Prostaglandin D2 receptor 2 (DP2 orCRTH2) is a humanprotein encoded by thePTGDR2 gene.[5] DP2 has also been designated asCD294 (cluster of differentiation 294). It is a member of the class ofprostaglandin receptors which bind with and respond to variousprostaglandins. DP2 along withprostaglandin DP1 receptor are receptors forprostglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognatereceptor 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 following standard prostaglandins have the following relative affinities and potencies in binding to and activating DP2: PGD2>>PGF2alpha=PGE2>PGI2=thromboxane A2. Thecyclopentenone 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 drugindomethacin is weak in activating DP2.[9]
The following compounds are selectivereceptor 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.[9]
G protein-coupled receptors (GPCRs) such as DP2 areintegral 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 {seeReceptor (biochemistry)#Constitutive activity}), mobilize one or more types ofHeterotrimeric 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 componenta)Gi alpha subunits (also termed Giα subunits) inhibitadenylyl cyclaseb)G beta-gamma complex of subunits (Gβγ) have many potential functions, including simulation ofphospholipase C to cleave phosphatidylinositol triphosphate intoinositol triphosphate (IP3) anddiacylglycerol (DAG), inhibition or stimulation ofadenylyl 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 certainprotein kinase C enzymes )PKCs) that phosphorylate and thereby regulate target proteins involved in cell signaling; and adenyl cyclase convertsAMP intocyclic AMP (cAMP) thereby down-regulating cAMP-responsive proteins involved in cell signalling.[10][11] Concurrently with the mobilization of these pathways, activated DP2 also mobilizesG protein-coupled receptor kinases (GRKs, GRK2, GRK3, and/or GRK6) andArrestin-2 (also termedArrestin 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 adaptorAP2, of the receptor internalization machinery. These pathways render DP2 unable to mobilize heterotrimereic G proteins[12] thereby rendering the cell less sensitive or insensitive to further stimulation by DP ligands. The process, termedHomologous desensitization, serves as a physiological limiter of cell responses to DP2 activators.[12][13][14]
Ligands that activate DP2 stimulate thein vitrochemotaxis (i.e. directed migration) ofleukocytes active in mediating allergic responses viz.,eosinophils,basophils, andTh2 cells. DP2 activation also stimulates eosinophils and basophils to release the many pro-allergic elements of their granules to the extracellular milieu.[10] Ligand-induced activation of DP2 has similar activitiesin vivo it stimulates the accumulation on and activation of eosinophils, basophils, and Th2 cells at sites of nascent inflammation in animal models.[11] PGD2, acting through DP2, stimulates the in vitro chemotaxis ofCD8+ cells, although the contribution of this to thein vivo function of DP2 has not been clarified.[15]
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.[15]
Mice genetically engineered to be deficient in DP2 (i.e. DP2−/-) mice are defective in mounting asthmatic responses in models of:a) allergen-induced asthma,b) dermal allergy,c)ACTH andcortisol release in response to inflammatory stimuli, andc) perception of pain caused by inflammation in peripheral tissues.[10][11][16] DP2−/- mice are also highly resistant to the gram (-) bacterial sepsis caused by cecal ligation and puncture; the protective effect was associated with lower bacterial load and lower production of pro-inflammatory cytokines (i.e. TNF-α, IL-6, and CCL3) and increased production of an anti-inflammatory cytokine (IL-10).[8]
Studies inDp2 gene-deficient (i.e. Dp2−/-) mice indicate that DP2 is essential for controlling cell cycle genes in fetal testes which contribute to the arrest of mitotic process and to the differentiate of germ cells. This control involves, at least in part, the DP2-dependent activation of the male germ cell marker Nanos2 and the inhibition ofmeiosis through repression of Stra8.[17]
The 1544G-1651Ghaplotype in the3'-untranslated region of theDP2 gene increased the stability of the gene'smRNA; this haplotype has been associated with an increased incidence of asthma in Chinese population and African but not Japanese sampling studies.[18][19] The rs11571288 C/GSingle-nucleotide polymorphism (SNP) variant[20] ofDP2 has been associated with an increase in the percentage of circulating eosinophils, an increase in the expression of DP2 by these cells, an enhanced rate of differentiation of precursor cells to Th2 cells in culture, enhanced Th2 cytokine (i.e.IL-4 andIL-13) production by these cells, and an increased incidence of asthma in a sampling of multi-ethnic Caucasian Canadians.[18][21]
Setipiprant (ACT-129968), a selective, orally activeantagonist of the DP2 receptor, proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patientclinical trials.[22][23] However, the drug, while supporting the concept that DP2 contributes to asthmatic disease, did not show sufficient advantage over existing drugs and was discontinued from further development for this application (seesetipiprant).[24]
Patients with the chronic spontaneous urticarial form ofhives exhibit significantly lower surface membrane expression of the DP22 receptor on their blood eosinophils and basophils, a result fully consistent with this receptor being initially activated and subsequently desensitization (refer to above section on "Mechanisms of cell activation").[25] The DP2 receptor antagonist, AZD1981, is in a phase 2 clinical trial for the treatment of chronic idiopathic urticarial.[26]
A randomized, partially-blinded, placebo-controlled, two-way crossover, proof of concept study comparing the efficacy of the DP2 receptor antagonist, QAV680, in the treatment of allergicrhinitis[27] and a study on the effectiveness of OC000459, a DP2 receptor antagonist, in reducing the exacerbation of asthma induced by experimentally-inducedrhinovirus infection in subjects[28] has just been completed or is underway, respectively.
Acting through DP2, PGD2 can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment.[29] A potential drug for blocking the DP2 receptor and thereby ameliorating baldness is the compoundsetipiprant.[30] A phase 2A study is underway to evaluate the safety, tolerability, and efficacy of oral setipiprant relative to aplacebo in 18- to 49-year-old males with androgeneticalopecia.[31]
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^abHohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y (2014). "Prostanoid receptors and acute inflammation in skin".Biochimie. 107 Pt A:78–81.doi:10.1016/j.biochi.2014.08.010.PMID25179301.
^Roy SJ, Parent A, Gallant MA, de Brum-Fernandes AJ, Stanková J, Parent JL (2010). "Characterization of C-terminal tail determinants involved in CRTH2 receptor trafficking: identification of a recycling motif".European Journal of Pharmacology.630 (1–3):10–8.doi:10.1016/j.ejphar.2009.12.022.PMID20035740.
^Maeda Y, Hizawa N, Takahashi D, Fukui Y, Konno S, Nishimura M (2007). "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".International Archives of Allergy and Immunology.142 (1):51–8.doi:10.1159/000095998.PMID17016057.S2CID24547755.
^Campos Alberto E, Maclean E, Davidson C, Palikhe NS, Storie J, Tse C, Brenner D, Mayers I, Vliagoftis H, El-Sohemy A, Cameron L (2012). "The single nucleotide polymorphism CRTh2 rs533116 is associated with allergic asthma and increased expression of CRTh2".Allergy.67 (11):1357–64.doi:10.1111/all.12003.PMID22947041.S2CID10104511.
^Sidharta PN, Diamant Z, Dingemanse J (2014). "Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects".Fundamental & Clinical Pharmacology.28 (6):690–9.doi:10.1111/fcp.12079.PMID24734908.S2CID8226504.
^Norman P (2014). "Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs".Expert Opinion on Investigational Drugs.23 (1):55–66.doi:10.1517/13543784.2013.839658.PMID24073896.S2CID19977989.
^Clinical trial numberNCT00784732 for "A Study to Compare the Efficacy of QAV680 Against Placebo in Treating Seasonal Allergic Rhinitis in an Environmental Exposure Chamber" atClinicalTrials.gov
^Clinical trial numberNCT02660489 for "Effect of OC459 on the Response to Rhinovirus Challenge in Asthma" atClinicalTrials.gov
^Mathiesen JM, Christopoulos A, Ulven T, Royer JF, Campillo M, Heinemann A, Pardo L, Kostenis E (April 2006). "On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2".Molecular Pharmacology.69 (4):1441–53.doi:10.1124/mol.105.017681.PMID16418339.S2CID6326585.
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Venet F, Lepape A, Debard AL, Bienvenu J, Bohé J, Monneret G (December 2004). "The Th2 response as monitored by CRTH2 or CCR3 expression is severely decreased during septic shock".Clinical Immunology.113 (3):278–84.doi:10.1016/j.clim.2004.07.005.PMID15507393.
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