Prostacyclin receptor

From Wikipedia, the free encyclopedia
Jump to: navigation, search
PTGIR
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PTGIR, IP, PRIPR, prostaglandin I2 (prostacyclin) receptor (IP)
External IDs MGI: 99535 HomoloGene: 7496 GeneCards: PTGIR
RNA expression pattern
PBB GE PTGIR 206187 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000960

NM_008967

RefSeq (protein)

NP_000951

NP_032993

Location (UCSC) Chr 19: 46.62 – 46.63 Mb Chr 7: 16.91 – 16.91 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

The Prostacyclin receptor , also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.


Gene[edit]

The PTGIR gene is located on human chromosome 19 at position q13.32 (i.e. 19q13.32), contains 6 exons, and codes for a G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14).[3]

Expression[edit]

IP is most highly expressed in brain and thymus and is readily detected in most other tissues. It is found throughout the vascular network on endothelium and smooth muscle cells.[3][4]

Ligands[edit]

Activating ligands[edit]

Standard prostanoids have the following relative efficacies as receptor ligands in binding to and activating IP: PGI2>>PGD2=PGE2=PGF2α>TXA2. In typical binding studies, PGI2 has one-half of its maximal binding capacity and cell-stimulating actions at ~1 nanomolar whereas the other prostaglandins are >50-fold to 100-fold weaker than this. However, PGI2 is very unstable, spontaneously converting to a far less active derivative 6-keto-PGF1 alpha within 1 minute of its formation. This instability makes defining the exact affinity of PGI2 for IP difficult. It also makes it important to have stable synthetic analogs of PGI2 for clinical usage. The most potent of these receptor agonists for binding to and activating IP are iloprost, taprostene, and esuberaprost which have Kd values (i.e. concentrations which bind to half of available IP receptors) in the low nanamole/liter range (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).[5]

Inhibiting ligands[edit]

Several synthetic compounds bind to, but do not activate, IP and thereby inhibit its activation by the activating ligands just described. These receptor antagonists include RO1138452, RO3244794, TG6-129, and BAY-73-1449, all of which have Kd values for IP at or beneath low nanomol/liter levels (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).

Mechanism of cell activation[edit]

IP is classified as a relaxant type of prostenoid receptor based on its ability, upon activation, to relax certain pre-contracted smooth muscle preparations and smooth muscle-containing tissues such as those of pulmonary arteries and veins.[6] When bound to PGI2 or other of its agonists, IP stimulates one or more of three types of G protein complexes, depending on cell type: a) Gs alpha subunit-Gβγ complexes which release Gs that then stimulates adenyl cyclase to raise intracellular levels of cAMP and thereby activate cAMP-regulated protein kinases A-dependent cell signaling pathways (see PKA); b) Gq alpha subunit-Gβγ complexes which release Gq that then stimulates other cell signaling pathways (e.g. phospholipase C/IP3/cell Ca2+ mobilization/diacylglycerol/protein kinase Cs, calmodulin-modulated myosin light chain kinase, RAF/MEK/Mitogen-activated protein kinases, PKC/Ca2+/Calcineurin/Nuclear factor of activated T-cells; and EGF cellular receptors; and c) Gi alpha subunit-Giβγ) complexes which releases Gi that then simulates phospholipase C to cleave phosphatidylinositol triphosphate into inositol triphosphate that raises intracellular CaCa2 levels thereby regulating Calcium signaling pathways and diacylglycerol that activates certain protein kinase C enzymes )that phosphorylate and thereby regulate target proteins involved in cell signaling (see Protein kinase C#Function). Studies suggest that stimulation of Gsβγ complexes is required for activation of the Gqβγ- and Giβγ-dependent pathways.[5][7][8][9] In certain cells, activation of FP also stimulates G12/G13-Gβγ G proteins to activate the Rho family of GTPases signaling proteins and Gi-Gβγ G proteins to activateRaf/MEK/mitogen-activated kinase pathways.

Functions[edit]

Studies using animals genetically engineered to lack FP and examining the actions of EP4 receptor agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. It has been regarded as the most successful therapeutic target among the 9 prostanoid receptors.[8]

Platelets[edit]

IP gene knockout mice (i.e. IP(-/-) mice) exhibit increased tendency to thrombosis in response to experimentally-induced Endothelium, a result which appears to reflect, at least in part, the loss of IP's anti-platelet activity.[10][11] IP activation of animal and human platelets inhibits their aggreatation response and as one consequence of this inhibition of platelet-dependent blood clotting. The PGI2-IP axis along with the production of nitric oxide, acting together additively and potentially synergistically, are powerful and physiological negative regulators of platelet function and thereby blood clotting in humans. Studies suggest that the 2-IP axis is impaired in patients with a tendency to develop pathological thrombosis such as occurs in obesity, diabetes, and coronary artery disease.[8][12]

Cardiovascular system[edit]

IP activation stimulates the dilation of arteries and veins in various animal models as well as in humans. It increases the blood flow through, for example, the pulmonary, coronary, retinal and choroid circulation. Inhaled PGI2 causes a modest fall in diastolic and small fall in systolic blood pressure in humans. This action involves IP's ability to relax vascular smooth muscle and is considered to be one of the fundamental functions of IP receptors. Furthermore, IP(-/-) mice on a high salt diet develop significantly higher levels of hypertension, cardiac fibrosis, and cardiac hypertrophy than control mice. The vasodilating and, perhaps, platelet-inhibiting effects of IP receptors likely underlie its ability suppress hypertension and protect tissues such as the heart in this model as well as the heart, brain, and gastrointestinal tract in various animal models of ischemic injury.[8] Indeed, IP agonists are used to treat patients pathological vasoconstriction diseases.[13] The injection of IP activators into the skin of rodents increases local capillary permeability and swelling; IP(-/-) mice fail to show this increased capillary permeability and swelling in response not only to IP activators but also in a model of carrageenan- or bradykinin-induced paw edema. IP antagonists likewise reduce experimentally-induced capillary permeability and swelling in rats. This actions is also considered a physiological function of IP receptors,[5][8] but can contribute to the toxicity of IP activators in patients by inducing, for example, life-threatening pulmonary edema.[13]

IP activators inhibit the adherence of circulating platelets and leukocytes adherence to vascular endothelium thereby blocking their entry into sites of tissue disturbance. The activators also inhibit vascular smooth muscle cells from proliferation by blocking these cells' growth cycle and triggering their apoptosis (i.e. cell death]]. These actions, along with its anti-inflammatory effects, may underlie the ability of IP gene knockout in an ApoE(−/−) mosue model to cause an accelerated rate of developing atherosclerosis.[5] [8]

Inflammation[edit]

Mouse studies indicate that the PGI2-IP axis activates cellular signaling pathways that tend to suppress allergic inflammation. The axis inhibits bone marrow-derived dendritic cells (i.e. antigen-presenting cells that process antigen material, present it on their surfaces for delivery to T cells, and otherwise regulate innate and adaptive immune system responses) from producing pro-inflammatory cytokines (e.g. IL-12, TNF-alpha, IL-1-alpha, and IL-6) while stimulating them to increase production of the anti-inflammatory cytokine, IL-10. IP receptor activation of these cells also blocks their lipopolysaccharide-stimulated expression of pro-inflammatory cell surface proteins (i.e. CD86, CD40, and MHC class II molecules) that are critical for developing adaptive immune responses. IL receptor-activated bone marrow-derived dendritic cells showed a greatly reduced ability to stimulate the proliferation of T helper cell as well as the ability of these cells to produce pro-allergic cytokines (i.e. IL-5 and IL-13)s. In a mouse model of allergic inflammation, PGI2 reduced the maturation and migration of lung mature dendritic cells to Mediastinal lymph nodes while increasing the egress of immature dendritic cells away from the lung. These effects resulted in a decrease in allergen-induced responses of the cells mediating allergic reactivity, TH-2 cells. These IP-induced responses likely contribute to its apparent function in inhibiting certain mouse inflammation responses as exemplified by the failure of IP receptor deficient mice to develop full lung airway allergic responses to ovalbumin in a model of allergic inflammation.[5][4]

In human studies, PGI2 failed to alter bronchoconstriction responses to allergen but did protect against exercise-induced and ultrasonic water-induced bronchoconstriction in asthmatic patients. It also caused bronchodilation in two asthmatic patients. However, these studies were done before the availability of potent and selective IP agonists. These agonists might produce more effective inhibitor results on airways allergic diseases but their toxicity (e.g. pulmonary edema, hypotension) has tended to restrict there study in asthmatic patients.[4]

IP receptors also appear involved in suppressing non-allergic inflammatory responses. IP receptor-deficient mice exhibit a reduction in the extent and progression of inflammation in a model of collagen-induced arthritis. This effect may result from regulating the expression of arthritis-related, pro-inflammatory genes (i.e. those for IL-6, VEGF-A, and RANKL).[6][8] On the other hand, IP receptors may serve to promote non-allergic inflammatory responses: IP receptor-deficient mice exhibited increased lung inflammation in a model of bleomycin-induced pulmonary fibrosis while mice made to over-express the PGI2-forming enzyme, Prostacyclin synthase, in their airway epithelial cells were protected against lung injury in this model.[4]

Pain perception[edit]

IP(-/-) mice exhibit little or no writhing responses in an acetic acid-induced pain model. The mouse IP receptor also appears to be involved in the development of heat-induced hyperalgesia. These and further studies using IP receptor antagonists in rats indicate that IP receptors on pain-perceiving sensory neurons of the dorsal root ganglia as well as on certain neurons in the spinal cord transmit signals for pain, particularly pain triggered by inflammation.[5][8]

Clinical significance[edit]

Toxicity[edit]

IP receptor agonists, particularly when used intravenously, have been associated with the rapid development of pulmonary edema, hypotension, bleeding due to inhibition of platelet aggregation, and tachycardia.[14][15] Clinical use of these agonists is contraindicated in patients suffering many conditions. For example, the IP agonist iloprost is contraindicated in patients with unstable angina; decompensated cardiac failure (unless under close medical supervision); severe cardiac arrhythmias; congenital or acquired heart valve defects; increased risk of bleeding; a history of myocardial infarction in the past 6 months; or a history of cerebrovascular events (e.g. stroke) within 3 months.

Vasoconstriction[edit]

IP receptor agonists are front-line drugs to treat pulmonary hypertension. Major drugs in this category include PGI2 itself (i.e. epoprostenol), iloprost, treprostinil, and beraprost with epoprostenol being favored in some studies.[14][16][17] However, newly developed IP agonists with favorable pharmacological features such as Selexipag have been granted by the US FDA Orphan Drug status for the treatment of pulmonary hypertension. IP agonists are also to treat severe vasoconstriction in Raynaud's disease, Raynaud's disease-like syndromes, and scleroderma.[18][19] Epoprostenol causes improvements in hemodynamic parameters and oxygenation in patients suffering the acute respiratory distress syndrome but due to the limited number of randomized clinical trials and lack of studies investigating mortality, its use cannot be recommended as standard of care for this disease and should be reserved for those refractory to traditional therapies.[15] A meta-analysis of 18 clinical trials on the use of prostanoids including prinicpally IP receptor agonists on patients with sever lower limb peripheral artery disease due to diverse causes found that these drugs may reduce the extent of limb tissue that needed to be amputated. However, the studies did not support extensive use of prostanoids in patients with critical limb ischemia as an adjunct to revascularization or as an alternative to major amputation in cases which cannot undergo revascularization.[20]

Thrombotic diseases[edit]

IP receptor agonists have been used to treat Thromboangiitis obliterans, a disease involving blood clotting and inflammation of the small and medium-sized arteries and veins in the hands and feet.[21]

Genomic studies[edit]

An adenine (A) to cytosine (C) synonymous substitution at base 984 (i.e. A984C) in exon 3 of PTGIR' is the most frequent single nucleotide polymorphism (SNP) variant in a sampling of Japanese. This variant was associated with an increase in platelet activation responses in vitro and an increase in incidence of cerebral ischemia. Two other synonymous SNP variants, V53V and S328S, in PTGIR in an Italian population study were associated with enhanced platelet activation response and deep vein thrombosis.[22] The rare SNP variant 795C of 794T in the PTGIR gene is associated with an increased incidence of Aspirin-induced asthma and a greater percentage fall in the forced expiratory volume response of airways to inhalation of an aspirin like compound (lysine-acetyl salicylic acid) in a Korean population sample.[23][24]

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ a b https://www.ncbi.nlm.nih.gov/gene/5739
  4. ^ a b c d Claar D, Hartert TV, Peebles RS (2015). "The role of prostaglandins in allergic lung inflammation and asthma". Expert Review of Respiratory Medicine. 9 (1): 55–72. PMC 4380345Freely accessible. PMID 25541289. doi:10.1586/17476348.2015.992783. 
  5. ^ a b c d e f Ricciotti E, FitzGerald GA (2011). "Prostaglandins and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (5): 986–1000. PMC 3081099Freely accessible. PMID 21508345. doi:10.1161/ATVBAHA.110.207449. 
  6. ^ a b Matsuoka T, Narumiya S (2008). "The roles of prostanoids in infection and sickness behaviors". Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy. 14 (4): 270–8. PMID 18709530. doi:10.1007/s10156-008-0622-3. 
  7. ^ Oguma T, Asano K, Ishizaka A (2008). "Role of prostaglandin D(2) and its receptors in the pathophysiology of asthma". Allergology International. 57 (4): 307–12. PMID 18946232. doi:10.2332/allergolint.08-RAI-0033. 
  8. ^ a b c d e f g h Woodward DF, Jones RL, Narumiya S (2011). "International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress". Pharmacological Reviews. 63 (3): 471–538. PMID 21752876. doi:10.1124/pr.110.003517. 
  9. ^ Moreno JJ (2017). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis". European Journal of Pharmacology. 796: 7–19. PMID 27940058. doi:10.1016/j.ejphar.2016.12.004. 
  10. ^ Stitham J, Hwa J (2016). "Prostacyclin, Atherothrombosis and Diabetes Mellitus: Physiologic and Clinical Considerations". Current Molecular Medicine. 16 (4): 328–42. PMID 26980701. 
  11. ^ Narumiya S, Sugimoto Y, Ushikubi F (1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. PMID 10508233. 
  12. ^ Procter NE, Hurst NL, Nooney VB, Imam H, De Caterina R, Chirkov YY, Horowitz JD (2016). "New Developments in Platelet Cyclic Nucleotide Signalling: Therapeutic Implications". Cardiovascular Drugs and Therapy. 30 (5): 505–513. PMID 27358171. doi:10.1007/s10557-016-6671-4. 
  13. ^ a b 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. PMID 23850788. doi:10.1016/j.prostaglandins.2013.07.001. 
  14. ^ a b McGinn K, Reichert M (2016). "A Comparison of Inhaled Nitric Oxide Versus Inhaled Epoprostenol for Acute Pulmonary Hypertension Following Cardiac Surgery". The Annals of Pharmacotherapy. 50 (1): 22–6. PMID 26438636. doi:10.1177/1060028015608865. 
  15. ^ a b Searcy RJ, Morales JR, Ferreira JA, Johnson DW (2015). "The role of inhaled prostacyclin in treating acute respiratory distress syndrome". Therapeutic Advances in Respiratory Disease. 9 (6): 302–12. PMID 26294418. doi:10.1177/1753465815599345. 
  16. ^ Zhang H, Li X, Huang J, Li H, Su Z, Wang J (2016). "Comparative Efficacy and Safety of Prostacyclin Analogs for Pulmonary Arterial Hypertension: A Network Meta-Analysis". Medicine. 95 (4): e2575. PMC 5291571Freely accessible. PMID 26825901. doi:10.1097/MD.0000000000002575. 
  17. ^ Sitbon O, Vonk Noordegraaf A (2017). "Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience". European Respiratory Review : an Official Journal of the European Respiratory Society. 26 (143). PMID 28096285. doi:10.1183/16000617.0055-2016. 
  18. ^ Poredos P, Poredos P (2016). "Raynaud's Syndrome: a neglected disease". International Angiology : a Journal of the International Union of Angiology. 35 (2): 117–21. PMID 25673314. 
  19. ^ Young A, Namas R, Dodge C, Khanna D (2016). "Hand Impairment in Systemic Sclerosis: Various Manifestations and Currently Available Treatment". Current Treatment Options in Rheumatology. 2 (3): 252–269. PMID 28018840. doi:10.1007/s40674-016-0052-9. 
  20. ^ Vitale V, Monami M, Mannucci E (2016). "Prostanoids in patients with peripheral arterial disease: A meta-analysis of placebo-controlled randomized clinical trials". Journal of Diabetes and Its Complications. 30 (1): 161–6. PMID 26516035. doi:10.1016/j.jdiacomp.2015.09.006. 
  21. ^ Cacione DG, Macedo CR, Baptista-Silva JC (2016). "Pharmacological treatment for Buerger's disease". The Cochrane Database of Systematic Reviews. 3: CD011033. PMID 26967103. doi:10.1002/14651858.CD011033.pub3. 
  22. ^ Cornejo-García JA, Perkins JR, Jurado-Escobar R, García-Martín E, Agúndez JA, Viguera E, Pérez-Sánchez N, Blanca-López N (2016). "Pharmacogenomics of Prostaglandin and Leukotriene Receptors". Frontiers in Pharmacology. 7: 316. PMC 5030812Freely accessible. PMID 27708579. doi:10.3389/fphar.2016.00316. 
  23. ^ Kim SH, Choi JH, Park HS, Holloway JW, Lee SK, Park CS, Shin HD (2005). "Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma". Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology. 35 (5): 585–90. PMID 15898979. doi:10.1111/j.1365-2222.2005.02220.x. 
  24. ^ Thompson MD, Capra V, Clunes MT, Rovati GE, Stankova J, Maj MC, Duffy DL (2016). "Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies". Frontiers in Pharmacology. 7: 299. PMC 5131607Freely accessible. PMID 27990118. doi:10.3389/fphar.2016.00299. 

Further reading[edit]

  • Coleman RA, Smith WL, Narumiya S (1994). "International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes". Pharmacol. Rev. 46 (2): 205–29. PMID 7938166. 
  • Rauvala H, Peng HB (1997). "HB-GAM (heparin-binding growth-associated molecule) and heparin-type glycans in the development and plasticity of neuron-target contacts". Prog. Neurobiol. 52 (2): 127–44. PMID 9185236. doi:10.1016/S0301-0082(97)00007-5. 
  • Smyth EM, FitzGerald GA (2003). "Human prostacyclin receptor". Vitam. Horm. Vitamins & Hormones. 65: 149–65. ISBN 978-0-12-709865-4. PMID 12481546. doi:10.1016/S0083-6729(02)65063-0. 
  • Boie Y, Rushmore TH, Darmon-Goodwin A, et al. (1994). "Cloning and expression of a cDNA for the human prostanoid IP receptor". J. Biol. Chem. 269 (16): 12173–8. PMID 7512962. 
  • Katsuyama M, Sugimoto Y, Namba T, et al. (1994). "Cloning and expression of a cDNA for the human prostacyclin receptor". FEBS Lett. 344 (1): 74–8. PMID 7514139. doi:10.1016/0014-5793(94)00355-6. 
  • Ogawa Y, Tanaka I, Inoue M, et al. (1995). "Structural organization and chromosomal assignment of the human prostacyclin receptor gene". Genomics. 27 (1): 142–8. PMID 7665161. doi:10.1006/geno.1995.1016. 
  • Duncan AM, Anderson LL, Funk CD, et al. (1995). "Chromosomal localization of the human prostanoid receptor gene family". Genomics. 25 (3): 740–2. PMID 7759114. doi:10.1016/0888-7543(95)80022-E. 
  • Nakagawa O, Tanaka I, Usui T, et al. (1994). "Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system". Circulation. 90 (4): 1643–7. PMID 7923647. doi:10.1161/01.cir.90.4.1643. 
  • Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. PMID 8889548. doi:10.1101/gr.6.9.791. 
  • Sasaki Y, Takahashi T, Tanaka I, et al. (1997). "Expression of prostacyclin receptor in human megakaryocytes". Blood. 90 (3): 1039–46. PMID 9242534. 
  • Fisch A, Tobusch K, Veit K, et al. (1997). "Prostacyclin receptor desensitization is a reversible phenomenon in human platelets". Circulation. 96 (3): 756–60. PMID 9264479. doi:10.1161/01.cir.96.3.756. 
  • Smyth EM, Li WH, FitzGerald GA (1998). "Phosphorylation of the prostacyclin receptor during homologous desensitization. A critical role for protein kinase c". J. Biol. Chem. 273 (36): 23258–66. PMID 9722557. doi:10.1074/jbc.273.36.23258. 
  • Kömhoff M, Lesener B, Nakao K, et al. (1999). "Localization of the prostacyclin receptor in human kidney". Kidney Int. 54 (6): 1899–908. PMID 9853255. doi:10.1046/j.1523-1755.1998.00213.x. 
  • Hayes JS, Lawler OA, Walsh MT, Kinsella BT (1999). "The prostacyclin receptor is isoprenylated. Isoprenylation is required for efficient receptor-effector coupling". J. Biol. Chem. 274 (34): 23707–18. PMID 10446129. doi:10.1074/jbc.274.34.23707. 
  • Smyth EM, Austin SC, Reilly MP, FitzGerald GA (2000). "Internalization and sequestration of the human prostacyclin receptor". J. Biol. Chem. 275 (41): 32037–45. PMID 10889200. doi:10.1074/jbc.M003873200. 
  • Lawler OA, Miggin SM, Kinsella BT (2001). "Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to G(s)-, to G(i)-, and to G(q)-coupled effector signaling". J. Biol. Chem. 276 (36): 33596–607. PMID 11443126. doi:10.1074/jbc.M104434200. 
  • Zhang Z, Austin SC, Smyth EM (2001). "Glycosylation of the human prostacyclin receptor: role in ligand binding and signal transduction". Mol. Pharmacol. 60 (3): 480–7. PMID 11502878. 
  • Fortier I, Patry C, Lora M, et al. (2001). "Immunohistochemical localization of the prostacyclin receptor (IP) human bone". Prostaglandins Leukot. Essent. Fatty Acids. 65 (2): 79–83. PMID 11545623. doi:10.1054/plef.2001.0292. 

External links[edit]

  • "Prostanoid Receptors: IP1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.