Theprostaglandin D2 receptor 1 (DP1), aG protein-coupled receptor encoded by thePTGDRgene (also termedPTGDR1), is primarily a receptor forprostaglandin D2 (PGD2).[5] The receptor is a member of theprostaglandin receptors belonging to thesubfamily A14 of rhodopsin-like receptors. Activation of DP1 by PGD2 or other cognatereceptor ligands is associated with a variety of physiological and pathological responses in animal models.
ThePTGDR gene is located on chromosome 14 at position q22.1, (i.e. 14q22.1), a chromosomal locus associated with asthma and other allergic disorders.[6]PTGDR, which consists of 4introns and 5exons, encodes for a ~44kilodalton protein but also multiple alternative spliced transcript variants.[7]
PGD2 binds to and activates DP1 at concentrations in the 0.5 to 1nanomolar range. Relative potencies in binding to and activating DP1 for the followingprostanoids are: PGD2>>PGE2>prostaglandin F2α>PGI2=thromboxane A2, with PGD2 being more than 100-fold more potent than PGE2 in binding to and stimulating DP1.[13] PDJ2, Δ12-PDJ2, and 15-deoxy-Δ12,14-PGJ2, which form in vitro and in vivo rapidly as non-enzymatic rearrangements of PGD2 (seecyclopentenone prostaglandins), also bind to and activate DP1, with PDJ2 doing so almost as effectively as PDG2 and the latter two PGJs doing so 100-fold and 300-fold less potently than PDG2.[14][15] Other compounds, e.g. L-644,698, BW 245C, BW A868C, and ZK 110841, have been synthesized, found to be about as potent as PGD2 in binding to and stimulating DP1, and used to study the function of this receptor.[14]
The drugtreprostinil is a high affinity ligand for and potent activator of not only DP1 but also two other prostanoid receptors,EP2 andIP.[16]
Studies of experimentally-induced allergic responses in animals further implicate DP1 in allergy. DP1gene knockout and/or DP1 inhibition byreceptor antagonists markedly reduces airway inflammation, obstruction, hypersensitivity, and pro-allergiccytokine andchemokine production in a mouse model of ovalbumin-induced asthma as well as allergic symptoms in a guinea pig model of allergicconjunctivitis,rhinitis, and asthma.[8][9] The administration of PGD2 into the skin of rats or into the eyes of rabbits causes local symptoms of allery. These responses are thought, but not yet proved, to be mediated by DP1 activation.[9] In contrast to these results, however, activation of DP1 by intratrachael administration of a selective DP1 activator activated DP1 on dendritic cells to suppress airway allergic inflammation by increasing the number of Foxp3+ CD4+regulatory T cells.[22] Furthermore, DP1 activation reduces eosinophilia in allergic inflammation and blocks antigen-presentinglangerhans cell function in mice.[23] This results suggest that DP1 can promote or suppress allergic responses depending on the animal model tested and, perhaps, the type of allergic reaction investigated.
Allergen inhalation challenge of humans produces rises in the PGD2 levels in theirbronchoalveolar lavage fluids. Furthermore, the administration of PGD2 into the nose or skin of human volunteers produces local symptoms of allergy and the inhalation of PGD2 into asthmatics causes constriction of the airways as well as the potentiation of airway constriction responses.[9] These reactions, similar to those produced in animal studies, may be mediated by DP1.
PGD2 is the most abundant prostanoid in the brains of humans and other mammals and DP1 receptors are located onarachnoid mater trabecular cells in mouse basal forebrain. The PGD2-DP1 pathway is involved in the regulation of non-rapid eye movement sleep in rodents: infusion of PGD2 into the lateral ventricle of mice or the brain of rats induces an increase in the amount of non-rapid eye movement sleep in wild-type (WT) but not DP1-deficient animals. This sleep-induction appears to involve the DP1-dependent stimulation ofadenosine formation and subsequent simulation of theadenosine A2A receptor by adenosine.[24][25] In humans, a genetic variant of ADA associated with the reduced metabolism of adenosine to inosine has been reported to deep sleep and SWA during sleep. These studies suggest that DP1 has a similar role in the sleep of humans.[25]
Pulmonary arterial hypertension in humans is commonly treated with specific pulmonary artery vasodilators that increase survival such as the prostacyclin I2 (PGI2) mimetics includingtreprostinil,epoprostenol,iloprost, andberaprost. Recent studies find that DP1 as well as the PGI2 receptor protein are expressed in human pulmonary arteries and veins; that treprostinil but not iloprost caused pulmonary vein relaxation in part by acting through DP1 in insolated human pulmonary vascular preparations; and that the effect of treprostinil on DP1 in human pulmonary veins may contribute to its therapeutic efficacy in primary pulmonary hypertension.[26]
Studies in male mice indicate that DP1 activation induces the translocation ofSOX9 into the nucleus thereby signaling for the maturation ofSertoli cells and embryonicgonads. Disruption of this DP1-activated circuit leads to disordered maturation of the male reproductive organs such ascryptorchidism (i.e. failure of testes descent into the scrotum) in mice and, it is suggested, may also do so in humans.[10]
Humangenomics studies have associatedsingle-nucleotide polymorphism variants with an increased incidence of allergic diseases. Studies in two different populations have replicated associations between -549T>C, -441C>T, and -197T>C variants and a study in a single population has associated the -613C>T variation with increased incidences ofnasal polyposis, asthma, and/oraspirin sensitivity; the -197T>C and -613 C>T variants were also associated with increased incidences of allergic reactions to pollen and mites. A single population study associated the -731A>C variant and studies in two different population associated the 6651C>T variant with increased incidences of asthma and/or bronchial hyper-reactivity. The intrinsic variants rs17831675, rs17831682, and rs58004654 (now termed rs7709505) have been associated with an increased incidence of asthma in single population studies.[27] A metaanalasis −549 C/T, −441 C/T, and −197 C/T found that of these three variants, only −549 C/T conferred susceptibility to asthma in Europeans and that this susceptibility was limited to adults.[6]
^Yagami T, Koma H, Yamamoto Y (2016). "Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System".Molecular Neurobiology.53 (7):4754–71.doi:10.1007/s12035-015-9355-3.PMID26328537.S2CID11624385.
^Straus DS, Glass CK (2001). "Cyclopentenone prostaglandins: new insights on biological activities and cellular targets".Medicinal Research Reviews.21 (3):185–210.doi:10.1002/med.1006.abs.PMID11301410.
^Norman P (Jan 2014). "Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs".Expert Opin Investig Drugs.23 (1):55–66.doi:10.1517/13543784.2013.839658.PMID24073896.S2CID19977989.
^Hohjoh 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.
^Kagawa S, Fukunaga K, Oguma T, Suzuki Y, Shiomi T, Sayama K, Kimura T, Hirai H, Nagata K, Nakamura M, Asano K (2011). "Role of prostaglandin D2 receptor CRTH2 in sustained eosinophil accumulation in the airways of mice with chronic asthma".International Archives of Allergy and Immunology.155 (Suppl 1):6–11.doi:10.1159/000327257.PMID21646789.S2CID34914925.
^Benyahia C, Boukais K, Gomez I, Silverstein A, Clapp L, Fabre A, Danel C, Leséche G, Longrois D, Norel X (2013). "A comparative study of PGI2 mimetics used clinically on the vasorelaxation of human pulmonary arteries and veins, role of the DP-receptor".Prostaglandins & Other Lipid Mediators.107:48–55.doi:10.1016/j.prostaglandins.2013.07.001.PMID23850788.
Chiba T, Kanda A, Ueki S, et al. (2007). "Possible novel receptor for PGD2 on human bronchial epithelial cells".Int. Arch. Allergy Immunol.143 (Suppl 1):23–7.doi:10.1159/000101400.PMID17541272.S2CID29630170.
Ishikawa TO, Tamai Y, Rochelle JM, et al. (1997). "Mapping of the genes encoding mouse prostaglandin D, E, and F and prostacyclin receptors".Genomics.32 (2):285–8.doi:10.1006/geno.1996.0118.PMID8833158.
Noguchi E, Shibasaki M, Kamioka M, et al. (2002). "New polymorphisms of haematopoietic prostaglandin D synthase and human prostanoid DP receptor genes".Clin. Exp. Allergy.32 (1):93–6.doi:10.1046/j.0022-0477.2001.01261.x.PMID12002745.S2CID24779233.
Moreland RB, Nehra A, Kim NN, et al. (2003). "Expression of functional prostaglandin D (DP) receptors in human corpus cavernosum smooth muscle".Int. J. Impot. Res.14 (6):446–52.doi:10.1038/sj.ijir.3900900.PMID12494276.S2CID25830532.
Hirano Y, Shichijo M, Deguchi M, et al. (2007). "Synergistic effect of PGD2 via prostanoid DP receptor on TNF-alpha-induced production of MCP-1 and IL-8 in human monocytic THP-1 cells".Eur. J. Pharmacol.560 (1):81–8.doi:10.1016/j.ejphar.2007.01.003.PMID17307163.
"Prostanoid Receptors: DP1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2008-12-09.
