Prostanoid Receptors

Prostanoids comprise prostaglandins (PGs) and thromboxanes (Txs). Prostanoid receptors can be classified into five types on the basis of sensitivity to the five naturally-occurring ligands; PGD₂, PGE₂, PGF₂, PGI₂ and TxA₂. These receptors are termed P receptors, with a preceding letter indicating the natural prostanoid to which each receptor is most sensitive - i.e. DP, EP, FP, IP and TP, respectively. Furthermore, EP receptors have been subdivided into four groups, EP₁, EP₂, EP₃ and EP₄, originally on the basis of their relative sensitivities to a range of selective agonists and antagonists, but subsequently, all have been cloned. It is important to appreciate that the recombinant EP₄ receptor was originally identified as EP₂, and all publications referring to recombinant EP₂ receptors prior to 1995 actually refer to EP₄ receptors. Evidence for a second subtype of DP receptor has been published, found in T-lymphocytes, and originally termed CRTH₂. Interestingly, this receptor is unrelated to the other prostanoid receptors, being more similar to the FPR and BLT chemotactic receptors. Indomethacin acts as an agonist at this receptor, and the TP antagonist, ramatroban, has antagonist activity. This 'new' DP-receptor may now tentatively be termed DP₂, with the existing DP receptor re-designated DP₁, although this is yet to be made official. Although there is now a substantial body of evidence for subdivision within IP and TP receptors, this has yet to be formally accepted and incorporated within the classification. Isoprostanes, prostanoids synthesized through non-enzymatic conversion of arachidonic acid have been suggested to act at their own receptors, distinct from those for other prostanoids, but the evidence is ambiguous, and the case not proven. In addition, it has been suggested that certain prostaglandins ethanolamides (prostamides) also act at receptors distinct from the ‘classical’ prostanoid receptors, but definitive evidence is still awaited.

The original basis for the classification was functional, and there are many agonists selective for the various prostanoid receptors. However, few agonists are truly selective for one type of receptor over all of the others, exceptions being BW245C at DP (DP₁) receptors, fluprostenol at FP receptors, and cicaprost at IP receptors. There are potent antagonists for DP, EP₁, EP₄ and TP receptors; EP₃ antagonists are just emerging, but there are still no well characterized potent selective antagonists at EP₂, FP or IP receptors.

Although it is now known that there are splice variants of FP, TP and EP₁ receptors, they are particularly well established for EP₃ receptors, where at least ten splice variants have been reported to date across a variety of species (four of which have been found in man). In all cases, the splicing occurs in the intracellular C-terminal region, and while there is no evidence that it affects ligand affinities, it does appear to influence the receptors’ coupling to particular signal transduction processes. The splice variant of the EP₁ receptor is distinct, in that the splice region incorporates the sixth and seventh intracellular domains, and the resulting receptor does not appear to couple directly to any recognized signal transduction process.

Prostanoid-induced effects are mainly transduced through modulation of the activity of either adenylyl cyclase or inositol phospholipid hydrolysis and calcium mobilization. DP₁, EP₂, EP₄ and IP receptors couple positively to adenylyl cyclase through binding to a G_q/11 protein. EP₃ receptors can either couple negatively to adenylyl cyclase through binding to a G_i protein, or like EP₁, FP and TP receptors, via G_q/11 binding to inositol phospholipid hydrolysis and calcium mobilization. IP receptors appear to be most unusual among the prostanoid receptors, and indeed among G protein-coupled receptors in general, in that the receptor protein requires isoprenylation in order to optimize agonist-induced activation.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Materials" section below.

Currently Accepted Name	EP1	EP2	EP3	EP4
Alternate Name	None	None	None	None
Structural Information	402 aa (human)	358 aa (human)	4 splice variants: 390, 388, 365, 374 aa (human)	488 aa (human)
Subtype Selective Agonists	17-Ph-ω-PGE2 Iloprostb	Butaprost (B6309) AH-13205 (A9102) CP-533,536 ONO-AE1-259	SC-46275 GR63799 Sulprostonee (S8692) ONO-AE-248	ONO-AE1-734 ONO-AE1-329
Subtype Selective Antagonists	SC-1922 (S3065) AH6809 (A1221) SC-51809	AH6809d (A1221)	L-798,106	AH23848f (A8227) L-161,982 (SML0690) ONO-AE3-208 GW627368
Receptor Selective Agonists	PGE2 (P5640)	PGE2 (P5640)	PGE2 (P5640) Misoprostol (M6932)	PGE2 (P5640)
Receptor Selective Antagonists	Not Known	Not Known	Not Known	Not Known
Signal Transduction Mechanisms	Gq/11 (increase IP3/DAG)	Gs (increase cAMP)	Gq/11 (increase IP3/DAG) Gi (cAMP modulation)	Gs (increase cAMP)
Radioligands of Choice	[3H]-PGE2	[3H]-PGE2	[3H]-PGE2 [3H]-Sulprostone	[3H]-PGE2
Tissue Expression	Kidney, myometrium, GI smooth muscle	Myometrium, airway smooth muscle, GI smooth muscle	Myometrium, kidney, GI mucosa	Ductus arteriosus, kidney, lymphocytes, mononuclear cells
Physiological Function	Modulation of pain, diuresis & natriuresis	Control of uterine contractility	Control of uterine contractility, natriuresis, GI cytoprotection	Control of ductus, bone metabolism
Disease Relevance	Inflammatory pain, diabetic nephropathy	Pre-term labor	Pre-term labor, gastric ulcer	Patent ductus, colonic inflammation

Currently Accepted Name	DPa	FP	IP	TP
Alternate Name	None	None	None	None
Structural Information	359 aa (human)	358 aa (human)	386 aa (human)	343 aa (human)
Subtype Selective Agonists	Not Known	Not Known	Not Known	AGN 192093
Subtype Selective Antagonists	Not Known	Not Known	Not Known	Not Known
Receptor Selective Agonists	PGD2 (P5172) BW245C (B9305) ZK 110841 RS 93520 SQ 27986 L-644,698	PGF2a (P0424) Fluprostenol (F8549) Cloprostenol (C6116) Latanoprost (L1167)	PGI2 (P6188) Cicaprost Iloprostb BMY 45778 Beraprost ONO-1301 (O2264)	U-46619 (D8174) STA2 I-BOP (SML0504) AGN 192093 SQ 26655
Receptor Selective Antagonists	BWA868C (B9180) AH6809 (A1221) S-5751 ZK 138,357	Not Known	Not Known	GR32191 (G5044) SQ 29548 (S144) BM 13505 (D7441) EP092 L-655,240 ICI 192605 (I2536) ONO 3708 BMS 180291 Ramatroban (R0531) KW-3635
Signal Transduction Mechanisms	Gs (increase cAMP)	Gq/11 (increase IP3/DAG)	Gs (increase cAMP) Gq/11 (increase IP3/DAG)	Gq/11 (increase IP3/DAG)
Radioligands of Choice	[3H]-PGD2	[3H]-PGF2a [3H]-17-Phe-ω-PGF2a	[3H]-PGI2 [3H]-Iloprost	[3H]-U-46619 [3H]-SQ 29548 [125I]-BOP
Tissue Expression	Blood platelets, myometrium, ciliary muscle, basophils	Corpus luteum, myometrium, ciliary body	Blood platelets, vascular smooth muscle, sensory nerves	Blood platelets, vascular smooth muscle, airways smooth muscle
Physiological Function	Regulation of sleep	Luteolysis, labor	Control of platelet, aggregation, vasodilatation, pain	Control of platelet aggregation, vasoconstriction, bronchoconstriction
Disease Relevance	Not Known	Not Known	Not Known	Diabetic vascular occlusion

Footnotes

a) DP receptor may now be re-designated DP₁, with CRTH₂ re-designated as DP₂.

b) Iloprost is a partial agonist at EP₁ receptors, but is a potent full agonist at IP receptors. Sulprostone is more potent as an EP₃ agonist.

c) Misoprostol is also an EP₃ agonist.

d) Human EP₂ receptors only; also antagonist at EP₁ and DP receptors.

e) Sulprostone also has moderate EP₁ agonistic activity.

f) AH23848 is also a potent TP receptor blocking drug.

 

Abbreviations

AGN 192093: (5Z,9a,11a,13E,15S)-Prosta-5,13-diene-1,9,11,15-tetrol-cyclic-9,11-carbonate
AH-13205: trans-2-(4-(1-Hydroxyhexyl)phenyl)-5-oxocyclopentaneheptanoic acid
AH-23848: [1a(Z),2b,5a]-(±)-7-[5-[[(1,1’-Biphenyl)-4-yl]methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid
AH-6809: 6-Isopropoxy-9-oxoxanthene-2-carboxylic acid
Beraprost: (rac-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-Tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate)
BM 13505 (Daltroban): 4-(2-(4-Chlorobenzenesulfonylamino)ethyl)benzeneacetic acid
BMS 180291 (Ifetroban): 1S-(1a,2a,3a,4a)]-2-[[3-[4-[(+++Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid
BMY 45778: (3-(4,5-Diphenyl(2,4'-bioxazol)-5'-yl)phenoxy)acetic acid
1-BOP: [1S[1a,2a(Z),3b(1E,3S*),4a]]-7-[3-[3-Hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo- [2.2.1]hept-2-yl]5-heptanoic acid
BW 245C: 3-(3-Cyclohexyl-3-hydroxypropyl)-2,5-dioxoimidazolidine-4-heptanoic acid
BW A868C: 3-Benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin
CP-533,536: (3-{[4-Tert-butyl-benzyl(pyridine-3-sulfonyl)-amino-methyl}-phenoxy)-acetic acid
EP092: (1a,2b(Z),3a,4a)-(±)-7-(3-(1-(((Phenylamino)thioxomethyl)hydrazono)ethyl)bicyclo(2.2.1)hept-2-yl)-5-heptenoic acid
GR 32191: (4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-Biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid
GR 63799: 7-(3-Hydroxy-2-(2-hydroxy-3-phenoxypropoxy)-5-oxocyclopentyl)-,4-(benzoylamino)phenyl ester,(1R-(1a(Z),2b(R*),3a))-4-heptenoic acid
GW 627368: (N-{2-[4-(4,9-Diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]-acetyl}benzenesulphonamide)
ICI 192605: (4Z)-rel-6-[(2R,4R,5S)-2-(2-Chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]-4-hexenoic acid
KW-3635: Sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate
L-161,982: [4’-[3-Butyl-5-oxo-1-(2-trifluoromethyl-phenyl)-1,5-dihydro-[1,2,4]triazol-4-ylmethyl]-biphenyl-2-sulfonic acid (3-methyl-thiophene-2-carbonyl)-amide]
L-644,698: ±(4-(3-(3-Hydroxyoctyl)-4-oxo-2-thiozolidinyl)propyl) benzoic acid
L-655,240: 3-(1-(4-Chlorobenzyl)-5-fluoro-3-methylindol-2-yl)-2,2-dimethylpropanoic acid
L-798,106: 5-Bromo-2-methoxy-N-[3-2-(naphthalen-2-yl-methylphenyl)-acryloyl]-benzenesulphonamide
ONO-1301: [7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]-aminooxy]ethyl]-1-naphtyloxy]acetic acid
ONO-3708: (1S-(1-a,2-b(Z),3-a(S*),5-a))-7-(3-((Cyclopentylhydroxyacetyl)amino)-6,6-dimethylbicyclo(3.1.1)hept-2-yl)-5-heptenoic acid
ONO-AE1-259: (16S-9-Deoxy-9β-chloro-15-deoxy-16-hydroxy-17,17-propano-19,20-didehydro PGE-2)
ONO-AE1-329: (16-(3-Methoxymethyl)phenyl-omega-tetranor-3,7-dithia PGE-1)
ONO-AE1-734: Methyl-7-[(1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-4-(m-methoxymethylphenyl)-1-butenyl]-5-oxocyclopenthl]-5-thiaheptanoate
ONO-AE3-208: 4-{4-Cyano-2-[2-(-fluoronaphthalen-1-yl)proprionylamino] phenyl}butyric acid
Ramatroban: (+)-(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazolepropanoic acid
RS 93520: (4Z)-4-[(1R,2R,3S,6R)-2-[(3S)-3-Cyclohexyl-3-hydroxy-1-propynyl]-3-hydroxybicyclo[4.2.0]oct-7-ylidene]butanoic acid
S-5751: ((Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid)
SC 19220: 1-Acetyl-2-[8-chloro-10,11-dihydrodibenz(b,f)(1,4)oxazepine-10-carbonyl]hydrazine
SC 46275: Methyl-7-(2b-(6-(1-cyclopentyl-yl)-4R-hydroxy-4-methyl-1E,5E-hexadienyl)-3a-hydroxy-5-oxo-1R,1a-cyclopentyl)-4Z-heptenoate
SC 51809: (8-Chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-(4-pyridinyl)propyl]hydrazide, monohydrochloride)
SQ 26655: 9-alpha,11alpha-epoxy-10a-homo-15S-hydroxy-prosta-5Z,13E-dienoic acid
SQ 27986: 7-(3-(3-Cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-h eptenoic acid
SQ 29548: 7-(3-((2-((Phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid
STA2: (5Z)-7-[(1S,2R,3R,5S)-3-[(1E,3S)-3-Hydroxy-1-octenyl]-6-thiabicyclo[3.1.1]hept-2-yl]-5-heptenoic acid
U-46619: (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-Hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid
ZK 110841: 9-Deoxy-9-chloro-16,17,18,19,20-pentanor-15-cyclohexyl- PGF 2a
ZK 138,357: (5Z)-7-[(2RS,4S,5S)-2-(2-chlorophenyl)-5-[(1E)-(3RS)-3-hydroxy-3-cyclohexyl-1-propenyl]-1,3-dioxolan-4-yl]-5-heptanoic acid

References

1. Coleman, R.A., et al., . 2000. Prostanoid receptors., in: The IUPHAR Compendium of Receptor Characterization and Classification, IUPHAR Media, London, UK.. 2nd edition, pp..337-353.

2. Díez-Dacal B, Pérez-Sala D. 2010. Anti-Inflammatory Prostanoids: Focus on the Interactions between Electrophile Signaling and Resolution of Inflammation. The Scientific World JOURNAL. 10655-675. https://doi.org/10.1100/tsw.2010.69

3. Furuyashiki T, Narumiya S. 2011. Stress responses: the contribution of prostaglandin E2 and its receptors. Nat Rev Endocrinol. 7(3):163-175. https://doi.org/10.1038/nrendo.2010.194

4. Hayes JS, Lawler OA, Walsh M, Kinsella BT. 1999. The Prostacyclin Receptor Is Isoprenylated. J. Biol. Chem.. 274(34):23707-23718. https://doi.org/10.1074/jbc.274.34.23707

5. Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Nakanishi S, Narumiya S. 1991. Cloning and expression of cDNA for a human thromboxane A2 receptor. Nature. 349(6310):617-620. https://doi.org/10.1038/349617a0

6. Hirata T, Narumiya S. 2012. Prostanoids as Regulators of Innate and Adaptive Immunity.143-174. https://doi.org/10.1016/b978-0-12-394300-2.00005-3

7. Honda T, Tokura Y, Miyachi Y, Kabashima K. 2010. Prostanoid Receptors as Possible Targets for Anti-Allergic Drugs: Recent Advances in Prostanoids on Allergy and Immunology. CDT. 11(12):1605-1613. https://doi.org/10.2174/1389450111009011605

8. Morrow, J.D., et al., . 1994. Free radical-induced generation of isoprostanes in vivo. Evidence for the formation of D-ring and E-ring isoprostanes., J. Biol. Chem., 269 ..4317-4326.

9. Nagata K, Hirai H. 2003. The second PGD2 receptor CRTH2: structure, properties, and functions in leukocytes. Prostaglandins, Leukotrienes and Essential Fatty Acids. 69(2-3):169-177. https://doi.org/10.1016/s0952-3278(03)00078-4

10. Okuda-Ashitaka E, Sakamoto K, Ezashi T, Miwa K, Ito S, Hayaishi O. 1996. Suppression of Prostaglandin E Receptor Signaling by the Variant Form of EP1Subtype. J. Biol. Chem.. 271(49):31255-31261. https://doi.org/10.1074/jbc.271.49.31255

11. Pierce KL, Bailey TJ, Hoyer PB, Gil DW, Woodward DF, Regan JW. 1997. Cloning of a Carboxyl-terminal Isoform of the Prostanoid FP Receptor. J. Biol. Chem.. 272(2):883-887. https://doi.org/10.1074/jbc.272.2.883

12. Praticò D, Smyth EM, Violi F, FitzGerald GA. 1996. Local Amplification of Platelet Function by 8-Epi Prostaglandin F2?Is Not Mediated by Thromboxane Receptor Isoforms. J. Biol. Chem.. 271(25):14916-14924. https://doi.org/10.1074/jbc.271.25.14916

13. Regan, J.W., et al., . 1994. Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype., 46.. Mol. Pharmacol..213-220 .

14. Schuligoi R, Sturm E, Luschnig P, Konya V, Philipose S, Sedej M, Waldhoer M, Peskar BA, Heinemann A. 2010. CRTH2 and D-Type Prostanoid Receptor Antagonists as Novel Therapeutic Agents for Inflammatory Diseases. Pharmacology. 85(6):372-382. https://doi.org/10.1159/000313836

15. Ushikubi F, Hirata M, Narumiya S. 1995. Molecular biology of prostanoid receptors; an overview. Journal of Lipid Mediators and Cell Signalling. 12(2-3):343-359. https://doi.org/10.1016/0929-7855(95)00022-i

16. Wise H, Joncs RL. 1996. Focus on prostacyclin and its novel mimetics. Trends in Pharmacological Sciences. 17(1):17-21. https://doi.org/10.1016/0165-6147(96)81565-3

17. Woodward DF, Pepperl DJ, Burkey TH, Regan JW. 1995. 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a human EP2 receptor antagonist. Biochemical Pharmacology. 50(10):1731-1733. https://doi.org/10.1016/0006-2952(95)02035-7