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.

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).

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.

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.

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.

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 Gi_α subunits) inhibit adenylyl cyclase b) G beta-gamma complex of subunits (G_βγ) 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.

Ligands that activate DP₂ stimulate the in vitro chemotaxis (i.e. directed migration) of leukocytes active in mediating allergic responses viz., eosinophils, basophils, and Th2 cells. DP₂ activation also stimulates eosinophils and basophils to release the many pro-allergic elements of their granules to the extracellular milieu. Ligand-induced activation of DP₂ has similar activities in vivo it stimulates the accumulation on and activation of eosinophils, basophils, and Th2 cells at sites of nascent inflammation in animal models. PGD₂, acting through DP₂, stimulates the in vitro chemotaxis of CD8+ cells, although the contribution of this to the in vivo function of DP₂ has not been clarified.

PDP₂ receptor antagonists have been shown to allergic reactions induced in the airways mice and sheep as well as the airways and nose of guinea pigs.