This page uses content from Wikipedia and is licensed under CC BY-SA.

Eicosanoid receptor

Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell (acting as an Autocrine signalling molecule) or on nearby cells (acting as a Paracrine signalling molecule) to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood (acting as a hormone-like messenger) to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction (see Fever § PGE2 release). An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.[1]

The following is a list of human eicosanoid GPCRs grouped according to the type of eicosanoid ligand that each binds:[2][3]





Resolvin E

Resolvin Es:

  • CMKLR1CMKLR1; CMKLR1, also termed Chemokine like receptor 1 or ChemR23, is the receptor for the eicosanoids resolvin E1 and 18S-resolvin E2 (see specialized pro-resolving mediators) as well as for chemerin, an adipokine protein; relative potencies in binding to and activating CMKLR1 are: resolvin E1>chemerin C-terminal peptide>18R-hydroxy-eicosapentaenoic acid (18R-EPE)>eicosapentaenoic acid ([]). Apparently, the resolvins activate this receptor in a different manner than chemerin: resolvins act through it to suppress while chemerin acts through it to stimulate pro-inflammatory responses in target cells[12][13][14]



  • Oxoeicosanoid (OXE) receptor 1OXER1; OXER1 is the receptor for 5-oxo-eicosatetraenoic acid (5-oxo-ETE) as well as certain other eicosanoids and long-chain polyunsaturated fatty acids that possess a 5-hydroxy or 5-oxo residue (see 5-Hydroxyeicosatetraenoic acid); relative potencies of the latter metabolites in binding to and activating OXER1 are: 5-oxoicosatetraenoic acid>5-oxo-15-hydroxy-eioxatetraenoic acid> 5S-hydroperoxy-eicosatetraenoic acid>5-Hydroxyeicosatetraenoic acid; the 5-oxo-eicosatrienoic and 5-oxo-octadecadienoic acid analogs of 5-oxo-ETE are as potent as 5-oxo-ETE in stimulating this receptor ([]). Activation of OXER1 is associated with pro-inflammatory and pro-allergic responses by cells and tissues as well as with the proliferation of various human cancer cell lines in culture.[16]


Prostanoids and Prostaglandin receptors

Prostanoids are prostaglandins (PG), thromboxanes (TX), and prostacyclins (PGI). Seven, structurally-related, prostanoid receptors fall into three categories based on the cell activation pathways and activities which they regulate. Relaxant prostanoid receptors (IP, DP1, EP2, and EP4) raise cellular cAMP levels; contractile prostanoid receptors (TP, FP, and EP1) mobilize intracellular calcium; and the inhibitory prostanoid receptor (EP3) lowers cAMP levels. A final prostanoid receptor, DP2, is structurally related to the chemotaxis class of receptors and unlike the other prostanoid receptors mediates eosinophil, basophil, and T helper cell (Th2 type) chemotactic responses. Prostanoids, particularly PGE2 and PGI2, are prominent regulators of inflammation and allergic responses as defined by studies primarily in animal models but also as suggested by studies with human tissues and, in certain cases, human subjects.[17]

  • PGD2: DP-(PGD2) (PGD2 receptor)
    • DP1 (PTGDR1) – PTGDR1; DP1 is a receptor for Prostaglandin D2; relative potencies in binding to and activating DP1 for the following prostanoids are: PGD2>>PGE2>PGF2α>PGI2=TXA2([]). Activation of DP2 is associated with the promotion of inflammatory and the early stage of allergic responses; in limited set of circumstances, however, DP1 activation may ameliorate inflammatory responses.[18]
    • DP2 (PTGDR2) – PTGDR2; DP2, also termed CRTH2, is a receptor for prostaglandin D2; relative potencies in binding to and stimulating PD2 are PGD2 >>PGF2α,PGE2>PGI2=TXA2 ([]). While DP1 activation causes the chemotaxis of pro-inflammatory cells such as basophils, eosinophils, and T cell lymphocytes, its deletion in mice is associated with a reduction in an acute allergic responses in a rodent model.[18] This and other observations suggest that DP2 and DP1 function to counteract each other.[19]
  • PGE2: EP-(PGE2) (PGE2 receptor)
    • EP1-(PGE2) (PTGER1) – PTGER1; EP1 is a receptor for prostaglandin E2; relative potencies in binding to and stimulating EP1 are PGE2>PGF2α=PGI2>PGD2=TXA2 ([]). EP1 activation is associated with the promotion of inflammation, particularly in the area of inflammation-based pain perception, and asthma, particularly in the area of airways constriction.[17][20]
    • EP2-(PGE2) (PTGER2) – PTGER2; EP2 is a receptor for prostaglandin E2; relative potencies in binding to and stimulating EP2 are PGE2>PGF2α=PGI2>PGD2=TXA2 ([]). EP2 activation is associated with the suppression of inflammation and inflammation-induced pulmonary fibrosis reactions as well as allergic reactions.[17][20]
    • EP3-(PGE2) (PTGER3) – PTGER3; EP3 is a receptor for prostaglandin E2; relative potencies in binding to and stimulating EP3 are PGE2>PGF2α=PGI2>PGD2+TXA2 ([]). Activation of EP3 is associated with the suppression of the early and late phases of allergic responses; EP3 activation is also responsible for febrile responses to inflammation.[17]
    • EP4-(PGE2) (PTGER4) – PTGER4; EP4 is a receptor for prostaglandin E2; relative potencies in binding to and stimulating EP4 are PGE2>PGF2α=PGI2>PGD2=TXA2 ([]). EP4, particularly in association with EP2, activation is critical for the development of arthritis in different animal models.[17]
  • PGF: FP-(PGF) (PTGFR) – PTGFR; FP is the receptor for prostaglandin F2 alpha; relative potencies in binding to and stimulating FP are PGF2α>PGD2>PGE2>PGI2=thromboxane A2 ([]). This receptor is the least selective of the prostanoid receptors in that both PGD2 and PGE2 bind to and stimulate it with potencies close to that of PGF2α. FP has two splice variants, FPa and FPb, which differ in the length of their C-terminus tails. PGF2α-induced activation of FP has pro-inflammatory effects as well as roles in ovulation, luteolysis, contraction of uterine smooth muscle, and initiation of parturition. Analogs of PGF2α have been developed for estrus synchronization, abortion in domestic animals, influencing human reproductive function, and reducing intraocular pressure in glaucoma.[18]
  • PGI2 (prostacyclin): IP-(PGI2) (PTGIR) – PTGIR; IP is the receptor for prostacyclin I2; relative potencies in binding to and stimulating IP are: PGI2>>PGD2= PGE2=PGF2α>TXA2 ([]). Activation of IP is associated with the promotion of capillary permeability in inflammation and allergic responses as well as partial suppression of experimental arthritis in animal models. IP is expressed in at least three alternatively spliced isoforms which differ in the length of their C-terminus and which also activate different cellular signaling pathways and responses.[17]
  • TXA2 (thromboxane): TP-(TXA2) (TBXA2R) – TBXA2R; TP is the receptor for thromboxane A2; relative potencies in binding to and stimulating TP are TXA2=PGH2>>PGD2=PGE2=PGF2α=PGI2 ([]). In addition to PGH2, several isoprostanes have been found to be potent stimulators of and to act in part through TP.[21] The TP receptor is expressed in most human cells types as two alternatively spliced isoforms, TP receptor-α and TP receptor β, which differ in the length of their C-terminus tail; these isoforms communicate with different G proteins, undergo heterodimerization, and thereby result in different changes in intracellular signaling (only the TP receptor α is expressed in mice). Activation of TP by TXA2 or isoprostanes is associated with pro-inflammatory responses in cells, tissues, and animal models.[18][21] TP activation is also associated with the promotion of platelet aggregation and thereby blood clotting and thrombosis.[22]


  1. ^ DuBois RN, Gupta R, Brockman J, Reddy BS, Krakow SL, Lazar MA (1998). "The nuclear eicosanoid receptor, PPAR-γ, is aberrantly expressed in colonic cancers". Carcinogenesis. 19 (1): 49–53. doi:10.1093/carcin/19.1.49. PMID 9472692.
  2. ^ 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.
  3. ^ Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Nicosia S, Serhan CN, Shimizu T, Yokomizo T (2003). "International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors". Pharmacol. Rev. 55 (1): 195–227. doi:10.1124/pr.55.1.8. PMID 12615958.
  4. ^ a b c d Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE (2014). "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". British Journal of Pharmacology. 171 (15): 3551–74. doi:10.1111/bph.12665. PMC 4128057. PMID 24588652.
  5. ^ a b Liu M, Yokomizo T (2015). "The role of leukotrienes in allergic diseases". Allergology International. 64 (1): 17–26. doi:10.1016/j.alit.2014.09.001. PMID 25572555.
  6. ^ Kanaoka Y, Maekawa A, Austen KF (2013). "Identification of GPR99 protein as a potential third cysteinyl leukotriene receptor with a preference for leukotriene E4 ligand". J. Biol. Chem. 288 (16): 10967–72. doi:10.1074/jbc.C113.453704. PMC 3630866. PMID 23504326.
  7. ^ Bankova LG, Lai J, Yoshimoto E, Boyce JA, Austen KF, Kanaoka Y, Barrett NA (2016). "Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99". Proceedings of the National Academy of Sciences of the United States of America. 113 (22): 6242–7. doi:10.1073/pnas.1605957113. PMC 4896673. PMID 27185938.
  8. ^ Marucci G, Dal Ben D, Lambertucci C, Santinelli C, Spinaci A, Thomas A, Volpini R, Buccioni M (2016). "The G Protein-Coupled Receptor GPR17: Overview and Update". ChemMedChem. 11 (23): 2567–2574. doi:10.1002/cmdc.201600453. PMID 27863043.
  9. ^ Fumagalli M, Lecca D, Abbracchio MP (2016). "CNS remyelination as a novel reparative approach to neurodegenerative diseases: The roles of purinergic signaling and the P2Y-like receptor GPR17". Neuropharmacology. 104: 82–93. doi:10.1016/j.neuropharm.2015.10.005. PMID 26453964.
  10. ^ Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM (2009). "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews. 61 (2): 119–61. doi:10.1124/pr.109.001578. PMC 2745437. PMID 19498085.
  11. ^ Lim JY, Park CK, Hwang SW (2015). "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International. 2015: 830930. doi:10.1155/2015/830930. PMC 4538417. PMID 26339646.
  12. ^ a b Serhan CN, Chiang N, Dalli J, Levy BD (2014). "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology. 7 (2): a016311. doi:10.1101/cshperspect.a016311. PMC 4315926. PMID 25359497.
  13. ^ Qu Q, Xuan W, Fan GH (2015). "Roles of resolvins in the resolution of acute inflammation". Cell Biology International. 39 (1): 3–22. doi:10.1002/cbin.10345. PMID 25052386.
  14. ^ Mariani F, Roncucci L (2015). "Chemerin/chemR23 axis in inflammation onset and resolution". Inflammation Research. 64 (2): 85–95. doi:10.1007/s00011-014-0792-7. PMID 25548799.
  15. ^ Brink C, Dahlén SE, Drazen J, Evans JF, Hay DW, Rovati GE, Serhan CN, Shimizu T, Yokomizo T (2004). "International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor". Pharmacol. Rev. 56 (1): 149–57. doi:10.1124/pr.56.1.4. PMID 15001665.
  16. ^ Powell WS, Rokach J (2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta. 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMC 5710736. PMID 25449650.
  17. ^ a b c d e f Matsuoka T, Narumiya S (2007). "Prostaglandin receptor signaling in disease". TheScientificWorldJournal. 7: 1329–47. doi:10.1100/tsw.2007.182. PMC 5901339. PMID 17767353.
  18. ^ a b c d Ricciotti E, FitzGerald GA (2011). "Prostaglandins and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (5): 986–1000. doi:10.1161/ATVBAHA.110.207449. PMC 3081099. PMID 21508345.
  19. ^ 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. PMID 25179301.
  20. ^ a b 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. doi:10.1586/17476348.2015.992783. PMC 4380345. PMID 25541289.
  21. ^ a b Bauer J, Ripperger A, Frantz S, Ergün S, Schwedhelm E, Benndorf RA (2014). "Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation". British Journal of Pharmacology. 171 (13): 3115–31. doi:10.1111/bph.12677. PMC 4080968. PMID 24646155.
  22. ^ Lüscher TF, Steffel J (2016). "Individualized antithrombotic therapy". Hamostaseologie. 36 (1): 26–32. doi:10.5482/HAMO-14-12-0080. PMID 25597592.

External links