Disease relevance of GPR44

• 3. Functional studies demonstrated that PGD(2) activation of recombinant CRTH2 results in decrease of intracellular cAMP in a pertussis toxin-sensitive manner [1].
• Furthermore, in atopic dermatitis patients, a preferential increase of CRTH2+ cells was noted within the disease-related cutaneous lymphocyte-associated antigen-positive, but not the cutaneous lymphocyte-associated antigen-negative, CD4+ lymphocyte compartment [2].
• In 58 patients with septic shock, we observed a reduced CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression on Th2 lymphocytes and regulatory T cells in comparison with 39 healthy volunteers [3].
• These findings implied the involvement of CRTH2 in mast cell-mediated immune responses such as allergic reactions [4].
• Pharmacologically, rat CRTH2 stably transfected in mouse preB lymphoma L1.2 cells behaved very similar compared with the mouse and human orthologs, showing a binding affinity for PGD2 of 11 nM, a functional calcium mobilization when exposed to agonist, and similar sensitivity to agonists and antagonists [5].

High impact information on GPR44

• We report that circulated human CD4+ T cells expressing the prostaglandin D2 receptor (CRTH2) are TH2 central memory T cells, characterized by their phenotype, TH2 cytokine production, gene-expression profile, and the ability to respond to allergens [6].
• Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2 [7].
• Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2 [7].
• In response to PGD2, CRTH2 induces intracellular Ca2+mobilization and chemotaxis in Th2 cells in a Galphai-dependent manner [7].
• Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability [8].

Chemical compound and disease context of GPR44

• CONCLUSIONS: Our experience suggests that the pathogenesis of eosinophilic otitis media is related to the pharmaceutical effects of ramatroban, i.e., inhibition of the thromboxane A(2) receptor (TP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) [9].

Biological context of GPR44

• 3, GPR44 to chromosome 11q12-q13.3, and GPR45 to chromosome 2q11 [10].
• Two PCR products partially encoding novel GPCRs, named GPR44 and GPR45, were discovered and used to isolate the full-length translational open reading frames from a human genomic library [10].
• High and low affinity binding sites for PGD(2) were identified in the CRTH2 receptor population by saturation analysis with respective equilibrium dissociation constants (K(D)) of 2.5 and 109 nM [1].
• 1. The recombinant human prostaglandin D(2) (PGD(2)) receptor, hCRTH2, has been expressed in HEK293(EBNA) and characterized with respect to radioligand binding and signal transduction properties [1].
• Family-based analysis of asthma and two common SNPs [G1544C and G1651A (rs545659)] in the 3'-untranslated region of CRTH2 showed significant evidence of linkage in the presence of disequilibrium for the 1651G allele (P = 0.003) of SNP rs545659 [8].

Anatomical context of GPR44

• Both GPR44 and GPR45 are expressed in the central nervous system and periphery [10].
• In addition, in situ hybridization studies revealed that CRTH2 mRNA is expressed in human eosinophils [1].
• 4. By Northern blot analysis, we showed that, besides haemopoietic cells, CRTH2 is expressed in many other tissues such as brain, heart, thymus, spleen and various tissues of the digestive system [1].
• Finally, radioligand binding studies demonstrated that two eosinophilic cell lines, butyric acid-differentiated HL-60 and AML 14.3D10, also endogenously express CRTH2 [1].
• In some cases, CD8+ T cells ( approximately 3.5%) expressed CRTH2 [11].

Associations of GPR44 with chemical compounds

• At a threshold concentration, 11-dehydro-TXB(2) had no antagonistic effect on CRTH2-mediated responses as induced by PGD2 [12].
• Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) is an important chemoattractant receptor expressed by eosinophils, basophils, and TH2 lymphocytes, and prostaglandin (PG)D(2) has been shown to be its principal ligand [12].
• In this study, we present evidence demonstrating that the novel PGD(2) receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) is another functional target for indomethacin [13].
• In addition, an allergen-induced proliferative response in fresh PBMCs was significantly and selectively reduced by subtracting CRTH2+ cells [11].
• 11-Dehydro-thromboxane B2, a stable thromboxane metabolite, is a full agonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) in human eosinophils and basophils [12].

Physical interactions of GPR44

• Therefore, we showed that CRTH2 can functionally couple to the G-protein G(alphai/o) [1].

Regulatory relationships of GPR44

• Characterization of DP receptor null mice in which antigen-induced airway and inflammatory responses are attenuated and identification of CRTH2 as a novel PGD(2) receptor have shed light on the role of PGD(2) in the immune and inflammatory responses [14].
• In the present study, the expression of chemokine receptor 5 (CCR5) as a Th1 marker and a chemoattractant receptor-homologs molecule expressed on Th2 cells (CRTH2) were investigated in order to analyze impaired Th1/Th2 responses in the colonic mucosa of UC patients [15].
• 15d-PGJ2 was thought to exert its effects on cells exclusively through peroxisome proliferator-activated receptor-gamma (PPARgamma) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), which are both expressed on human eosinophils [16].
• We show that following in vitro stimulation with N. meningitidis serogroup B (MenB) antigens, approximately 66% of the dividing mucosal CD4(+)CD45RO(+) memory population express the Th1-associated IL18-R while the remainder express CRTH2, a Th2-associated marker [17].
• Genetic Impact of Functional Single Nucleotide Polymorphisms in the 3'-UTR Region of the Chemoattractant Receptor Expressed on Th2 Cells (CRTH2) Gene on Asthma and Atopy in a Japanese Population [18].

Other interactions of GPR44

• This revealed that the affinity of PGD(2) for CRTH2 is eight times less than its affinity for the DP receptor [1].
• The receptor encoded by GPR34 is most similar to the P2Y receptor subfamily, while the receptor encoded by GPR44 is most similar to chemoattractant receptors [10].
• We hypothesize that the restoration of CRTH2/CCR3 expression may be an indicator for optimal recovery after septic shock [3].
• Inhibition of cytokine/chemokine secretion implicates at least in part DP, but not CRTH2 [19].
• Pretreatment with ramatroban (CRTH2 antagonist) and AL8810 (FP antagonist) did not reduce the production of these cytokines [20].

Analytical, diagnostic and therapeutic context of GPR44

• To investigate the structural determinants of CRTH2 ligand binding, we performed site-directed mutagenesis of putative mCRTH2 ligand-binding residues, and we evaluated mutant receptor ligand binding and functional properties [21].
• Enzyme-linked immunosorbent assays show that they do not alter the total number of CRTH2 receptors on the cell surface [22].
• Inflammatory cascades mediated by CRTH2 ligation may therefore represent an important early step in the elicitation and maintenance of Th2-dependent skin inflammation [23].
• Method: The CRTH2/DP expression was examined by RT-PCR and flow-cytometric analysis [20].
• We previously identified the mouse CRTH2 homolog of human CRTH2 and suggest that animal models would provide a clear understanding on the precise function of CRTH2 in allergic disorders [24].

References