Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with prostaglandin DP1 receptor are receptors for prostglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.
Gene The PTGDR2 gene is located on human chromosome 11 at position q12.2 (i.e. 11q12.2). It consists of two introns and three exons and codes for a G protein coupled receptor (GPCR) composed of 472 amino acids. DP2, is related to members of the chemotactic factor class of GPCRs, sharing an amino acid sequence identity of 29% with the C5a receptor, Formyl peptide receptor 1, and Formyl peptide receptor 2 receptors. DP2 has little or no such amino acid sequence relationship to the eight other Prostanoid receptors (see Eicosanoid receptor#Prostenoid receptors).
Expression DP2 was found to stimulate the directed movement or chemotaxis of human T-helper type 2 cells (see T helper cell#Th1/Th2 Model for helper T cells) by binding to a receptor initially termed GPR44 and thereafter CRTH2 (for Chemoattractant Receptor-homologous molecule expressed on T-Helper type 2 cells). In addition to these T helper cells, DP2 messenger RNA is also expressed by human basophils, eosinophils, a subpopulation of cytotoxic T cells (i.e. CD8+ T cells), thalamus, ovary, and spleen, and, in the central nervous system, by the frontal cortex, pons, hippocampus, and at lower levels, hypothalamus and caudate nucleus/putamen. These transcripts are also detected in fetal liver and thymus.
Ligands
Activating ligands The following standard prostaglandins have the following relative affinities and potencies in binding to and activating DP2: PGD2>>PGF2alpha=PGE2>PGI2=thromboxane A2. The cyclopentenone prostaglandins, PGJ2, Δ12-PGJ2, and 15-d-Δ12,14-PGJ2 are spontaneously formed or protein-facilitated derivatives of PGD2 that are generated in vitro as well as in vivo; these derivatives have binding affinities and activating potencies on DP2 that are similar to PGD2. Studies suggest that at least some if not most or all of the cytotoxic effects of cylopenenone prostaglandin derivatives of PGD2 act independently of DP2. Certain metabolites and derivatives of PGD2 viz., 13,14-dihydro-15-keto-PGD2 and 15(S)-15-methyl-PGD2, are ~10-fold less active than PGD2 while the drug indomethacin is weak in activating DP2.
Inhibiting ligands The following compounds are selective receptor antagonists of and thereby inhibit the activation of DP2: fevipiprant, setipiprant, ADC-3680, AZD-1981, MK-1029, MK-7246, OC-459, OC000459, QAV-680, and TM30089. Ramatroban and vidupiprant are non-selective (i.e. known to influence other receptors) antagonists of DP2.
Mechanisms of cell activation G protein-coupled receptors (GPCRs) such as DP2 are integral membrane proteins that, when bound by their cognate ligands (or, in some cases, even when not ligand-bound and thereby acting continuously in a constitutive manner {see Receptor (biochemistry)#Constitutive activity}), mobilize one or more types of Heterotrimeric G proteins. DP2 is classified as a "contractile" prostanoid receptor in that it can cause the contraction of smooth muscle. As evidenced by its initial discovery as a receptor for PGD2 in T-helper type 2 cells, activated DP2 triggers Gi alpha subunit-linked heterotrimeric G proteins to dissociate into their component a) Gi alpha subunits (also termed Giα subunits) inhibit adenylyl cyclase b) G beta-gamma complex of subunits (Gβγ) have many potential functions, including simulation of phospholipase C to cleave phosphatidylinositol triphosphate into inositol triphosphate (IP3) and diacylglycerol (DAG), inhibition or stimulation of adenylyl cyclase depending on the isoform, activation of GIRK channels and activation of GRK. IP3 raises cytosolic Ca2 levels thereby regulating Ca2-sensitive signal pathways; DAG activates certain protein kinase C enzymes )PKCs) that phosphorylate and thereby regulate target proteins involved in cell signaling; and adenyl cyclase converts AMP into cyclic AMP (cAMP) thereby down-regulating cAMP-responsive proteins involved in cell signalling. Concurrently with the mobilization of these pathways, activated DP2 also mobilizes G protein-coupled receptor kinases (GRKs, GRK2, GRK3, and/or GRK6) and Arrestin-2 (also termed Arrestin beta 1 or β-arrestin). The GRKs, along with the DAG-activated PKCs, phosphorylate DP2 to promote its internalization while arrestin-2 inhibits DP2 from further activating heterotrimeric G proteins while also linking DP2 to elements, clathrin and clathrin adaptor AP2, of the receptor internalization machinery. These pathways render DP2 unable to mobilize heterotrimereic G proteins thereby rendering the cell less sensitive or insensitive to further stimulation by DP ligands. The process, termed Homologous desensitization, serves as a physiological limiter of cell responses to DP2 activators.
Function
… excerpt ends here. Continue reading the full article.
