compounds

• Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1 [3].
• Acidic extracellular pH also stimulated prostaglandin I2 (PGI(2)) production, which was again inhibited by OGR1 siRNA [6].
• The inhibitory psychosine effect was also observed for pH-dependent actions in OGR1- and GPR4-expressing cells but not for prostaglandin E(2)- and sphingosine 1-phosphate-induced actions in any pH in native and sphingosine 1-phosphate receptor-expressing cells [10].
• It has been reported that ovarian cancer G protein-coupled receptor 1 (OGR1) is a high affinity receptor for SPC, and its closely related homologue GPR4 is a high affinity receptor for SPC with low affinity for lysophosphatidylcholine (LPC) [11].
• We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation [2].

Other interactions of GPR68

• As OGR1 and GPR4 were reported as proton-sensing GPCRs (Ludwig, M. G., Vanek, M., Guerini, D., Gasser, J. A., Jones, C. E., Junker, U., Hofstetter, H., Wolf, R. M., and Seuwen, K. (2003) Nature 425, 93-98), we evaluated the proton-sensing function of G2A [12].
• A novel G protein-coupled receptor, named GPR12A, was cloned by a PCR strategy using degenerate primers designed from sequences conserved among receptors for inflammatory mediators [8].
• Here we review the status of this field and we confirm that GPR4, OGR1, and TDAG8 should be considered as proton-sensing receptors [13].
• The cAMP accumulation may occur through OGR1-mediated stimulation of the phospholipase C/cyclooxygenase/PGI(2) pathway [6].

Analytical, diagnostic and therapeutic context of GPR68

• Strong induction of OGR1 mRNA was also observed by microarray, real-time RT-PCR, and immunoblotting when mouse bone marrow mononuclear cells and RAW 264.7 pre-osteoclast-like cells were treated with RANKL to induce osteoclast differentiation [5].

References