Prostaglandin DP2 receptor
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| Location (UCSC) | Chr 11: 60.85 – 60.86 Mb | Chr 19: 10.91 – 10.92 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human
Gene
The PTGDR2 gene is located on human chromosome 11 at position q12.2 (i.e. 11q12.2). It consists of two
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.[8][7][9]
Ligands
Activating ligands
The following standard prostaglandins have the following relative affinities and potencies in binding to and activating DP2: PGD2>>
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.[9]
Mechanisms of cell activation
G protein-coupled receptors (GPCRs) such as DP2 are
Function
Allergy
Ligands that activate DP2 stimulate the
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)
Embryogenesis
Studies in Dp2 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 of meiosis through repression of Stra8.[17]
Human genomics studies
The 1544G-1651G
Clinical studies
Allergic Diseases
Setipiprant (ACT-129968), a selective, orally active antagonist of the (DP2) receptor, proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patient clinical 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 (see setipiprant).[24]
Patients with the chronic spontaneous urticarial form of hives 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 allergic rhinitis[27] and a study on the effectiveness of OC000459, a DP2 receptor antagonist, in reducing the exacerbation of asthma induced by experimentally-induced rhinovirus infection in subjects[28] has just been completed or is underway, respectively.
Other diseases and conditions
Baldness
Acting through DP2, PGD2 can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment.
See also
- Prostaglandin DP1 receptor
- Prostaglandin receptors
- Prostanoid receptors
- Eicosanoid receptor
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000183134 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034117 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: GPR44 G protein-coupled receptor 44".
- ^ "PTGDR2 prostaglandin D2 receptor 2". Gene Resources NCBI.
- ^ PMID 10036181.
- ^ PMID 22544936.
- ^ a b c "DP2 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
- ^ PMID 18946232.
- ^ PMID 21508345.
- ^ PMID 25179301.
- PMID 20035740.
- PMID 25343148.
- ^ PMID 25541289.
- S2CID 207058745.
- PMID 25269616.
- ^ PMID 27708579.
- S2CID 24547755.
- ^ "No items found - Gene - NCBI". www.ncbi.nlm.nih.gov.
- S2CID 10104511.
- S2CID 5222512.
- S2CID 8226504.
- S2CID 19977989.
- PMID 26194547.
- ^ "Efficacy and Safety of Chemoattractant Receptor-homologous Molecule Expressed on T Helper Type 2 (CRTh2) Antagonist AZD1981 in Chronic Idiopathic Urticaria (CIU) Antihistamines - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 13 June 2017.
- ^ Clinical trial number NCT00784732 for "A Study to Compare the Efficacy of QAV680 Against Placebo in Treating Seasonal Allergic Rhinitis in an Environmental Exposure Chamber" at ClinicalTrials.gov
- ^ Clinical trial number NCT02660489 for "Effect of OC459 on the Response to Rhinovirus Challenge in Asthma" at ClinicalTrials.gov
- PMID 22440736.
- S2CID 6326585.
- ^ Clinical trial number 2A Study of Setipiprant Tablets in Androgenetic Alopecia in Males NCT02781311Phase 2A Study of Setipiprant Tablets in Androgenetic Alopecia in Males at ClinicalTrials.gov
Further reading
- Nagata K (2004). "CRTH2". Journal of Biological Regulators and Homeostatic Agents. 17 (4): 334–7. PMID 15065763.
- Chiba T, Kanda A, Ueki S, Ito W, Yamaguchi K, Kamada Y, Takeda M, Tanigai T, Oyamada H, Kayaba H, Chihara J (2007). "Possible novel receptor for PGD2 on human bronchial epithelial cells". International Archives of Allergy and Immunology. 143 (Suppl 1): 23–7. S2CID 29630170.
- Nagata K, Tanaka K, Ogawa K, Kemmotsu K, Imai T, Yoshie O, Abe H, Tada K, Nakamura M, Sugamura K, Takano S (February 1999). "Selective expression of a novel surface molecule by human Th2 cells in vivo". Journal of Immunology. 162 (3): 1278–86. S2CID 43616076.
- Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata K (January 2001). "Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2". The Journal of Experimental Medicine. 193 (2): 255–61. PMID 11208866.
- Hirai H, Tanaka K, Takano S, Ichimasa M, Nakamura M, Nagata K (February 2002). "Cutting edge: agonistic effect of indomethacin on a prostaglandin D2 receptor, CRTH2". Journal of Immunology. 168 (3): 981–5. PMID 11801628.
- Iwasaki M, Nagata K, Takano S, Takahashi K, Ishii N, Ikezawa Z (September 2002). "Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis". The Journal of Investigative Dermatology. 119 (3): 609–16. PMID 12230502.
- Böhm E, Sturm GJ, Weiglhofer I, Sandig H, Shichijo M, McNamee A, Pease JE, Kollroser M, Peskar BA, Heinemann A (February 2004). "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". The Journal of Biological Chemistry. 279 (9): 7663–70. PMID 14668348.
- Huang JL, Gao PS, Mathias RA, Yao TC, Chen LC, Kuo ML, Hsu SC, Plunkett B, Togias A, Barnes KC, Stellato C, Beaty TH, Huang SK (November 2004). "Sequence variants of the gene encoding chemoattractant receptor expressed on Th2 cells (CRTH2) are associated with asthma and differentially influence mRNA stability". Human Molecular Genetics. 13 (21): 2691–7. PMID 15345705.
- 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. PMID 15507393.
- Gazi L, Gyles S, Rose J, Lees S, Allan C, Xue L, Jassal R, Speight G, Gamble V, Pettipher R (January 2005). "Delta12-prostaglandin D2 is a potent and selective CRTH2 receptor agonist and causes activation of human eosinophils and Th2 lymphocytes". Prostaglandins & Other Lipid Mediators. 75 (1–4): 153–67. PMID 15789622.
- Hata AN, Lybrand TP, Breyer RM (September 2005). "Identification of determinants of ligand binding affinity and selectivity in the prostaglandin D2 receptor CRTH2". The Journal of Biological Chemistry. 280 (37): 32442–51. PMID 16030019.
- Sandig H, Andrew D, Barnes AA, Sabroe I, Pease J (January 2006). "9alpha,11beta-PGF2 and its stereoisomer PGF2alpha are novel agonists of the chemoattractant receptor, CRTH2". FEBS Letters. 580 (2): 373–9. S2CID 83931863.
- Schratl P, Royer JF, Kostenis E, Ulven T, Sturm EM, Waldhoer M, Hoefler G, Schuligoi R, Lippe IT, Peskar BA, Heinemann A (October 2007). "The role of the prostaglandin D2 receptor, DP, in eosinophil trafficking". Journal of Immunology. 179 (7): 4792–9. PMID 17878378.
External links
- "Prostanoid Receptors: DP2". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2008-12-09.
- GPR44+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.