Prostanoid receptors: Introduction

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General

Fatty acid cyclo-oxygenase (COX) converts arachidonic acid to prostaglandin H2 (PGH2), from which further prostanoids, PGD2, PGE2, PGF, PGI2 (prostacyclin) and thromboxane A2 (TXA2), may be enzymatically derived. Based on the agonist potencies of the latter prostanoids (and the limited use of receptor antagonists), five prostanoid receptors were recognized and correspondingly named DP, EP, FP, IP and TP receptors [12]. Additionally, EP receptors have been subdivided into four groups, termed EP1, EP2, EP3 and EP4. In the early 1990s, cDNA cloning identified a family of eight G-protein coupled receptors (GPCRs) that correspond to these pharmacologically-defined receptors. cDNA cloning also revealed the presence of an additional GPCR called CRTH2 that mediates some PGD2 actions. Therefore, the DP receptor now has two subtypes, DP1 and DP2 (CRTH2). Heterodimerization of prostanoid receptors is a rapidly growing area of study, particularly in relation to prostamide receptors, which are activated by C1-amide agonists [50]. Studies on the evolution of prostanoid receptors suggest that a PGE2-sensitve entity was the ancestral receptor [7,15,73]. Prostanoid receptor gene knock-out has revealed much useful information about the patho-physiological roles of prostanoid receptors [33,41].

Specific agonists and antagonists [28] have been developed for all nine prostanoid receptors: useful summary tables may be found on the current Guide to PHARMACOLOGY webpage for prostanoid receptors. Recent progress in this area has been based on high-throughput screening using cloned receptors expressed in suitable cell lines. Comprehensive details of the 9 prostanoid receptors, their ligands and their therapeutic indications may be found in a recent NC-IUPHAR sponsored review [71].

In terms of nomenclature, NC-IUPHAR endorses the use (for example) of prostanoid EP1 receptor (not prostaglandin EP1 receptor) on first mention in manuscript text and in table headings, EP1 receptor on repetitive use, and discourages the use of EP1 alone.

DP receptors

DP1 receptors are coupled to adenylate cyclase via a Gs protein [2,25,60], while DP2 receptors inhibit adenylate cyclase through Gi [17,52]. The DP2 receptor is structurally distinct from all of the other known prostanoid receptors, being more closely related to chemoattractant receptors such as fMLP and BLT receptors. In this context, DP1 receptors require a 15(S)-hydroxyl group for optimum bioactivity (e.g. BW-245C), whereas DP2 receptors can unusually tolerate a range of moieties at C15, including a 15-oxo group (the product of substrates for 15-OH-prostaglandin dehydrogenase) [27,45]. Non-prostanoid selective DP2 receptor agonists, structurally related to indomethacin, have been synthesized [18]. Selective DP1 receptor antagonists both prostanoid (e.g. BW-A868C) and non-prostanoid (e.g. laropiprant, ONO-AE3-237) in structure are available [see [28]]. DP2 receptor antagonists with a range of structures have been synthesized [62], including analogues of ramatroban, which was originally developed as a TP receptor antagonist [57].

Activation of DP1 receptors leads to inhibition of platelet activation and vasodilatation [11]. DP1 receptors are expressed in the brain, where they may be involved in the regulation of sleep [63]. Activation of DP2 receptors expressed on eosinophil, basophil, monocytes, CD4+ Th2 cells, CD8+ Th2 cells and type 2 innate lymphoid cells leads to activation and chemotaxis contributing to the effector phase of the allergic response. DP2 receptor is also involved in the process of allergic sensitisation and consequently antagonists hold promise as anti-inflammatory agents, particularly in eosinophilic asthma [46]. The interaction of the DP receptor subtypes in the control of inflammation is complex however (see [4] for a review).

EP receptors

As a broad generalization, EP1 and EP3 receptors mediate excitatory effects, while EP2 and EP4 receptors mediate inhibitory effects. EP1 receptors are believed to be coupled via regulatory G proteins to (PLC-independent) influx of extracellular Ca2+; phosphatidylinostol hydrolysis ensues as a consequence of this influx [31]. EP3 receptors are subject to splice variance at the C-terminus [40,64] and, to date, ten isoforms have been identified across species, six of these being expressed in man [3]. These isoforms differ in their G-protein coupling thereby contributing to the wide spectrum of EP3 receptor actions: contraction of smooth muscle, enhancement of platelet aggregation, inhibition of autonomic neurotransmitter release, inhibition of gastric acid secretion, and inhibition of fat cell lipolysis [11,56]. There is no published evidence that splice variance influences ligand affinity. EP2 and EP4 receptors preferentially couple through Gs protein to stimulate adenylate cyclase [11]. The functional selectivity of natural and synthetic EP4 receptor agonists has been assessed in terms of cAMP production, Gαi1 activation and β-arrestin 2 recruitment [34]. Both EP receptor subtypes may be present on smooth muscle cells with the latter usually showing considerably higher sensitivity to PGE2.

Selective agonists based on the PGE2 structure exist for all four EP receptor subtypes [28]. In addition, agonists with a non-prostanoid structure exist for EP2, EP3 and EP4 receptors. Saturation of the 5,6 double bond to produce 1-series analogues tends to promote IP receptor agonism. The first EP1 receptor antagonist was reported in 1969 [51]; later and more potent antagonists have progressed into clinical trials as analgesic/anti-inflammatory agents. Several chemical classes of selective EP3 receptor antagonist have emerged (some individual compounds are highly lipophilic). Recently, EP3 receptor antagonism has been investigated for inhibition of platelet activation in atherothrombotic disease [22,54]. Currently there is interest in selective EP4 receptors antagonists as anti-inflammatory agents [19,28] . Recently selective and potent EP2 receptor antagonists have emerged [1]; AH-6809, which blocks EP2, EP1 and DP1 receptors, has now become redundant.

FP receptors

FP receptors are believed to be coupled via a regulatory G protein to stimulation of PI hydrolysis [11,49,70]. They are found in smooth muscle, being particularly widely distributed in cats and dogs, where they mediate contraction. Fluprostenol is a highly selective FP agonist. FP receptors present in the corpus luteum of many species mediate luteolysis, and PGF analogues (fluprostenol, cloprostenol) have been used in animal husbandry to synchronize oestrus and induce parturition [32]. FP receptor-stimulation also profoundly lowers intraocular pressure in laboratory animal species and man [55,72] and FP receptor agonists applied topically as C1-ester pro-drugs (latanoprost, travoprost) are increasingly used as anti-glaucoma drugs [24]. FP receptor antagonists have been slow to emerge; AS-604872 [9] has been used to a limited extent. The PGF analogue AL-8810 appears to be a partial agonist at the FP receptor [20].

IP receptors

The classical prostacyclin (IP) receptor is coupled via a Gs protein to stimulation of adenylate cyclase [2] resulting in relaxation of vascular smooth muscle, inhibition of platelet aggregation and inhibition of cell proliferation [10,37]. In previous versions of this database, the term IP1 was used for this receptor on the basis of differing autoradiographic and pharmacological behaviours [59] indicative of a second (IP2) subtype (see [67] for a review). However, molecular biological evidence is not available at this time to support the subdivision and we have therefore reverted to the use of IP receptor.

Prostacyclin itself is rarely used as a standard IP receptor agonist owing to its instability under physiological conditions. Of the stable prostacyclin analogues available, cicaprost and selexipag are the most selective IP receptor agonists [5,13]; other commonly used agonists (carbacyclin, iloprost) have sufficient EP1 receptor and/or EP3 receptor agonism to oppose their IP-receptor-mediated actions (reviewed in [10]). Treprostinil also shows potent DP1 receptor and EP2 receptor agonism [58,66]. A large range of non-prostanoid prostacyclin mimetics exists [5,37]; while some of these agents appear to be IP receptor partial agonists, analysis is hampered by their ability to inhibit PLC-driven events via a non-prostanoid mechanism [8]. Selective IP receptor antagonists that competitively block the vasodilator, antiproliferative and platelet-inhibitory actions of IP receptor agonists have recently been described [6,14,30]. However, the most commonly used agent, RO-1138452, has reasonable affinity for α2 and imidazoline receptors, which may compromise its utility in isolated tissue studies.

The potential benefits of activation of IP receptors by endogenous prostacyclin in cardiovascular disease has received intense scrutiny of late owing to the tendency of selective COX-2 inhibitors to cause more adverse cardiovascular events than traditional COX-1/COX-2 inhibitors (see [21] for a review). However, PGI2 may not always have beneficial actions in the body as shown by the ability of IP antagonists to suppress hyperalgesia and oedema in animal models of inflammation [6]. Prostacyclin and a few of its stable analogues are used to treat pulmonary hypertension [10,37], with careful attention to dosage to avoid excessive lowering of arterial blood pressure in those patients with evidence of left heart disease [37].

TP receptors

TP receptors are present in nearly all mammalian blood vessels, airways and blood platelets, where they mediate smooth muscle contraction and platelet aggregation. Signal transduction occurs via regulatory G proteins linking to stimulation of PI hydrolysis [26]. Both PGH2 and TXA2 are potent agonists for the TP receptor, but are rarely used in characterization studies owing to the instability of their bicyclic ring systems. They are usually replaced by either 11,9-epoxymethano PGH2 (U-46619) or STA2, which are full agonists; other analogues often exhibit partial agonism (9,11-epoxymethano PGH2, CTA2, PTA2). Introduction of a 16-p-halophenoxy terminus dramatically increases TP receptor agonist potency (e.g. EP-171, I-BOP) [29,53], but their utility is often compromised by their slow onset/slow offset on isolated tissue preparations. There are many TP receptor antagonists, some of which are obviously analogues of PGH2/TXA2, while others bear little structural resemblance to prostanoids. GR-32191 [36] and SQ-29548 [43] are in common use. Heterogeneity in the affinities of TP receptor antagonists [42,61,65] has stimulated much debate about the existence of subtypes of TP receptor; however, species differences may account for much of the variation. On the other hand, there is now evidence for splice variance within TP receptors [23,48], and a resulting C-terminus extended form of the TP receptor has been shown to be particularly highly expressed in vascular endothelial cells [48]. Simple TP receptor antagonists have found little use in cardiovascular disease; preventative treatment with low-dosage aspirin is sufficient to tip the balance away from thromboxane [44]. However, the area is still active: terutroban improved endothelial function in high-cardiovascular-risk patients with atherosclerosis [35]. Agents combining TP receptor antagonism and TX synthase inhibition (ridogrel) have shown more promise [68].

Isoprostanes

There is interest in the isoprostanes [38-39], a class of prostanoids that are not products of the enzyme cyclo-oxygenase, but are rather formed by direct oxidation of membrane phospholipids. The isoprostanes exhibit a wide range of biological actions, and most evidence suggests that they act at the same receptors as the 'classical' prostanoids [16]. There is evidence, however, that 8-epi PGF may act at a receptor that, although similar to a TP receptor, is not identical [47].

Prostamide receptors

PGF-1-ethanolamide (prostamide PGF) and its analogue bimatoprost (an antiglaucoma drug) show a different pharmacology to their carboxylic acid counterparts. This has been explained in terms of heterodimerization of the wild-type FP receptor and an alternative mRNA splicing variant to give a ‘prostamide F receptor’ [73]. AGN-211336 (which bears some resemblance to the TP receptor antagonist BMS-180291), blocks the prostamide FP receptor but not the FP receptor [69].

References

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72. Woodward DF, Lawrence RA, Fairbairn CE, Shan T, Williams LS. (1993) Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies. J Lipid Mediat6 (1-3): 545-53. [PMID:8358015]

73. Woodward DF, Liang Y, Krauss AH. (2008) Prostamides (prostaglandin-ethanolamides) and their pharmacology. Br. J. Pharmacol.153 (3): 410-9. [PMID:17721551]

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To cite this family introduction, please use the following:

Robert L. Jones, Shuh Narumiya, David F. Woodward, Mark Giembycz, Xavier Norel.
Prostanoid receptors, introduction. Last modified on 05/09/2016. Accessed on 24/01/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=58.