Biology:Eicosanoid receptor

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Short description: Integral membrane protein G protein-coupled 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]

Leukotriene

Leukotrienes:

Lipoxin

Lipoxins:

  • ALX/FPR2 (also termed FPR2, ALX, ALX/FPR, formyl peptide receptor-like 1) – FPR2; receptor for Lipoxin A4 and 15-epi-Lipoxin A4 (or AT-LxA4) eicosanoids but also many other agents including the docosanoids resolvin D1, resolvin D2, and 17R-resolvin D1 (see specialized pro-resolving mediators; oligopeptides such as N-Formylmethionine-leucyl-phenylalanine; and various proteins such as the amino acid 1 to 42 fragment of Amyloid beta, Humanin, and the N-terminally truncated form of the chemotactic chemokine, CCL23 (see FPR2#Ligands and ligand-based disease-related activities). Relative potencies in binding to and activating ALX/FPR are: lipoxin A4=aspirin-triggered lipoxin A4>leukotriene C4=leukotriene D4>>15-deoxy-LXA4>>N-Formylmethionine-leucyl-phenylalanine (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=223}. Activation of ALX/FPR2 by the lipoxins is associated with anti-inflammatory responses by target cells and tissues.[10][11][12] Receptors that bind and respond to a wide range of ligands with such seemingly different structural similarities as those of ALX/FPR are often termed promiscuous.

Resolvin E

Resolvin Es:

Oxoeicosanoid

Oxoeicosanoid:[15]

Prostanoid

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 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=338). 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 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=339&familyId=58&familyType=GPCR). 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)
  • PGF2α: FP-(PGF2α) (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 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=344). 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 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345). 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 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=346&familyId=58&familyType=GPCR). 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]

References

  1. ↑ "The nuclear eicosanoid receptor, PPAR-γ, is aberrantly expressed in colonic cancers". Carcinogenesis 19 (1): 49–53. 1998. doi:10.1093/carcin/19.1.49. PMID 9472692. 
  2. ↑ "International Union of Pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes". Pharmacol. Rev. 46 (2): 205–29. 1994. PMID 7938166. 
  3. ↑ "International Union of Pharmacology XXXVII. Nomenclature for leukotriene and lipoxin receptors". Pharmacol. Rev. 55 (1): 195–227. 2003. doi:10.1124/pr.55.1.8. PMID 12615958. 
  4. ↑ 4.0 4.1 4.2 4.3 "Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7". British Journal of Pharmacology 171 (15): 3551–74. 2014. doi:10.1111/bph.12665. PMID 24588652. 
  5. ↑ 5.0 5.1 "The role of leukotrienes in allergic diseases". Allergology International 64 (1): 17–26. 2015. doi:10.1016/j.alit.2014.09.001. PMID 25572555. 
  6. ↑ "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. 2013. doi:10.1074/jbc.C113.453704. PMID 23504326. 
  7. ↑ "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. 2016. doi:10.1073/pnas.1605957113. PMID 27185938. Bibcode: 2016PNAS..113.6242B. 
  8. ↑ "The G Protein-Coupled Receptor GPR17: Overview and Update". ChemMedChem 11 (23): 2567–2574. 2016. doi:10.1002/cmdc.201600453. PMID 27863043. 
  9. ↑ "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. 2016. doi:10.1016/j.neuropharm.2015.10.005. PMID 26453964. 
  10. ↑ "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews 61 (2): 119–61. 2009. doi:10.1124/pr.109.001578. PMID 19498085. 
  11. ↑ "Biological Roles of Resolvins and Related Substances in the Resolution of Pain". BioMed Research International 2015: 830930. 2015. doi:10.1155/2015/830930. PMID 26339646. 
  12. ↑ 12.0 12.1 "Lipid mediators in the resolution of inflammation". Cold Spring Harbor Perspectives in Biology 7 (2): a016311. 2014. doi:10.1101/cshperspect.a016311. PMID 25359497. 
  13. ↑ "Roles of resolvins in the resolution of acute inflammation". Cell Biology International 39 (1): 3–22. 2015. doi:10.1002/cbin.10345. PMID 25052386. 
  14. ↑ "Chemerin/chemR23 axis in inflammation onset and resolution". Inflammation Research 64 (2): 85–95. 2015. doi:10.1007/s00011-014-0792-7. PMID 25548799. 
  15. ↑ "International Union of Pharmacology XLIV. Nomenclature for the oxoeicosanoid receptor". Pharmacol. Rev. 56 (1): 149–57. 2004. doi:10.1124/pr.56.1.4. PMID 15001665. 
  16. ↑ "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851 (4): 340–55. 2015. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 "Prostaglandin receptor signaling in disease". TheScientificWorldJournal 7: 1329–47. 2007. doi:10.1100/tsw.2007.182. PMID 17767353. 
  18. ↑ 18.0 18.1 18.2 18.3 "Prostaglandins and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology 31 (5): 986–1000. 2011. doi:10.1161/ATVBAHA.110.207449. PMID 21508345. 
  19. ↑ "Prostanoid receptors and acute inflammation in skin". Biochimie 107 Pt A: 78–81. 2014. doi:10.1016/j.biochi.2014.08.010. PMID 25179301. 
  20. ↑ 20.0 20.1 "The role of prostaglandins in allergic lung inflammation and asthma". Expert Review of Respiratory Medicine 9 (1): 55–72. 2015. doi:10.1586/17476348.2015.992783. PMID 25541289. 
  21. ↑ 21.0 21.1 "Pathophysiology of isoprostanes in the cardiovascular system: implications of isoprostane-mediated thromboxane A2 receptor activation". British Journal of Pharmacology 171 (13): 3115–31. 2014. doi:10.1111/bph.12677. PMID 24646155. 
  22. ↑ "Individualized antithrombotic therapy". Hamostaseologie 36 (1): 26–32. 2016. doi:10.5482/HAMO-14-12-0080. PMID 25597592. 

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