1

MINIREVIEW

Prostaglandin E Receptors*

Yukihiko Sugimoto‡ and Shuh Narumiya§1

From the ‡Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, and the

§Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan

Abstract

Prostaglandin (PG) E2 exerts its actions by acting

on a group of G-protein-coupled receptors

(GPCRs). There are four GPCRs responding to

PGE2 designated subtypes EP1, EP2, EP3 and EP4

and multiple splicing isoforms of the subtype EP3.

The EP subtypes exhibit differences in signal

transduction, tissue localization and regulation of

expression. This molecular and biochemical

heterogeneity of PGE receptors leads to PGE2

being the most versatile prostanoid. Studies on

knockout mice deficient in each EP subtype have

defined PGE2 actions mediated by each subtype

and identified the role each EP subtype plays in

various physiological and pathophysiological

responses. Here we review recent advances in PGE

receptor research.

1. Introduction

Prostanoids including various

prostaglandins (PGs2) and thromboxanes (TXs) are

cyclooxygenase (COX) metabolites of C20-

unsaturated fatty acids such as arachidonic acid.

These substances are synthesized in response to

various stimuli in a variety of cells, released

immediately after synthesis, and act in the vicinity

of their synthesis to maintain local homeostasis (1).

Among prostanoids, the E type PGs, particularly

PGE2 derived from arachidonic acid, is most widely

produced in the body, most widely found in animal

species and exhibits most versatile actions.

Receptors mediating prostanoid actions were

characterized first by pharmacological analysis,

which indicated the presence of one receptor each,

named DP, FP, IP and TP, for PGs of the D, F and I

types and TXA, respectively, and four different

receptors designated EP1, EP2, EP3 and EP4 for

the E type PGs (Reviewed in 2,3). Molecular

identification of these receptors was achieved by

their cDNA cloning, which revealed that the

prostanoid receptors are G-protein coupled

receptors (GPCRs), and that there is indeed a

family of eight GPCRs that correspond to the

pharmacologically-defined receptors. In addition, a

recent study revealed the presence of the 9th

prostanoid receptor that belongs not to the

prostanoid receptor family described above but to

the chemoattaractant receptor family (4). This

http://www.jbc.org/cgi/doi/10.1074/jbc.R600038200The latest version is at JBC Papers in Press. Published on February 28, 2007 as Manuscript R600038200

Copyright 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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receptor called CRTH2 or DP2 is expressed in Th2

cells and eosinophils and mediates some of PGD2

actions on these cells such as chemotaxis. cDNA

cloning also revealed the presence of several

splicing variants for EP3. Thus, there are four

GPCRs designated subtypes EP1, EP2, EP3 and

EP4 and EP3 variants mediating PGE2 actions.

Subsequent analysis has revealed distinct

biochemical properties and tissue and cellular

localization of each EP subtype. The cloned EP

subtypes have also been used in the development of

compounds specific to each subtype.

2. Biochemical properties of PGE receptor

subtypes and isoforms

2-1. Molecular structures----- Fig. 1 shows an

alignment of the primary amino acid sequences of

the mouse EP1, EP2, EP4 and three isoforms of

mouse EP3 receptors. The mouse EP1, EP2, EP3

(EP3α) and EP4 receptors consist of 405, 362, 366

and 513 amino acids, respectively. EP4 has the

longest intracellular carboxyl terminus and a

relatively long intracellular third loop. The EP1

receptor also has a long third loop, while the EP2

and EP3 receptors have a more compact structure.

A remarkable feature distinguishing the EP3

receptor from the other EP receptors is the

existence of multiple variants generated by

alternative splicing of the C-terminal tail. In mouse,

alternative splicing creates three EP3 splice

isoforms, α, β and γ, containing C-terminal tails of

30, 26 and 29 amino acids that do not share any

structural motifs or hydrophobic features (5,6).

These isoforms show similar ligand binding

properties but have different signal transduction

properties as described below. Multiple splice

isoforms for EP3 also exist in other species

including rat, rabbit, bovine and human (3).

Although all of the four EP subtypes respond to

PGE2, the amino acid identity among the EPs is

limited; the identity of EP1 to EP2, EP3 and EP4 is

30%, 33% and 28% respectively. The amino acid

identity is only 31% even between the two EPs

–EP2 and EP4- that couple to the activation of

adenylate cyclase. The EP2 receptor is more

homologous to IP (40%) and DP (44%), the other

two adenylate cyclase-stimulatory prostanoid

receptors, than any other EPs and that the EP1

receptor is more homologous to FP (35%) and TP

(34%) than other EPs. This limited homology

among EPs probably reflects the phylogenetic

relationship among the prostanoid receptors (7).

2-2. Ligand binding properties ----- The EP

subtypes bind most potently to PGE2 with Kd values

in the range of 1-40 nM. Iloprost, an IP-agonist,

also binds to EP1 and EP3 with Ki values of about

20 nM. The PGE analogs that have been used in

conventional studies are not specific for any given

EP subtype except butaprost, which is specific for

EP2. Several compounds highly selective for each

EP subtype have been developed using cultured cell

lines stably expressing each subtype. Examples are

shown in Fig. 2 (8-11).

2-3. Signal transduction properties ----- Signal

transduction pathways of EP subtypes have been

studied by examining agonist-induced changes in

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second messengers such as cAMP, Ca2+, and

inositol phosphates, and agonist-induced changes in

activities of downstream kinases. The EP1 receptor

mediates a PGE2-induced elevation of the free Ca2+

concentration in CHO cells. This increase is

dependent on extracellular Ca2+ and occurs without

a detectable phosphatidylinositide response (12),

suggesting that EP1 regulates Ca2+ channel gating

via an unidentified G protein. It was reported that

EP1 expressed in Xenopus oocytes can couple to

TRP5, a candidate for the receptor-activated Ca2+

channel (RACC), and this coupling is inhibited by

an anti-sense oligonucleotide for Gq/G11 but not by

one for Gi1 (13). The EP2 and EP4 receptors couple

to Gs and mediate increases in cAMP

concentrations. The major signaling pathway of the

EP3 receptor is inhibition of adenylate cyclase via

Gi. It should be noted, however, that the EP

receptors do not couple exclusively to the pathways

described but often to more than one G protein and

signal transduction pathway (Table 1). Of interest

in this respect is the presence of two EPs, EP2 and

EP4, that are coupled to increases in cAMP. They

apparently function redundantly in some processes.

For example, both EP2 and EP4 mediate induction

of RANKL through cAMP by PGE2 in

osteoclastogenesis, although the extent of the

contribution by each receptor may be different

(14,15). On the other hand, there are processes in

which EP2 and EP4 play distinct roles. Some of

these may be due to selective expression of either

of them in relevant cells such as the action of EP2

during cumulus expansion in ovulation and

fertilization (16) and that of EP4 in closure of the

ductus arteriosus (17). However, only EP4

regulates migration of dendritic cells in the mouse,

although both EP2 and EP4 are expressed in these

cells (18). This EP4-selective action may be

related to the fact that EP4 but not EP2 couples to

PI 3-kinase, probably via Gi, in addition to

activation of adenylate cyclase (19, 20). It is

interesting in this respect that EP4 is also

implicated in cell migration during tumor invasion

(21), for ductus arteriosus closure (22) and for

zebrafish gastrulation (23). As described, the EP3

receptor consists of multiple isoforms generated by

alternative splicing of the C-terminal tail.

Functional differences among these splice variants

have been reported, including coupling to different

signal transduction pathways (Table 1) (24),

different sensitivities to agonist-induced

desensitization (25), different extents of

constitutive activity (26), different intracellular

trafficking patterns (27), and different agonist-

induced internalization patterns (28).

2-4. Tissue distribution and cellular localization --

--- Northern blot analysis and in situ hybridization

have provided detailed information about EP

receptor distribution, and have shown that each

receptor is specifically distributed in the body and

that the expression levels are variable among

tissues. The tissue distribution of the mouse EP

subtypes assessed by Northern blot analyses is

presented in Fig. 3A (29-32). Among the four EPs,

EP3 and EP4 receptors are the most widely

distributed, with their mRNAs being expressed in

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almost all mouse tissues examined. In contrast,

the distribution of EP1 mRNA is restricted to

several organs, such as the kidney, lung and

stomach, and EP2 is the least abundant of the EP

receptors. Within tissues, each EP subtype shows

a distinct cellular localization. For example, in

the kidney, EP3 is expressed in the tubular

epithelium, the thick ascending limb and the

cortical collecting ducts in the outer medulla, EP1

in the papillary collecting ducts and EP4 in the

glomerulus (33) (Fig. 3B). This distribution pattern

appears to correlate with the PGE2-mediated

regulation of ion transport, water reabsorption and

glomerular filtration, respectively. A similar

distribution of EPs in the kidney has been reported

in the rabbit and human (34, 35). These analyses

did not detect signals for EP2 mRNA in the kidney.

2-5. Regulation of expression ----- Expression of

EP genes is regulated by various physiological and

pathophysiological stimuli. In peritoneal resident

macrophages (36) and a macrophage cell line,

J774.1 (37), EP4 is expressed under basal

conditions. The addition of lipopolysaccharide

(LPS) induces EP2 expression markedly in both

types of cells, but enhances the EP4 expression

only slightly in J774.1 cells, and suppresses the

expression of EP4 in the resident macrophages (36).

Macrophages produce a large amount of PGE2 in

response to LPS, and suppression of the EP4

expression in the resident macrophages was

prevented by treatment with indomethacin and was

mimicked by the addition of dibutyryl cAMP or

PGE2 but not butaprost, suggesting that EP4

expression is regulated through a negative feedback

loop. The presence of EP2 and EP4 and

augmentation of their expression by LPS

stimulation was also seen in the RAW 264.7 murine

macrophage-like cell line (38). Quantative RT-PCR

analysis indicated a 3-fold increase in EP4 mRNA

2.5 h after LPS stimulation. In thioglycolate-

elicited macrophages, macrophage engagement

with extracellular matrix (ECM) induces expression

of both EP2 and EP4 and COX-2 in a MAPKerk1/2-

dependent manner (39).

In female reproductive organs such as

the ovary and uterus, hormonal exposure induces

expression of the EP subtypes in specific cell types.

In the ovary, the EP4 expression is found in oocytes

in preantral follicles. Upon gonadotropin

stimulation, this expression disappears, and EP4 is

expressed first in both granulosa cells and cumulus

cells and then only in granulosa cells in

preovulatory follicles. EP2 expression is found in

both granulosa cells and cumulus cells in preantral

follicles. This expression increases upon

gonadotropin stimulation, and becomes confined to

the cumulus cells just before ovulation.

Interestingly, COX-2 expression changes in a

similar pattern to EP2 upon gonadotropin

stimulation in cumulus and mural granulosa cells

(40). In the uterus, when mice are primed with

gonadotropins and undergo pseudopregnancy, EP2

is transiently expressed on day 5 in luminal

epithelial cells. EP4 expression is limited to

luminal epithelial cells on day 0, sharply increases

on day 3 and is then found in endometrial stromal

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cells as well as glandular epithelium. EP3

expression is found in longitudinal muscle layer

before stimulation. After stimulation, this

expression disappears and EP3 is expressed in

circular smooth muscles with a further increase on

days 3 and 5 (41).

Promoter analysis has been done for EP2

and EP4. Several consensus sequences relevant to

inflammatory stimuli such as those for NF-IL6,

NFκB and AP2 are found, and several regions

responsive to progesterone have been characterized

in the promoter region of the EP2 gene (42). The

promoter region of the EP4 gene contains several

putative cis-acting elements such as sites for AP1,

AP2, Sp1, NFκB, MyoD, and NF-IL6 as well as a

putative glucocorticoid response element.

Functional analysis detected an LPS/serum

responsive region between -554 and -116 bp (38).

3. Physiological functions of the EP subtypes

Mice deficient in each EP subtype

individually have been generated and studies using

these knockout mice and subtype-specific EP

agonists/antagonists have identified EP subtypes

mediating various PGE2 actions (Table 2). EP

subtypes mediate many processes known to be

inhibited by non-steroidal anti-inflammatory drugs

(NSAIDs). For example, the EP3 receptor mediates

generation of pyrogenic fever (54), and EP1 and

EP3 signals converge at the paraventricular nucleus

of the hypothalamus and mediate neuroendocrine

stress response by facilitating release of

corticotropin releasing hormone (43). EP2

facilitates ovulation and fertilization by inducing

expansion of the cumulus, thus clarifying the

mechanism for the inhibitory effect of NSAIDs on

ovulation (16). Other studies have revealed that

different EP subtypes as well as the IP receptor

function in hyperalgesia both at the periphery and

in the CNS. For example, the acetic acid writhing

test revealed the involvement of both IP and EP3 in

hyperalgesia (57, 61). Pain sensation that is

induced by pH and heat and mediated by the

capsaicin receptor TRPV1 is augmented by PGE2

and PGI2 acting on EP1 and IP, respectively (46).

Furthermore, in the spinal cord, PGE2 acting on

EP2 in glycinergic neurons abolishes the glycine-

induced tonic inhibition of pain neuron in the

dorsal horn and facilitates the propagation of

nociceptive signals through the spinal cord to

higher areas of the CNS (48).

Prostanoids, particularly PGE2, have

been thought to play a major role in acute

inflammation by acting on the peripheral

circulation and inducing hyperemia and swelling.

One of the lessons learned from the knockout

mouse studies, however, is that prostanoids

including PGE2 exert both pro-inflammatory and

anti-inflammatory responses and these actions are

often produced through regulation of gene

expression in relevant tissues. For example,

consistent with the anti-inflammatory and anti-

arthritic effect of NSAIDs, EP2 and EP4 (and IP)

redundantly mediate development of collagen-

induced arthritis (49). Intriguingly, however, the

pro-inflammatory actions of these prostanoid

receptors are elicited mainly by induction of

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arthritis-associated genes in the joint. As for

inflammatory swelling, studies using the

carrageenin-induced paw edema model revealed

involvement of IP (61), and those using

carrageenin-induced pleurisy revealed participation

of EP2, EP3 and IP in inflammatory exudation (62).

Anti-inflammatory actions of prostanoids are seen

typically in allergic or immune inflammation, and

are usually balanced by pro-inflammatory actions

of other prostanoids. This may explain why

NSAIDs are without effects on allergy and immune

responses. Examples are the antagonism between

the PGD2-DP (63) and the PGE2-EP3 (55) pathways

in elicitation of allergic asthma. DP and EP3 are

both present in the airway epithelium and activation

of the latter suppresses expression of a series of

allergy-related genes and progression of allergic

inflammation. Knockout mice studies have also

revealed that prostanoids work at multiple steps in

hapten-induced immune responses. Interestingly,

most of these actions are found in the immunization

and not in the elicitation process. The PGD2-DP

pathway suppresses (64) and the PGE2-EP4

pathway facilitates (18) mobilization, migration

and maturation of Langerhans cells in the skin, and

the TXA2-TP pathway negatively modulates

interaction between activated Langerhans cells and

naïve T-cells, thereby suppressing T cell

proliferation and differentiation (65). PGE2 together

with other prostanoids can thus modulate various

steps of inflammation in a context-dependent

manner and coordinate the whole process in both

pro-inflammatory and anti-inflammatory directions.

4. Concluding remark

The mechanisms whereby PGE2 exerts

its pleiotropic, once a mystery in physiology, have

been clarified through the biochemical

identification and cDNA cloning of the four EP

subtype receptors. Furthermore, development of

highly selective agonists and antagonists to each EP

subtype and information obtained by studies on

mice deficient in each EP receptor now provide

opportunities to apply our knowledge to manipulate

various PGE2-mediated pathological processes.

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Acknowledgments

We regret being unable to cite all relevant references, due to space constraints. We thank all members of ourdepartments and all collaborators on prostanoid receptors.

Footnotes* This minireview will be reprinted in the 2006 Minireview Compendium, which will be available in January,2007. Work in our laboratories was supported in part by Grants-in-Aid for Scientific Research from theMinistry of Education, Culture, Sports Science and Technology of Japan and from the Ministry of Health andLabor of Japan.

1To whom correspondence should be addressed. Tel:81-75-753-4392; Fax: 81-75-753-4693; E-mail:snaru@mfour.med.kyoto-u.ac.jp2The abbreviations used are: CNS, central nervous system; COX, cyclooxygenase; ECM, extracellularmatrix; GPCR, G-protein coupled receptor; LPS, lipopolysaccharide; MAPK, mitogen-activated proteinkinase; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin; TNF, tumor necrosis factor; TX,thromboxane

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TABLE 1. Signal transduction properties of EP receptor subtypes and EP3 isoforms

Data obtained from mouse EP subtypes are summarized, and representative signal transduction pathways foreach receptor are shown. PI3K, phosphatidylinositol 3-kinase; ↑, increase; ↓, decrease.

Subtype IsoformAmino

acid G protein Signaling DesensitizationConstitutive

activityEP2 362 Gs cAMP↑ NoEP4 513 Gs (Gi) cAMP↑, PI3K YesEP1 405 unknown Ca2+↑ −EP3 EP3α

EP3βEP3γ

366362365

Gi, G12

Gi, G12

Gi, Gs

cAMP↓, IP3/Ca2+↑,RhocAMP↓, IP3/Ca2+↑,Rho

cAMP↓, cAMP↑, IP3/Ca2+↑

YesNo-

++-+

TABLE 2. Physiological function of EP receptor subtypes

Physiological and pathophysiological actions of EP receptor subtypes based on the studies using eachreceptor-deficient mice are shown.

Subtype Function Reference

EP1 mediates stress responses (ACTH secretion & stress behavior) 43, 44

promotes chemical carcinogenesis 45

mediates inflammatory thermal hyperalgesia 46

EP2 facilitates ovulation and fertilization 16

mediates intestinal polyp formation in Apc∆716 mice 47

facilitates pain transmission by abolishing glycinergic inhibition 48

mediates joint inflammation in collagen-induced arthritis 49

suppresses dendritic cell differentiation 50

facilitates neutrophil recruitment by G-CSF production 51

promotes amyloid-β formation in Alzheimer’s disease 52

mediates COX-2-induced mammary hyperplasia 53

EP3 mediates fever generation 54

suppresses type I allergy 55

mediates angiogenesis associated with tumor and chronic inflammation 11

regulates duodenal secretion 56

induces endotoxin-elicited enhanced pain perception 57

mediates pain associated with virus infection 58, 59

EP4 facilitates closure of ductus arteriosus 17, 22

induces bone formation 60

protects against inflammatory bowel disease 10

facilitates Langerhans cell migration and maturation 18

mediates joint inflammation in collagen-induced arthritis 49

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FIGURE LEGENDS

FIGURE 1. Amino acid sequence alignments of the mouse EP2, EP4, EP1 and three isoforms of EP3

receptors. Amino acid identity (three or four out of four subtypes) is indicated by shading, predicted

transmembrane domains are shown by overlining and gaps are indicated by dashes.

FIGURE 2. Structures of prostaglandin E2 and EP-selective agonists and antagonists. The Ki values

(nM) of the compounds obtained by competition-binding isotherms to displace [3H]PGE2 binding to the EP1,

EP2, EP3 and EP4 receptors are shown in parentheses (8-11). Additional information about the structures

and binding affinities of other synthetic compounds for EPs is available at the IUPHAR Receptor Database

site. (http://www.iuphar-db.org/GPCR/index.html)

FIGURE 3. A. Tissue distribution of EP subtypes. Poly(A)+ RNA isolated from the indicated tissues (5 µg

for EP1 and EP2; 10 µg for EP3 and EP4) was applied in each lane. Hybridization was carried out using

the anti-sense RNA probes (EP1 and EP2) or cDNA fragment probes (EP3 and EP4) (29-32). B.

Localization of EP subtypes in mouse kidney. In situ hybridization signals for EP1, EP3 and EP4 in renal

sections are presented in a dark-field manner (33). Bar = 1 mm.

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Yukihiko Sugimoto and Shuh NarumiyaProstaglandin E receptor

published online February 28, 2007J. Biol. Chem. 

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