Alternative titles; symbolsG PROTEIN-COUPLED RECEPTOR 44; GPR44CRTH2HGNC Approved Gene Symbol: PTGDR2Cytogenetic location: 11q12.2 Genomic coordinates (GRCh3...
Alternative titles; symbols
HGNC Approved Gene Symbol: PTGDR2
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38): 11:60,850,932-60,855,949 (from NCBI)
G protein-coupled receptors (GPCRs), such as GPR44, are integral membrane proteins containing 7 putative transmembrane domains (TMs). These proteins mediate signals to the interior of the cell via activation of heterotrimeric G proteins that in turn activate various effector proteins, ultimately resulting in a physiologic response.
▼ Cloning and Expression
By PCR amplification of human genomic DNA using degenerate oligonucleotides corresponding to transmembrane domains 3 and 7 of the mouse delta-opioid receptor and somatostatin receptors, Marchese et al. (1999) isolated a partial cDNA for a novel G protein-coupled receptor, which they designated GPR44. They obtained a full-length clone by screening a lambda human genomic library. GPR44 encodes a 472-amino acid protein that is closely related to chemoattractant receptors. Northern blot analysis revealed a 3.5-kb GPR44 transcript primarily in thalamus, frontal cortex, pons, and hippocampus and at lower levels in hypothalamus and caudate/putamen. A 3.4-kb transcript was detected in fetal liver, leukocytes, and thymus.
Using differential expression screening, Nagata et al. (1999) identified a cDNA that is selectively expressed in vivo in activated T-helper-2 (Th2) cells, including allergen-responsive Th2 cells, but not in B or NK cells. They termed the 395-amino acid protein CRTH2 for chemoattractant receptor-homologous molecule expressed on Th2. Incubation of PHA-stimulated peripheral blood mononuclear cells or Th2 clones with the Th2-promoting cytokine IL4 (147780) but not with the Th1-promoting cytokine IL12 (161560) resulted in enhancement of CRTH2 expression.
By fluorescence in situ hybridization, Marchese et al. (1999) mapped the PTGDR2 gene to chromosome 11q12-q13.3.
Gross (2015) mapped the PTGDR2 gene to chromosome 11q12.2 based on an alignment of the PTGDR2 sequence (GenBank AB008535) with the genomic sequence (GRCh38).
▼ Gene Function
Prostaglandin D2 (PGD2; see 176803) and other prostanoids are synthesized by the constitutive cyclooxygenase COX1 (PTGS1; 176805) and its inducible isoform, COX2 (PTGS2; 600262). PGD2, which is implicated in allergic disease, elicits its biologic function through interaction with the DP receptor (PTGDR; 604687). Hirai et al. (2001) showed that PGD2 produced by activated mast cells uses CRTH2 to induce intracellular calcium mobilization and chemotaxis in Th2 cells in a G-alpha(i) (GNAI1; 139310)-dependent manner. In addition, they found that CRTH2 rather than DP mediates PGD2-dependent migration of blood eosinophils and basophils. Functional analysis indicated that PGD2 signaling through DP is coupled to G-alpha(s) (GNAS; 139320) and does not induce chemotaxis.
Indomethacin and other nonsteroidal antiinflammatory drugs (NSAIDS) inhibit COX activity. Hirai et al. (2002) reported that cells expressing CRTH2 mobilized calcium and were attracted to indomethacin but not other NSAIDS. They concluded that a widely used COX inhibitor can stimulate rather than inhibit a chemoattractant receptor.
▼ Molecular Genetics
Huang et al. (2004) conducted a family-based analysis of asthma (600807) and the common 1544G/C and 1651G/A (rs545659) SNPs in the 3-prime untranslated region of CRTH2. The authors reported significant evidence of linkage for the 1651G allele (P = 0.003). Haplotype analysis yielded additional evidence of linkage disequilibrium for the GG haplotype (P less than 0.001). Population-based case-control analysis in 2 independent populations demonstrated significant association of the GG haplotype with asthma in an African American population (P = 0.004) and in Chinese children (P less than 0.001). In the Chinese children, the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild to moderate asthmatics (P = 0.001) and normal controls (P less than 0.001). Transcriptional pulsing experiments showed that the GG haplotype conferred a significantly higher level of reporter mRNA stability, when compared with a nontransmitted CA haplotype, suggesting that the CRTH2 gene on chromosome 11q may be a strong candidate gene for asthma.
▼ Animal Model
Ishii et al. (2012) found that Crth2 -/- mice were highly resistant to sepsis induced by cecal ligation and puncture, and that this resistance was associated with lower bacterial load, lower production of Tnf (191160), Il6 (147620), and Ccl3 (182283), and higher production of antiinflammatory Il10 (124092). Neutrophil accumulation in peritoneum was higher in Crth2 -/- mice and was associated with higher Cxcr2 (146928) expression. Pharmacologic depletion of neutrophils or inhibition of Cxcr2 abrogated the survival benefit in Crth2 -/- mice. Ishii et al. (2012) concluded that ablation of Crth2 improves impaired neutrophil migration and survival during sepsis in a manner mechanistically associated with epigenetically mediated Cxcr2 expression.
Tsubosaka et al. (2014) observed production of prostaglandin D2 (PGD2) and paw swelling in both wildtype and Crth2 -/- mice following injection of complete Freund adjuvant (CFA) in ankle joint; however, arthritis was more severe in Crth2 -/- mice. Bone marrow transplantation studies revealed that Crth2 -/- donor cells were involved in disease progression by accelerating infiltration of macrophages into the inflamed paw. Treatment with a macrophage inactivator improved symptoms in Crth2 -/- mice, whereas adoptive transfer of Crth2 -/- macrophages exacerbated joint inflammation in wildtype mice. Crth2 deficiency accelerated expression of Gmcsf (CSF2; 138960) and Cxcr2 in CFA-treated peritoneal macrophages, but Crth2 agonism inhibited expression. Tsubosaka et al. (2014) concluded that PGD2-CRTH2 signaling plays a protective role in joint inflammation by attenuating macrophage infiltration.