Prostaglandin receptor

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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, (i.e. PGD2), PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. [1] 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.

Contents

All of the prostanoid receptors are G protein-coupled receptors belonging to the Subfamily A14 of the rhodopsin-like receptor family except for the Prostaglandin DP2 receptor which is more closely related in amino acid sequence and functionality to chemotactic factor receptors such as the receptors for C5a and leukotriene B4. [2]

Prostanoid receptors bind and respond principally to metabolites of the straight chain polyunsaturated fatty acid (PUFA), arachidonic acid. These metabolites contain two double bonds and are named series 2 prostanoids, i.e. PGD2, PGE2, PGF2α, PGI2, TXA2 and PGH2. However, the same enzymes that metabolize arachidonic acid to series 2 prostanoids similarly metabolize two other straight chain PUFAs: they metabolize gamma-Linolenic acid, which has one less double bond than arachidonic acid, to series 1 prostanoids (PGD1, PGE1, etc.), which have one less double bond than the series 2 prostanoids, and they metabolize eicosapentaenoic acid, which has one more double bond than arachidonic acid, to series 3 prostanoids (PGD3, PGE3, etc.), which have one more double bond than the series 2 prostanoids. In general, receptors for the series 2 prostanoids also bind with and respond to the series 1 and 3 prostanoids. Typically, prostanoid receptors show somewhat less affinity and responsiveness to the 1 and 3 series prostanoids. [3]

There are 9 established prostanoid receptors. The following table gives these receptors: a) full name; b) shortened names; c) activating prostanoids (presented in order of decreasing potencies); [4] d) time-honored classification as contractile (i.e. contracting smooth muscle), relaxant (i.e. relaxing smooth muscle), or inhibitory (i.e. inhibiting adenyl cyclase (AC) production of cyclic AMP [cAMP]); [5] e) G proteins types to which they link and activate, i.e. those containing the Gs alpha subunit, Gi alpha subunit, Gq alpha subunit and/or G12 subunit; [2] [4] and f) signaling pathways which they regulate including Adenyl cyclase which when activated increases cellular cAMP and when inhibited reduces the cellular levels of this secondary messenger; Phosphoinositide 3-kinase which when activated is responsible for forming phosphatidylinositol 3-phosphate, phosphatidylinositol (3,4)-bisphosphate, and phosphatidylinositol (3,4,5)-trisphosphate secondary messengers; Phospholipase C (PLC) which when activated is responsible for forming Inositol trisphosphate (IP3) and diacylglycerol secondary messengers that are, respectively, responsible for raising the levels of Ca2+ in the cellular cytosol to control the activity of Ca2+-cell signaling agents and for activating protein kinase C (PKC) secondary messengers; and Extracellular signal-regulated kinases (ERK), p38 mitogen-activated protein kinases (p38 Mpk), and cAMP response element-binding protein (CREB) which when activated phosphorylate and thereby influence the activity of key proteins that govern cell function. [2]

Full nameshortened nameactivating prostanoidsclassification [5] G protein linkage [2] pathways [2]
Prostaglandin DP1 receptor DP1 PGD2>>PGE2>PGF2α>PGI2=TXA2 [6] relaxant Gs alpha subunit activates AC, increases cAMP, raises Ca2+
Prostaglandin DP2 receptor DP2 PGD2>>PGF2α=PGE2>PGI2=TXA2 [7]  ? Gi alpha subunit inhibits AC to depress cAMP levels
Prostaglandin EP1 receptor EP1 PGE2>PGF2α=PGI2>PGD2=TXA2 [8] contractile Gq alpha subunit stimulates PLC, IP3, PKC, ERK, p38 Mpk, and CREB
Prostaglandin EP2 receptor EP2 PGE2>PGF2α=PGI2>PGD2=TXA2 [9] relaxantGs alpha subunitstimulates AC, raises cAMP, stimulates beta catenin and Glycogen synthase kinase 3
Prostaglandin EP3 receptor EP3 PGE2>PGF2α,PGI2>PGD2=TXA2 [10] inhibitoryGi & G12 subunit inhibits AC, decreases cAMP, stimulates PLC & IP3, raises Ca2+
Prostaglandin EP4 receptor EP4 PGE2>PGF2α=PGI2>PGD2=TXA2 [11] relaxantGs alpha subunitstimulates AC, PKA, PI3K, AKT, ERK, p38 Mpk, & CREB; raises cAMP
Prostaglandin F2α receptor FP PGF2α>PGD2>PGE2>PGI2=TXA2 [12] contractileGq alpha subunitstimulates PLC, IP3, & PKC; raises Ca2+
Prostacyclin I2 receptor IP PGI2>>PGD2=PGE2=PGF2α>TXA2 [13] relaxantGs alpha subunitstimulates AC & PKA; raises cAMP
Thromboxane A2 receptor TP TXA=PGH2>>PGD2=PGE2=PGF2α=PGI2 [14] contractileGq alpha subunitstimulates PLC & IP3; raises Ca2+

There is indirect evidence for a second PGI2 receptor in BEAS-2B human airway epithelial cells but this finding has not been collaborated and the putative receptor has not been otherwise defined. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Prostaglandin</span> 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.

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

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, around 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.

<span class="mw-page-title-main">Prostacyclin</span> Chemical compound

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.

Prostanoids are active lipid mediators that regulate inflammatory response. Prostanoids are a subclass of eicosanoids consisting of the prostaglandins, the thromboxanes, and the prostacyclins. Prostanoids are seen to target NSAIDS which allow for therapeutic potential. Prostanoids are present within areas of the body such as the gastrointestinal tract, urinary tract, respiratory and cardiology systems, reproductive tract and vascular system. Prostanoids can even be seen with aid to the water and ion transportation within cells. Prostanoids help release prostaglandins upon activation, receptors may open possibilities for treatments within different systems.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

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.

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 or on nearby cells 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 to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.

Prostaglandin H<sub>2</sub> Chemical compound

Prostaglandin H2 is a type of prostaglandin and a precursor for many other biologically significant molecules. It is synthesized from arachidonic acid in a reaction catalyzed by a cyclooxygenase enzyme. The conversion from Arachidonic acid to Prostaglandin H2 is a two step process. First, COX-1 catalyzes the addition of two free oxygens to form the 1,2-Dioxane bridge and a peroxide functional group to form Prostaglandin G2. Second, COX-2 reduces the peroxide functional group to a Secondary alcohol, forming Prostaglandin H2. Other peroxidases like Hydroquinone have been observed to reduce PGG2 to PGH2. PGH2 is unstable at room temperature, with a half life of 90-100 seconds, so it is often converted into a different prostaglandin.

Prostaglandin DP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Prostaglandin-endoperoxide synthase 2</span> Human enzyme involved in inflammation

Prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the PTGS2 gene. In humans it is one of two cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation.

Prostaglandin EP<sub>4</sub> receptor Protein-coding gene in the species Homo sapiens

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.

Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

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.

Prostaglandin EP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

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 Protein-coding gene in the species Homo sapiens

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 Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Prostaglandin F receptor</span> Protein-coding gene in the species Homo sapiens

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 F2α (PGF2α). It is encoded in humans by the PTGFR gene.

<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

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.

Thromboregulation is the series of mechanisms in how a primary clot is regulated. These mechanisms include, competitive inhibition or negative feedback. It includes primary hemostasis, which is the process of how blood platelets adhere to the endothelium of an injured blood vessel. Platelet aggregation is fundamental to repair vascular damage and the initiation of the blood thrombus formation. The elimination of clots is also part of thromboregulation. Failure in platelet clot regulation may cause hemorrhage or thrombosis. Substances called thromboregulators control every part of these events.

<span class="mw-page-title-main">12-Hydroxyheptadecatrienoic acid</span> Chemical compound

12-Hydroxyheptadecatrenoic acid (also termed 12-HHT, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, or 12(S)-HHTrE) 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 (i.e. endoplasmic reticulum) 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.

The prostaglandin D2 (PGD2) receptors are G protein-coupled receptors that bind and are activated by prostaglandin D2. Also known as PTGDR or DP receptors, they are important for various functions of the nervous system and inflammation. They include the following proteins:

References

  1. ↑ Tsuboi K, Sugimoto Y, Ichikawa A (2002). "Prostanoid receptor subtypes". Prostaglandins Other Lipid Mediat. 68–69: 535–56. doi:10.1016/S0090-6980(02)00054-0. PMID   12432942.
  2. 1 2 3 4 5 Moreno JJ (2016). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis". European Journal of Pharmacology. 796: 7–19. doi:10.1016/j.ejphar.2016.12.004. PMID   27940058. S2CID   1513449.
  3. ↑ Narumiya S, Sugimoto Y, Ushikubi F (1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. doi:10.1152/physrev.1999.79.4.1193. PMID   10508233. S2CID   7766467.
  4. 1 2 "Prostanoid receptors - G protein-coupled receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  5. 1 2 Matsuoka T, Narumiya S (2008). "The roles of prostanoids in infection and sickness behaviors". Journal of Infection and Chemotherapy. 14 (4): 270–8. doi:10.1007/s10156-008-0622-3. PMID   18709530. S2CID   207058745.
  6. ↑ "DP1 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  7. ↑ "DP2 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  8. ↑ "EP1 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  9. ↑ "EP2 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  10. ↑ "EP3 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  11. ↑ "EP4 receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  12. ↑ "FP receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  13. ↑ "IP receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  14. ↑ "TP receptor - Prostanoid receptors - IUPHAR/BPS Guide to PHARMACOLOGY". www.guidetopharmacology.org.
  15. ↑ Wilson SM, Sheddan NA, Newton R, Giembycz MA (2011). "Evidence for a second receptor for prostacyclin on human airway epithelial cells that mediates inhibition of CXCL9 and CXCL10 release". Molecular Pharmacology. 79 (3): 586–95. doi:10.1124/mol.110.069674. PMID   21173040. S2CID   11882621.
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