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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 386 | 19q13.32 | PTGIR | prostaglandin I2 receptor | 9,49 |
| Mouse | 7 | 415 | 7 9.15 cM | Ptgir | prostaglandin I receptor (IP) | 51 |
| Rat | 7 | 416 | 1q21 | Ptgir | prostaglandin I2 receptor | 59 |
| Previous and Unofficial Names |
| prostanoid IP receptor | prostacyclin receptor | prostaglandin I2 receptor | prostaglandin I2 (prostacyclin) receptor (IP) |
| Database Links |
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| Specialist databases | |
| GPCRdb | pi2r_human (Hs), pi2r_mouse (Mm), pi2r_rat (Rn) |
| Other databases | |
| Alphafold | P43119 (Hs), P43252 (Mm), P43253 (Rn) |
| ChEMBL Target | CHEMBL1995 (Hs), CHEMBL3322 (Rn) |
| DrugBank Target | P43119 (Hs) |
| Ensembl Gene | ENSG00000160013 (Hs), ENSMUSG00000043017 (Mm), ENSRNOG00000016756 (Rn) |
| Entrez Gene | 5739 (Hs), 19222 (Mm), 292661 (Rn) |
| Human Protein Atlas | ENSG00000160013 (Hs) |
| KEGG Gene | hsa:5739 (Hs), mmu:19222 (Mm), rno:292661 (Rn) |
| OMIM | 600022 (Hs) |
| Pharos | P43119 (Hs) |
| RefSeq Nucleotide | NM_000960 (Hs), NM_008967 (Mm), NM_001077644 (Rn) |
| RefSeq Protein | NP_000951 (Hs), NP_032993 (Mm), NP_001071112 (Rn) |
| UniProtKB | P43119 (Hs), P43252 (Mm), P43253 (Rn) |
| Wikipedia | PTGIR (Hs) |
| Natural/Endogenous Ligands |
| PGD2 |
| PGE1 |
| PGE2 |
| PGF2α |
| PGI2 |
| Comments: PGI2 is the principal endogenous agonist |
| Potency order of endogenous ligands |
| PGI2 >> PGE1 > PGD2, PGF2α > thromboxane A2 |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| References [12,31] use human platelet preparations instead of transfected cells. Stable analogues of prostacyclin (e.g. iloprost, carbacyclin, AFP-07) often show potent EP1 agonist and modest EP3 agonism; cicaprost is the most selective IP agonist [15,40]. Treprostinil has high affinity for the DP1 and EP2 receptors with pKi values of 8.36 and 8.44 respectively [76]. IP receptor agonism is generated by the introduction of a diaryl-heteroatomic unit into PGH analogues (e.g. EP-157) and other n-alkylcarboxylic acids (BMY-45778, ONO-1301, MRE-269) often designated as 'non-prostanoid prostacyclin mimetics' [32,43]. MRE 269 is the biologically-active metabolite of the pro-drug, NS304 (ACT-293987) which has the INN selexipag. |
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| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| RO-1138452 has similar pA2 values (8.1 - 8.4) for human, guinea-pig and rabbit IP receptors [33]. However, it also has moderately high affinity for imidazoline I2 and PAF receptors [8]. RO-3244794 appears to be more specific [8]. RO-1138452 may behave as a pseudo-irreversible antagonist [5,52]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulator Comments | ||
| A positive modulator for the human IP receptor has been reported (the [R] enantiomer of 1,2,3,4-tetrahydroisoquinoline derivative IPPAM-1) [83]. |
| Immunopharmacology Comments |
| Although primarily recognised for vasodilatory and antihypertensive action in pulmonary arterial hypertension (PAH) the importance of PGI2 as an immunomodulatory agent has been investigated more recently. PGI2 regulates both the innate and adaptive immune systems and its effects are thought to be mainly anti-inflammatory or immunosuppressive, which may have implications for clinical use. Note also that the prostacyclin analog, cicaprost, exhibits potent anti-inflammatory activity in human primary immune cells [72]. Papers have appeared on immune responses modulation by PGI2 via IP signaling [87], as well on PGI2 promoting in vivo Th17 differentiation, with possible clinical implications for the use of PGI2 and its analogs in PAH treatment [86]. |
| Immuno Process Associations | ||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gs family | Adenylyl cyclase stimulation |
| References: 51,60 | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
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Gi/Go family Gq/G11 family |
Adenylyl cyclase inhibition Phospholipase C stimulation |
| Comments: Gq signalling has been reported in heterologous expression systems but it is unclear whether this coupling occurs widely in native cells or tissues [44]. | |
| References: 44,60 | |
| Tissue Distribution
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| Functional Assays
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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| General Comments |
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Human IP forms homo-oligomers via disulfide bonds, which might be essential for receptor trafficking to the cell surface [19]. The IP receptor was the first to be described to form heterodimers, most interestingly with its physiologic opponent, the TP receptor, leading to unexpected TP-mediated cAMP formation [28,78-79]. Pharmacological evidence for a second IP receptor, denoted IP2, in the central nervous system [67,73] and in the BEAS-2B human airway epithelial cell line [80] is available. This receptor is selectively activated by 15R-17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin (15R-TIC) and 15R-Deoxy 17,18,19,20-tetranor-16-m-tolyl-isocarbacyclin (15-deoxy-TIC). However, molecular biological evidence for the IP2 subtype is currently lacking. |
1. Abramovitz M, Adam M, Boie Y, Carrière M, Denis D, Godbout C, Lamontagne S, Rochette C, Sawyer N, Tremblay NM et al.. (2000) The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta, 1483 (2): 285-93. [PMID:10634944]
2. Arehart E, Stitham J, Asselbergs FW, Douville K, MacKenzie T, Fetalvero KM, Gleim S, Kasza Z, Rao Y, Martel L et al.. (2008) Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circ Res, 102 (8): 986-93. [PMID:18323528]
3. Armstrong RA, Jones RL, MacDermot J, Wilson NH. (1986) Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics. Br J Pharmacol, 87 (3): 543-51. [PMID:3026540]
4. Armstrong RA, Lawrence RA, Jones RL, Wilson NH, Collier A. (1989) Functional and ligand binding studies suggest heterogeneity of platelet prostacyclin receptors. Br J Pharmacol, 97: 657-668. [PMID:2474350]
5. Ayer LM, Wilson SM, Traves SL, Proud D, Giembycz MA. (2008) 4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) is a selective, pseudo-irreversible orthosteric antagonist at the prostacyclin (IP)-receptor expressed by human airway epithelial cells: IP-receptor-mediated inhibition of CXCL9 and CXCL10 release. J Pharmacol Exp Ther, 324 (2): 815-26. [PMID:17962517]
6. 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 Mediat, 107: 48-55. [PMID:23850788]
7. Bexis S, McCormick PA, Docherty JR. (2008) Vascular actions of the prostacyclin receptor antagonist BAY 73-1449 in the portal hypertensive rat. Eur J Pharmacol, 590 (1-3): 322-6. [PMID:18603238]
8. Bley KR, Bhattacharya A, Daniels DV, Gever J, Jahangir A, O'Yang C, Smith S, Srinivasan D, Ford AP, Jett MF. (2006) RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol, 147 (3): 335-45. [PMID:16331286]
9. Boie Y, Rushmore TH, Darmon-Goodwin A, Grygorczyk R, Slipetz DM, Metters KM, Abramovitz M. (1994) Cloning and expression of a cDNA for the human prostanoid IP receptor. J Biol Chem, 269 (16): 12173-8. [PMID:7512962]
10. Bondesen BA, Jones KA, Glasgow WC, Pavlath GK. (2007) Inhibition of myoblast migration by prostacyclin is associated with enhanced cell fusion. FASEB J, 21 (12): 3338-45. [PMID:17488951]
11. Chan EC, Dusting GJ, Guo N, Peshavariya HM, Taylor CJ, Dilley R, Narumiya S, Jiang F. (2010) Prostacyclin receptor suppresses cardiac fibrosis: role of CREB phosphorylation. J Mol Cell Cardiol, 49 (2): 176-85. [PMID:20403362]
12. Chang CS, Negishi M, Nakano T, Morizawa Y, Matsumura Y, Ichikawa A. (1997) 7,7-Difluoroprostacyclin derivative, AFP-07, a highly selective and potent agonist for the prostacyclin receptor. Prostaglandins, 53 (2): 83-90. [PMID:9112287]
13. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GA. (2002) Role of prostacyclin in the cardiovascular response to thromboxane A2. Science, 296 (5567): 539-41. [PMID:11964481]
14. Clarke DL, Belvisi MG, Smith SJ, Hardaker E, Yacoub MH, Meja KK, Newton R, Slater DM, Giembycz MA. (2005) Prostanoid receptor expression by human airway smooth muscle cells and regulation of the secretion of granulocyte colony-stimulating factor. Am J Physiol Lung Cell Mol Physiol, 288 (2): L238-50. [PMID:15640521]
15. Dong YJ, Jones RL, Wilson NH. (1986) Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues. Br J Pharmacol, 87 (1): 97-107. [PMID:2420404]
16. Feoktistov I, Breyer RM, Biaggioni I. (1997) Prostanoid receptor with a novel pharmacological profile in human erythroleukemia cells. Biochem Pharmacol, 54 (8): 917-26. [PMID:9354592]
17. Francois H, Athirakul K, Howell D, Dash R, Mao L, Kim HS, Rockman HA, Fitzgerald GA, Koller BH, Coffman TM. (2005) Prostacyclin protects against elevated blood pressure and cardiac fibrosis. Cell Metab, 2 (3): 201-7. [PMID:16154102]
18. Ganesh T, Jiang J, Shashidharamurthy R, Dingledine R. (2013) Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists. ACS Med Chem Lett, 4 (7): 616-621. [PMID:23914286]
19. Giguère V, Gallant MA, de Brum-Fernandes AJ, Parent JL. (2004) Role of extracellular cysteine residues in dimerization/oligomerization of the human prostacyclin receptor. Eur J Pharmacol, 494 (1): 11-22. [PMID:15194446]
20. Grygorczyk R, Abramovitz M, Boie Y, Bastien L, Adam M. (1995) Detection of adenylate cyclase-coupled receptors in Xenopus oocytes by coexpression with cystic fibrosis transmembrane conductance regulator. Anal Biochem, 227: 27-31. [PMID:7545356]
21. Hara A, Yuhki K, Fujino T, Yamada T, Takayama K, Kuriyama S, Takahata O, Karibe H, Okada Y, Xiao CY et al.. (2005) Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptor. Circulation, 112 (1): 84-92. [PMID:15983244]
22. Hashimoto K, Graham BS, Geraci MW, FitzGerald GA, Egan K, Zhou W, Goleniewska K, O'Neal JF, Morrow JD, Durbin RK et al.. (2004) Signaling through the prostaglandin I2 receptor IP protects against respiratory syncytial virus-induced illness. J Virol, 78 (19): 10303-9. [PMID:15367596]
23. Hattori K, Tanaka A, Okitsu O, Tabuchi S, Taniguchi K, Nishio M, Koyama S, Higaki M, Seki J, Sakane K. (2005) Discovery of diphenylcarbamate derivatives as highly potent and selective IP receptor agonists: orally active prostacyclin mimetics. Part 3. Bioorg Med Chem Lett, 15 (12): 3091-5. [PMID:15914004]
24. Haye-Legrand I, Bourdillat B, Labat C, Cerrina J, Norel X, Benveniste J, Brink C. (1987) Relaxation of isolated human pulmonary muscle preparations with prostacyclin (PGI2) and its analogs. Prostaglandins, 33 (6): 845-54. [PMID:2445003]
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target has curated data in GtoImmuPdb
