Disease relevance of GPR135

• An additional 45 k.Da band of PAF-R was found in psoriasis that might stand for a truncated receptor [1].
• In the epithelial tumor cell line HaCaT and the HT29 colon cancer cell line PAF-R characterizes the anti-apoptotic effect of this receptor propagating tumor proliferation [1].
• In the present study, we show that gp170 has the capacity to drive constitutive PAF-R expression on tumor cells, which could be responsible for hypersensitivity to NK lysis and accelerated cell death [2].
• It is hypothesized that such activators might modulate inflammation and apoptosis upon atherogenesis by decreasing the expression of PAF receptor [3].
• Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086 [4].

Psychiatry related information on GPR135

• Taken together, these results demonstrate that PMS777 possesses dual activities for PAF receptor antagonism and AChE inhibition, suggesting that this compound may be a promising lead compound for further investigation related to the treatment for Alzheimer's disease [5].
• In the presence of a PAF-receptor antagonist, IL-8 acting alone induced conversion of rolling to stationary adhesion in as little as 80 ms after the initial attachment of a neutrophil, with a median response time of 240 ms [6].

High impact information on GPR135

• The discovery of PAF receptor antagonists and structure-activity relationships of such antagonists (159) will make this determination possible in the near future [7].
• This action of PAF was receptor mediated, as it was dose dependently inhibited by the PAF receptor antagonist WEB 2086 and blocked by pertussis toxin [8].
• Finally, we measured levels of LTA that were adequate to stimulate PAF-R in vitro on the skin of subjects with infected atopic dermatitis [9].
• Intradermal injections of LTA and the PAF-R agonist 1-hexadecyl-2-N-methylcarbamoyl glycerophosphocholine (CPAF) induced cutaneous inflammation in wild-type but not PAF-R-deficient mice [9].
• The cultured endothelial cells also exhibited enhanced neutrophil adhesion in response to alpha toxin which was mediated through the PAF receptor and P-selectin [10].

Chemical compound and disease context of GPR135

• WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status [4].
• The results suggest that PAF is involved in the BLEO-induced lung fibrosis and that PAF-receptor antagonist may therefore be potentially useful in the attenuation of lung fibrosis caused by bleomycin [11].
• These results suggest that in differentiated U-937 cells PAF receptor is coupled through a pertussis toxin-insensitive guanine nucleotide binding protein to a phosphoinositide specific phospholipase C. Inositol-trisphosphate, and possibly diacylglycerol, could be the intracellular messengers for PAF receptor in U-937 cells [12].
• The aim of this study was to investigate whether platelet-activating factor (PAF), PAF receptors, and PAF receptor-mediated effects in the human myocardium play a role in cardiac depression during anaphylaxis or septic shock [13].
• Intracellular Ca2+ mobilization and the release of free fatty acids and inositol phosphates were not inhibited by pretreatment of platelets with pertussis toxin (PTX) or the PAF receptor antagonist WEB 2086 [14].

Biological context of GPR135

• Analysis of expressed sequence tag (EST) sequences indicated individual expression patterns, such as for GPR135, which was found in a wide variety of tissues including eye, brain, cervix, stomach and testis [15].
• Expression of the PAF-R in KB cells did not affect base-line growth or apoptosis, yet resulted in a decrease in the lag time between treatment of the cells and the induction of apoptosis following irradiation with 400 J/m2 UVB [16].
• A modified human PAF receptor cDNA was constructed by inserting an additional 30 nucleotides after the 5'-ATG, encoding the amino acid sequence MDYKDDDDKEF, which is specifically recognized by a monoclonal antibody [17].
• Southern analysis using this cDNA indicates that the PAF receptor gene is present as a single copy in the human genome [17].
• The aim of this study was to evaluate the binding capacity of the major component of PAF-like oxidized phospholipids, namely the 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) to PAF-receptor (PAF-R) on the surface of human monocytes/macrophages and to further characterize the gene expression induced by such binding [18].

Anatomical context of GPR135

• Interestingly, UVB irradiation was found to stimulate PAF synthesis only in PAF-R-expressing KB cell clones [16].
• Thus, we suggest, that POVPC signals in mature macrophages only in part through the PAF-R, a part of its effects may involve other receptors [18].
• These results suggest that the increased expression of PAF-R in eosinophils may be relevant to the pathogenesis of atopic asthma [19].
• We aimed to study PAF-R in a range of dermal cell lines and in samples of normal and psoriatic human skin to learn about its further role in humans [1].
• Cloned PAF receptor, which belongs to the G protein-coupled receptor superfamily, transduces pleiotropic functions including cell motility, smooth muscle contraction, and synthesis and release of mediators and cytokines via multiple heterotrimeric G proteins [20].

Associations of GPR135 with chemical compounds

• We show that, POVPC binds to cultured human macrophages via PAF-R and transduces the signals leading to the intracellular Ca(2+) fluxes and modifies the transcription levels of numerous pro-inflammatory and pro-atherogenic genes [18].
• Sodium decreased specific (3)H-PAF and antagonist (3)H-WEB2086 binding to the PAF receptor, but the aspartate 63 residue was not involved in this regulation, contrary to cognate aspartate residues in other GPCRs [21].
• We investigated the effect of oxidized low-density lipoprotein (oxLDL) on lipopolysaccharide (LPS)-induced PAF receptor (PAF-R) expression in human macrophages and the implication of the nuclear factor (NF)-kappaB in this regulation [22].
• In contrast, highly oxidized low-density lipoprotein [ox24hLDL; 100 microg.mL(-1); thiobarbituric acid reacting substances: 31 +/- 3 nmol equiv. malondialdehyde (MDA).mg protein LDL-1] diminished PAF-R expression (-69%; P < 0.05) and mRNA level (- 45%; P < 0.01) [22].
• Three specific PAF-receptor antagonists, WEB2086, CV3988, and CV6209, reversed this effect of PAF [23].

Regulatory relationships of GPR135

• Ultraviolet B irradiation of PAF-receptor-expressing KB cells resulted in significant increases in both interleukin-8 mRNA and protein in comparison to ultraviolet-B-treated control KB cells [24].
• The cell motility induced by VEGF was inhibited by PAF-receptor antagonists [25].

Other interactions of GPR135

• These studies suggest that the epidermal PAF receptor may be a pharmacologic target for ultraviolet B radiation in skin and thus may act to augment ultraviolet-B-mediated production of cytokines such as interleukin-8 [24].
• The results obtained demonstrate that the neoangiogenesis induced by VEGF in vivo was associated with a local synthesis of PAF and was inhibited by WEB2170 and CV3988, 2 chemically unrelated, specific PAF-receptor antagonists [25].
• Administration of the PAF receptor antagonist SRI 63-441 or indomethacin blocked the early (0.25-0.5 h) and attenuated the later increases in PVR and Ppa; indomethacin also attenuated the increase in Pt and hypoxemia associated with TNF-alpha infusion [26].
• We conclude that SRI 63-441 is a less specific PAF receptor antagonist in vivo compared with WEB 2086 and that cyclooxygenase products, but not PAF, contribute significantly to the cardiopulmonary responses induced by exogenously infused TNF-alpha in pigs [26].

Analytical, diagnostic and therapeutic context of GPR135

• We compared expression levels of mRNA for the PAF receptor (PAF-R) in peripheral blood eosinophils from atopic asthmatic patients with those from normal healthy subjects using a relative quantification method based on the reverse transcription-polymerase chain reaction (RT-PCR) [19].
• PAF-receptor in inflammatory versus non inflammatory human epidermis, cell cultures and embryonal cells [1].
• Northern blotting showed that RA and T3 regulated PAFR gene expression only in rat tissues that express PAFR transcript 2 [27].
• Northern blot analysis, flow cytometry, and immunoblotting with anti-hPAF-R antibody indicated that monocytic, neutrophilic, and B-lymphocytic cell lines all shared a similar hPAF-R species, whereas resting T-cell and natural killer cell lines failed to express detectable levels of either hPAF-R protein or mRNA [28].
• We have used site-directed mutagenesis and functional expression studies to examine the role of the Phe97 and Phe98 residues located in the third transmembrane helix and Asn285 and Asp289 of the seventh transmembrane helix in ligand binding and activation of the human PAF receptor in transiently transfected COS-7 cells [29].

References