Alternative titles; symbols
HGNC Approved Gene Symbol: PTGIR
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:46,610,687-46,625,089 (from NCBI)
Prostacyclin (also known as prostaglandin I2 or PGI2) is a labile metabolite of arachidonic acid produced in concert with the bis-enoic prostaglandins via the cyclooxygenase pathway. PGI2 plays a major physiologic role as a potent mediator of vasodilation and inhibitor of platelet activation. Thus, PGI2 causes relaxation of arterial smooth muscle and inhibition of platelet aggregation, degranulation, and shape change, and is therefore thought to be important in maintaining vascular homeostasis. The actions of PGI2 are mediated via specific cell surface IP receptors, members of the G protein-coupled receptor gene superfamily, which upon activation cause an elevation in intracellular cAMP via direct stimulation of adenylate cyclase. The distribution of IP receptors mirrors the physiologic actions of PGI2. Prostanoid receptors of the EP1 (176802), EP2 (176804), EP3 (176806), and EP4 (601586) types cloned in the mouse and/or human were reviewed by Coleman et al. (1994).
Boie et al. (1994) cloned the human IP receptor from a lung cDNA library. They found that the protein consists of 386 amino acid residues with a predicted molecular mass of 40,961, and has the 7 putative transmembrane domains characteristic of G protein-coupled receptors. Studies of the PTGIR gene product indicated that it is functionally coupled to a signaling pathway involving stimulation of intracellular cAMP production.
Duncan et al. (1995) mapped PTGIR to 19q13.3 by in situ hybridization. Ogawa et al. (1995) used human-rodent somatic cell hybrid DNAs to assign the gene to chromosome 19. By Southern blot analysis, they demonstrated a single copy of the human PTGIR gene in the human genome. The PTGIR gene spans approximately 7.0 kb and is composed of 3 exons separated by 2 introns. The first intron occurs in the 5-prime untranslated region, 13 bp upstream of the ATG start codon. The second intron is located at the end of the sixth transmembrane domain, thereby separating it from the downstream coding region and the 3-prime untranslated region. Ogawa et al. (1995) also characterized the putative cis-acting regulatory elements in the 5-prime flanking region of the gene.
Using a panel of interspecific backcross mice, Ishikawa et al. (1996) mapped the Ptgir gene to proximal mouse chromosome 7.
Murata et al. (1997) disrupted the prostacyclin receptor gene in mice by using homologous recombination in embryonic stem (ES) cells. The receptor-deficient mice were viable, fertile, and normotensive. However, their susceptibility to thrombosis was increased, and their inflammatory and pain responses were reduced to the levels observed in indomethacin-treated wildtype mice. The results established that prostaglandin is an antithrombotic agent in vivo and provided evidence for its role as a mediator of inflammation and pain.
Cheng et al. (2002) demonstrated that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor but are depressed in mice genetically deficient in the TXA2 receptor (188070) or treated with a TXA2 receptor antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TXA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX2 inhibitors, which, unlike aspirin and nonsteroidal antiinflammatory drugs, inhibit PGI2 but not TXA2.
In a 2-kidney, 1-clip model of renovascular hypertension, Fujino et al. (2004) demonstrated that the increase in blood pressure was significantly lower in Pgi2 receptor-deficient mice than in wildtype mice. Similarly, increases in plasma renin activity, renal renin mRNA, and plasma aldosterone were all significantly lower in Ip-null mice than in wildtype mice. A selective inhibitor of COX2, the enzyme that produces PGI2, significantly reduced the increases in plasma renin activity and renin mRNA expression in wildtype but not Ip-null mice. When the renin-angiotensin-aldosterone system was activated by salt depletion, the COX2 inhibitor blunted the response in wildtype but not Ip-null mice. Fujino et al. (2004) concluded that PGI2 derived from COX2 plays a critical role in regulating the release of renin and consequently in renovascular hypertension in vivo.
Boie, Y., Rushmore, T. H., Darmon-Goodwin, A., Grygorczyk, R., Slipetz, D. M., Metters, K. M., Abramovitz, M. Cloning and expression of a cDNA for the human prostanoid IP receptor. J. Biol. Chem. 269: 12173-12178, 1994. [PubMed: 7512962]
Cheng, Y., Austin, S. C., Rocca, B., Koller, B. H., Coffman, T. M., Grosser, T., Lawson, J. A., FitzGerald, G. A. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296: 539-541, 2002. [PubMed: 11964481] [Full Text: https://doi.org/10.1126/science.1068711]
Coleman, R. A., Smith, W. L., Narumiya, S. VIII. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharm. Rev. 46: 205-229, 1994. [PubMed: 7938166]
Duncan, A. M. V., Anderson, L. L., Funk, C. D., Abramovitz, M., Adam, M. Chromosomal localization of the human prostanoid receptor gene family. Genomics 25: 740-742, 1995. [PubMed: 7759114] [Full Text: https://doi.org/10.1016/0888-7543(95)80022-e]
Fujino, T., Nakagawa, N., Yuhki, K., Hara, A., Yamada, T., Takayama, K., Kuriyama, S., Hosoki, Y., Takahata, O., Taniguchi, T., Fukuzawa, J., Hasebe, N., Kikuchi, K., Narumiya, S., Ushikubi, F. Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I(2) receptor IP. J. Clin. Invest. 114: 805-812, 2004. [PubMed: 15372104] [Full Text: https://doi.org/10.1172/JCI21382]
Ishikawa, T., Tamai, Y., Rochelle, J. M., Hirata, M., Namba, T., Sugimoto, Y., Ichikawa, A., Narumiya, S., Taketo, M. M., Seldin, M. F. Mapping of the genes encoding mouse prostaglandin D, E, and F and prostacyclin receptors. Genomics 32: 285-288, 1996. [PubMed: 8833158] [Full Text: https://doi.org/10.1006/geno.1996.0118]
Murata, T., Ushikubi, F., Matsuoka, T., Hirata, M., Yamasaki, A., Sugimoto, Y., Ichikawa, A., Aze, Y., Tanaka, T., Yoshida, N., Ueno, A., Oh-ishi, S., Narumiya, S. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 388: 678-682, 1997. [PubMed: 9262402] [Full Text: https://doi.org/10.1038/41780]
Ogawa, Y., Tanaka, I., Inoue, M., Yoshitake, Y., Isse, N., Nakagawa, O., Usui, T., Itoh, H., Yoshimasa, T., Narumiya, S., Nakao, K. Structural organization and chromosomal assignment of the human prostacyclin receptor gene. Genomics 27: 142-148, 1995. [PubMed: 7665161] [Full Text: https://doi.org/10.1006/geno.1995.1016]