Eicosanoid receptor

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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]

Contents

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:

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]

Related Research Articles

Prostaglandin Group of physiologically active lipid compounds

The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

Eicosanoid

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Eicosanoids may also act as endocrine agents to control the function of distant cells.

Prostacyclin

Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.

Lipoxin Acronym for lipoxygenase interaction product

A lipoxin (LX or Lx), an acronym for lipoxygenase interaction product, is a bioactive autacoid metabolite of arachidonic acid made by various cell types. They are categorized as nonclassic eicosanoids and members of the specialized pro-resolving mediators (SPMs) family of polyunsaturated fatty acid (PUFA) metabolites. Like other SPMs, LXs form during, and then act to resolve, inflammatory responses. Initially, two lipoxins were identified, lipoxin A4 (LXA4) and LXB4, but more recent studies have identified epimers of these two LXs: the epi-lipoxins, 15-epi-LXA4 and 15-epi-LXB4 respectively.

Prostanoids are a subclass of eicosanoids consisting of the prostaglandins, the thromboxanes, and the prostacyclins

The effects on humans of the ω-3 (omega-3) and ω-6 (omega-6) essential fatty acids (EFAs) are best characterized by their interactions.

Thromboxane receptor

The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2,, PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. They are named based on the prostanoid to which they preferentially bind and respond, e.g. the receptor responsive to PGI2 at lower concentrations than any other prostanoid is named the Prostacyclin receptor (IP). One exception to this rule is the receptor for thromboxane A2 (TP) which binds and responds to PGH2 and TXA2 equally well.

Prostaglandin DP<sub>1</sub> receptor

The Prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), is primarily a receptor for prostaglandin D2 (PGD2). The receptor is a member of the Prostaglandin receptors belonging to the Subfamily A14 of rhodopsin-like receptors. Activation of DP1 by PGD2 or other cognate receptor ligands is associated with a variety of physiological and pathological responses in animal models.

Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.

Prostaglandin EP<sub>4</sub> receptor

Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP4 has been implicated in various physiological and pathological responses in animal models and humans.

Cysteinyl leukotriene receptor 1

Cysteinyl leukotriene receptor 1, also termed CYSLTR1, is a receptor for cysteinyl leukotrienes (LT). CYSLTR1, by binding these cysteinyl LTs contributes to mediating various allergic and hypersensitivity reactions in humans as well as models of the reactions in other animals.

Prostaglandin DP<sub>2</sub> receptor

Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.

OXGR1

2-Oxoglutarate receptor 1 (OXGR1), also known as cysteinyl leukotriene receptor E (CysLTE) and GPR99, is a protein that in humans is encoded by the OXGR1 gene. The Gene has recently been nominated as a receptor not only for 2-oxogluterate but also for the three cysteinyl leukotrienes (CysLTs), particularly leukotriene E4 (LTE4) and to far lesser extents LTC4 and LTE4. Recent studies implicate GPR99 as a cellular receptor which is activated by LTE4 thereby causing these cells to contribute to mediating various allergic and hypersensitivity responses.

Prostaglandin EP<sub>1</sub> receptor

Prostaglandin E2 receptor 1 (EP1) is a 42kDa prostaglandin receptor encoded by the PTGER1 gene. EP1 is one of four identified EP receptors, EP1, EP2, EP3, and EP4 which bind with and mediate cellular responses principally to prostaglandin E2) (PGE2) and also but generally with lesser affinity and responsiveness to certain other prostanoids (see Prostaglandin receptors). Animal model studies have implicated EP1 in various physiological and pathological responses. However, key differences in the distribution of EP1 between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease.

Prostaglandin EP<sub>2</sub> receptor

Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

Prostaglandin EP<sub>3</sub> receptor

Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.

Prostaglandin F receptor

Prostaglandin F receptor (FP) is a receptor belonging to the prostaglandin (PG) group of receptors. FP binds to and mediates the biological actions of Prostaglandin F (PGF). It is encoded in humans by the PTGFR gene.

Prostacyclin receptor

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.

12-Hydroxyheptadecatrienoic acid Chemical compound

12-Hydroxyheptadecatrenoic acid is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was first detected and structurally defined by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.

References

  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. S2CID   1584172.
  4. 1 2 3 4 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. 1 2 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. hdl: 11581/394099 . PMID   27863043. S2CID   10935349.
  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. hdl: 2434/349470 . PMID   26453964. S2CID   26235050.
  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. 1 2 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. S2CID   10160642.
  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. S2CID   18957311.
  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. S2CID   7229884.
  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 (BBA) - Molecular and Cell Biology of Lipids. 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMC   5710736 . PMID   25449650.
  17. 1 2 3 4 5 6 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. 1 2 3 4 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. 1 2 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. 1 2 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.