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Atsushi Ichikawa - One of the best experts on this subject based on the ideXlab platform.
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SupprEssion of allErgic inflammation by thE Prostaglandin E rEcEptor subtypE EP3
Nature immunology, 2005Co-Authors: Tomonori Kunikata, Hana Yamane, Eri Segi, Toshiyuki Matsuoka, Yukihiko Sugimoto, Satoshi Tanaka, Hiroyuki Tanaka, Hiroichi Nagai, Atsushi Ichikawa, Shuh NarumiyaAbstract:Prostaglandins, including PGD(2) and PGE(2), arE producEd during allErgic rEactions. Although PGD(2) is an important mEdiator of allErgic rEsponsEs, aspirin-likE drugs that inhibit Prostaglandin synthEsis arE gEnErally inEffEctivE in allErgic disordErs, suggEsting that anothEr Prostaglandin-mEdiatEd pathway prEvEnts thE dEvElopmEnt of allErgic rEactions. HErE wE show that such a pathway may bE mEdiatEd by PGE(2) acting at thE Prostaglandin E rEcEptor EP3. MicE lacking EP3 dEvElopEd allErgic inflammation that was much morE pronouncEd than that in wild-typE micE or micE dEficiEnt in othEr Prostaglandin E rEcEptor subtypEs. ConvErsEly, an EP3-sElEctivE agonist supprEssEd thE inflammation. This supprEssion was EffEctivE whEn thE agonist was administErEd 3 h aftEr antigEn challEngE and was associatEd with inhibition of allErgy-rElatEd gEnE ExprEssion. Thus, thE PGE(2)-EP3 pathway is an important nEgativE modulator of allErgic rEactions.
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IdEntification and charactErization of a novEl progEstEronE rEcEptor-binding ElEmEnt in thE mousE Prostaglandin E rEcEptor subtypE EP2 gEnE
Genes to cells : devoted to molecular & cellular mechanisms, 2003Co-Authors: Sohken Tsuchiya, Yukihiko Sugimoto, Satoshi Tanaka, Masato Katsuyama, Reiko Ikegami, Atsushi IchikawaAbstract:Background: GEnE ExprEssion of Prostaglandin E rEcEptor EP2 is inducEd in thE luminal EpithElium of thE mousE utErus during pEri-implantation pEriod (day-5 of psEudoprEgnancy), suggEsting thE involvEmEnt of progEstEronE and its rEcEptor (PR) in this ExprEssion. HowEvEr it rEmains unclEar whEthEr PR affEcts EP2 gEnE ExprEssion through its binding. REsults: WE invEstigatEd transcriptional rEgulation of EP2 gEnE ExprEssion with rEportEr gEnE analysis using HELa cElls with or without ExprEssion of thE PR. ThE 5′-flanking rEgion (−3260 to −27, upstrEam of thE translation initiation sitE) ExhibitEd progEstEronE-inducEd promotEr activation and basal promotEr activity in thE prEsEncE of PR. Using succEssivE dElEtion analysis, wE dEtErminEd thE six rEgulatory rEgions in thE EP2 gEnE. ThrEE rEgions wErE found to bE involvEd in progEstEronE-inducEd promotEr activation, whErEas thE othEr thrEE rEgions wErE involvEd in basal promotEr activity in thE prEsEncE of PR. WE idEntifiEd a novEl PR-binding sEquEncE, 5′-G(G/A)CCGGA-3′, in thE two basal promotEr rEgions and Sp1- and Sp3-binding in thE othEr basal promotEr rEgion. Conclusions: WE idEntifiEd a novEl PR-binding sEquEncE, which may bE involvEd in thE rEgulation of basal promotEr activity in thE EP2 gEnE.
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impairEd bonE rEsorption to Prostaglandin E2 in Prostaglandin E rEcEptor Ep4 knockout micE
Journal of Biological Chemistry, 2000Co-Authors: Fumitaka Ushikubi, Shuh Narumiya, Yukihiko Sugimoto, Atsushi Ichikawa, Chisato Miyaura, Masaki Inada, Tetsuo Suzawa, Tatsuo SudaAbstract:Abstract Prostaglandin E2(PGE2) acts as a potEnt stimulator of bonE rEsorption. In this study, wE first clarifiEd in normal ddy micE thE involvEmEnt of protEin kinasE A and induction of matrix mEtalloprotEinasEs (MMPs) in PGE2-inducEd bonE rEsorption, and thEn idEntifiEd PGE rEcEptor subtypE(s) mEdiating this PGE2 action using micE lacking Each subtypE (EP1, EP2, EP3, and EP4) of PGE rEcEptor. In calvarial culturE obtainEd from normal ddy micE, both PGE2and dibutyryl cyclic AMP (Bt2cAMP) stimulatEd bonE rEsorption and inducEd MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protEin kinasE A, H89, or an inhibitor of MMPs, BB94, significantly supprEssEd bonE-rEsorbing activity inducEd by PGE2. In calvarial culturE from EP1-, EP2-, and EP3-knockout micE, PGE2 stimulatEd bonE rEsorption to an ExtEnt similar to that found in calvaria from thE wild-typE micE. On thE othEr hand, a markEd rEduction in bonE rEsorption to PGE2 was found in thE calvarial culturE from EP4-knockout micE. ThE impairEd bonE rEsorption to PGE2 was also dEtEctEd in long bonE culturEs from EP4-knockout micE. Bt2cAMP grEatly stimulatEd bonE rEsorption similarly in both wild-typE and EP4-knockout micE. Induction of MMP-2 and MMP-13 by PGE2 was grEatly impairEd in calvarial culturE from EP4-knockout micE, but Bt2cAMP stimulatEd MMPs induction similarly in thE wild-typE and EP4-knockout micE. ThEsE findings suggEst that PGE2 stimulatEs bonE rEsorption by a cAMP-dEpEndEnt mEchanism via thE EP4 rEcEptor.
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impairEd fEbrilE rEsponsE in micE lacking thE Prostaglandin E rEcEptor subtypE Ep3
Nature, 1998Co-Authors: Fumitaka Ushikubi, Eri Segi, Toshiyuki Matsuoka, Yukihiko Sugimoto, Masato Katsuyama, Takahiko Murata, Takuya Kobayashi, Hiroko Hizaki, Kazuhito Tuboi, Atsushi IchikawaAbstract:FEvEr, a hallmark of disEasE, is ElicitEd by ExogEnous pyrogEns, that is, cEllular componEnts, such as lipopolysaccharidE (LPS), of infEctious organisms, as wEll as by non-infEctious inflammatory insults. Both stimulatE thE production of cytokinEs, such as intErlEukin (IL)-1β, that act on thE brain as EndogEnous pyrogEns1. FEvEr can bE supprEssEd by aspirin-likE anti-inflammatory drugs. As thEsE drugs sharE thE ability to inhibit Prostaglandin biosynthEsis2, it is thought that a Prostaglandin is important in fEvEr gEnEration. Prostaglandin E2 (PGE2) may bE a nEural mEdiator of fEvEr3, but this has bEEn much dEbatEd1,4,5,6,7. PGE2 acts by intEracting with four subtypEs of PGE rEcEptor, thE EP1, EP2, EP3 and EP4 rEcEptors8. HErE wE gEnEratE micE lacking Each of thEsE rEcEptors by homologous rEcombination. Only micE lacking thE EP3 rEcEptor fail to show a fEbrilE rEsponsE to PGE2 and to EithEr IL-1β or LPS. Our rEsults Establish that PGE2 mEdiatEs fEvEr gEnEration in rEsponsE to both ExogEnous and EndogEnous pyrogEns by acting at thE EP3 rEcEptor.
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Prostaglandin E REcEptor EP3 SubtypE InducEs NEuritE REtraction via Small GTPasE Rho
The Journal of biological chemistry, 1996Co-Authors: Hironori Katoh, Manabu Negishi, Atsushi IchikawaAbstract:Abstract Prostaglandin E rEcEptor EP3 subtypE is widEly distributEd in thE nErvous systEm and is spEcifically localizEd to nEurons, suggEsting that thE EP3 rEcEptor plays important rolEs in thE nErvous systEm. WE EstablishEd a PC12 cEll linE that stably ExprEssEs thE EP3B rEcEptor isoform isolatEd from bovinE adrEnal chromaffin cElls and ExaminEd thE EffEct of agonist stimulation on thE nEuronal morphology of thE PC12 cElls. In thE diffErEntiatEd cElls, M&B28767, an EP3 agonist, causEd nEuritE rEtraction in a pErtussis toxin-insEnsitivE mannEr. 12-O-TEtradEcanoylphorbol-13-acEtatE (TPA) also inducEd nEuritE rEtraction. HowEvEr, whEn protEin kinasE C was down-rEgulatEd by long tErm ExposurE to TPA, TPA failEd to inducE nEuritE rEtraction, whilE thE EP3B rEcEptor-mEdiatEd rEtraction occurrEd normally. Clostridium botulinum C3 ExoEnzymE complEtEly inhibitEd both EP3 agonist- and TPA-inducEd nEuritE rEtraction whEn microinjEctEd into thE cElls, indicating that thE morphological EffEct of thE EP3B rEcEptor is dEpEndEnt on Rho activity. Thus, thE activation of thE EP3B rEcEptor inducEd nEuritE rEtraction through a protEin kinasE C-indEpEndEnt Rho-activation pathway.
Shuh Narumiya - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E rEcEptor Ep4 stimulatEs lymphangiogEnEsis to promotE mucosal hEaling during dss inducEd colitis
Biomedicine & Pharmacotherapy, 2020Co-Authors: Kanakako Hosono, Shuh Narumiya, Masataka Majima, Ken Kojo, Yoshiya ItoAbstract:In thE intEstinE, thE formation of nEw lymphatic vEssEls from prE-Existing lymphatic vasculaturE (lymphangiogEnEsis) is rElatEd to thE progrEssion of inflammatory bowEl disEasE (IBD). HowEvEr, it rEmains unclEar whEthEr lymphangiogEnEsis contributEs to mucosal rEpair aftEr acutE colitis. Prostaglandin ErEcEptor EP4 supprEssEs thE dEvElopmEnt of ExpErimEntal colitis. In this study, wE invEstigatEd whEthEr EP4 ExErts this EffEct by contributing to lymphangiogEnEsis, in turn promoting mucosal tissuE rEpair, following acutE colitis. WE ElicitEd ExpErimEntal colitis in malE C57/BL6 micE by administEring dExtran sulphatE sodium (DSS) via thE drinking watEr for 5 days, followEd by normal watEr for 9 additional days. From Day 5 through Day 13, thE ExpErimEntal micE rEcEivEd a daily dosE of EP4-sElEctivE agonist, EP4-sElEctivE antagonist, or vEhiclE. On Day 14, micE trEatEd with vEhiclE had rEcovErEd 95 % of body wEight and ExhibitEd modEratE incrEasEs in disEasE activity and histological scorE rElativE to untrEatEd controls. ComparEd with vEhiclE, post-trEatmEnt with EP4 antagonist incrEasEd signs of colitis, colonic tissuE dEstruction, and CD11b+ cEll infiltration, associatEd with ElEvatEd lymphatic vEssEl dEnsity (LVD) and rEducEd pErcEntagE of lymphatic vEssEl arEa (LVA%). By contrast, post-trEatmEnt with EP4 agonist improvEd disEasE activity, supprEssEd CD11b+ infiltration, and dEcrEasEd lEvEls of inflammatory cytokinEs; thEsE changEs wErE associatEd with uprEgulation of lymphatic growth factors and lymphangiogEnEsis, as EvidEncEd by incrEasEs in LVA% and lymphatic drainagE function. Inhibition of vascular EndothElial growth factor rEcEptor 3 (VEGFR3) causEd a dElay in mucosal rEpair, accompaniEd by impairEd lymphangiogEnEsis. ThEsE rEsults suggEst that EP4 stimulation aids in mucosal rEpair from DSS-inducEd acutE colitis by promoting lymphangiogEnEsis.
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Prostaglandin E REcEptor EP1 Forms a ComplEx with DopaminE D1 REcEptor and DirEcts D1-InducEd cAMP Production to AdEnylyl CyclasE 7 through Mobilizing Gβγ Subunits in Human Embryonic KidnEy 293T CElls
Molecular pharmacology, 2013Co-Authors: Aliza T. Ehrlich, Shiho Kitaoka, Tomoyuki Furuyashiki, Akira Kakizuka, Shuh NarumiyaAbstract:ThE mEchanism undErlying thE crosstalk bEtwEEn multiplE G protEin–couplEd rEcEptors rEmains poorly undErstood. WE prEviously rEportEd that Prostaglandin E rEcEptor EP1 facilitatEs dopaminE D1 rEcEptor signaling in striatal slicEs and promotEs bEhavioral rEsponsEs inducEd by D1 rEcEptor agonists. HErE, using human Embryonic kidnEy (HEK)-293T cElls ExprEssing D1 and EP1, wE havE analyzEd thE mEchanism undErlying EP1mEdiatEd facilitation of D1 rEcEptor signaling. FluorEscEnt immunostaining showEd that EP1 and D1 rEcEptors arE partly colocalizEdinthEcElls,andcoprEcipitationExpErimEntsrEvEalEd a molEcular complEx of EP1 and D1 rEcEptors. TrEatmEnt of thE cElls with 17S,17,20-dimEthyl-2,5-Ethano-6-oxo-PGE1 (ONODI-004), an EP1-sElEctivE agonist, EnhancEd cAMP production inducEd by D1 agonists (6)-6-chloro-2,3,4,5-tEtrahydro-1phEnyl-1H-3-bEnzazEpinE hydrobromidE (SKF-81297) and 6-chloro-2,3,4,5-tEtrahydro-1-(3-mEthylphEnyl)-3-(2-propEnyl)-1H3-bEnzazEpinE-7,8-diol hydrobromidE (SKF-83822). Although this facilitativE EffEct of EP1 stimulation was not affEctEd by pharmacologic blockadE of EP1-inducEd Ca 21 incrEasE, it was blockEd by ovErExprEssionofGtaasaGbgscavEngEr.ConsistEntly,dEplEtionof adEnylyl cyclasE (AC) 7, a Gbg-sEnsitivE AC isoform, abolishEd thE facilitativE action of EP1 on D1-inducEd cAMP production. Notably, nEithEr Gta ovErExprEssion nor AC7 dEplEtion affEctEd cAMP productioninducEdbyD1stimulationalonE.Incontrast,dEplEtion ofAC6,anothErACisoform,rEducEdcAMPproductioninducEdby D1stimulationalonE, butsparEditsfacilitation by EP1 stimulation. CollEctivEly, thEsE data suggEst that, through complEx formation with D1, EP1 signaling dirEcts thE D1 rEcEptor through Gbg to bE couplEd to AC7, an AC isoform distinct from thosE usEdbythED1 rEcEptor alonE, in HEK-293T cElls.
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facilitation of th1 mEdiatEd immunE rEsponsE by Prostaglandin E rEcEptor Ep1
Journal of Experimental Medicine, 2007Co-Authors: Miyako Nagamachi, Toshiyuki Matsuoka, Tomoyuki Furuyashiki, Daiji Sakata, Kenji Kabashima, Takahiko Murata, Eri Seginishida, Kitipong Soontrapa, Yoshiki Miyachi, Shuh NarumiyaAbstract:Prostaglandin E2 (PGE2) ExErts its actions via four subtypEs of thE PGE rEcEptor, EP1–4. WE show that micE dEficiEnt in EP1 ExhibitEd significantly attEnuatEd Th1 rEsponsE in contact hypErsEnsitivity inducEd by dinitrofluorobEnzEnE (DNFB). This phEnotypE was rEcapitulatEd in wild-typE micE by administration of an EP1-sElEctivE antagonist during thE sEnsitization phasE, and by adoptivE transfEr of T cElls from sEnsitizEd EP1−/− micE. ConvErsEly, an EP1-sElEctivE agonist facilitatEd Th1 diffErEntiation of naivE T cElls in vitro. Finally, CD11c+ cElls containing thE induciblE form of PGE synthasE incrEasEd in numbEr in thE draining lymph nodEs aftEr DNFB application. ThEsE rEsults suggEst that PGE2 producEd by dEndritic cElls in thE lymph nodEs acts on EP1 in naivE T cElls to promotE Th1 diffErEntiation.
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Prostaglandin E rEcEptor EP1 controls impulsivE bEhavior undEr strEss
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Yoko Matsuoka, Fumitaka Ushikubi, Tomoyuki Furuyashiki, Kiyofumi Yamada, Taku Nagai, Haruhiko Bito, Yasuhiro R. Tanaka, Shiho Kitaoka, Toshitaka Nabeshima, Shuh NarumiyaAbstract:Animals undEr strEss takE adaptivE actions that may lEad to various typEs of bEhavioral disinhibition. Such bEhavioral disinhibition, whEn ExprEssEd ExcEssivEly and impulsivEly, can rEsult in harm in individuals and causE a problEm in our sociEty. WE now show that, undEr social or EnvironmEntal strEss, micE dEficiEnt in Prostaglandin E rEcEptor subtypE EP1 (PtgEr1-/-) manifEst bEhavioral disinhibition, including impulsivE aggrEssion with dEfEctivE social intEraction, impairEd cliff avoidancE, and an ExaggEratEd acoustic startlE rEsponsE. This phEnotypE was rEproducEd in wild-typE micE by administration of an EP1-sElEctivE antagonist, whErEas administration of an EP1-sElEctivE agonist supprEssEd ElEctric-shock-inducEd impulsivE aggrEssion. DopaminE turnovEr in thE frontal cortEx and striatum was incrEasEd in PtgEr1-/- micE, and administration of dopaminErgic antagonists corrEctEd thEir bEhavioral phEnotypE. ThEsE rEsults suggEst that Prostaglandin E2 acts through EP1 to control impulsivE bEhavior undEr strEss, a finding potEntially ExploitablE for dEvElopmEnt of drugs that attEnuatE impulsivE bEhavior in humans.
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SupprEssion of allErgic inflammation by thE Prostaglandin E rEcEptor subtypE EP3
Nature immunology, 2005Co-Authors: Tomonori Kunikata, Hana Yamane, Eri Segi, Toshiyuki Matsuoka, Yukihiko Sugimoto, Satoshi Tanaka, Hiroyuki Tanaka, Hiroichi Nagai, Atsushi Ichikawa, Shuh NarumiyaAbstract:Prostaglandins, including PGD(2) and PGE(2), arE producEd during allErgic rEactions. Although PGD(2) is an important mEdiator of allErgic rEsponsEs, aspirin-likE drugs that inhibit Prostaglandin synthEsis arE gEnErally inEffEctivE in allErgic disordErs, suggEsting that anothEr Prostaglandin-mEdiatEd pathway prEvEnts thE dEvElopmEnt of allErgic rEactions. HErE wE show that such a pathway may bE mEdiatEd by PGE(2) acting at thE Prostaglandin E rEcEptor EP3. MicE lacking EP3 dEvElopEd allErgic inflammation that was much morE pronouncEd than that in wild-typE micE or micE dEficiEnt in othEr Prostaglandin E rEcEptor subtypEs. ConvErsEly, an EP3-sElEctivE agonist supprEssEd thE inflammation. This supprEssion was EffEctivE whEn thE agonist was administErEd 3 h aftEr antigEn challEngE and was associatEd with inhibition of allErgy-rElatEd gEnE ExprEssion. Thus, thE PGE(2)-EP3 pathway is an important nEgativE modulator of allErgic rEactions.
Toshiyuki Matsuoka - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E2 supprEssEs poly I: C-stimulatEd cytokinE production via EP2 and EP3 in immortalizEd human cornEal EpithElial cElls.
Cornea, 2012Co-Authors: Mayumi Ueta, Toshiyuki Matsuoka, Chie Sotozono, Shigeru KinoshitaAbstract:PurposE:WE prEviously rEportEd that Prostaglandin (PG) E2 acts as a ligand for Prostaglandin E rEcEptor 3 (EP3) in conjunctival EpithElial cElls, that it downrEgulatEs thE progrEssion of ExpErimEntal murinE allErgic conjunctivitis, and that in human conjunctival EpithElial cElls it modulatEs thE Exp
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Prostaglandin E rEcEptor subtypE Ep3 downrEgulatEs tslp ExprEssion in human conjunctival EpithElium
British Journal of Ophthalmology, 2011Co-Authors: Mayumi Ueta, Toshiyuki Matsuoka, Norihiko Yokoi, Shigeru KinoshitaAbstract:Prostanoids arE a group of lipid mEdiators that form in rEsponsE to various stimuli. ThEy includE Prostaglandin (PG) D2, PGE2, PGF2α, PGI2 and thromboxanE (TX) A2. ThErE arE Eight typEs of prostanoid rEcEptors that arE consErvEd in mammals, ranging from micE to humans: thE PGD rEcEptor (DP), four subtypEs of thE PGE rEcEptor (EP1, EP2, EP3 and EP4), thE PGF rEcEptor (FP), thE PGI rEcEptor (IP) and thE TXA rEcEptor (TP). In rEgard to PGE rEcEptor subtypE EP3, it is rEportEd that thE PGE2-EP3 pathway nEgativEly rEgulatEs allErgic rEactions in a murinE allErgic asthma modEl1 and that it inhibits kEratinocytE activation and ExErts anti-inflammatory actions in mousE contact hypErsEnsitivity.2 WE also prEviously rEportEd that PGE2 acts as a ligand for EP3 in murinE conjunctival EpithElium and downrEgulatEs thE progrEssion of murinE ExpErimEntal allErgic conjunctivitis.3 On thE othEr hand, thymic stromal lymphopoiEtin (TSLP) plays a kEy rolE in allErgic inflammation4 and is inducEd by polyI:C stimulation in EpithElial cElls, including human conjunctival EpithElial cElls (HCjECs)5 or kEratinocytEs. In this study, wE ExaminEd whEthEr an EP3 agonist could supprEss thE …
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Prostaglandin E rEcEptor EP1 EnhancEs GABA‐mEdiatEd inhibition of dopaminErgic nEurons in thE substantia nigra pars compacta and rEgulatEs dopaminE lEvEl in thE dorsal striatum
The European journal of neuroscience, 2009Co-Authors: Yasuhiro R. Tanaka, Tomoyuki Furuyashiki, Toshihiko Momiyama, Hisaaki Namba, Akira Mizoguchi, Tomoyuki Mitsumori, Tetsuro Kayahara, Hitoshi Shichi, Kazushi Kimura, Toshiyuki MatsuokaAbstract:DopaminE (DA) is a nEuromodulator that is critical for sEnsory-motor, cognitivE and Emotional functions. WE prEviously found that micE lacking Prostaglandin E rEcEptor EP1 showEd impulsivE Emotional bEhaviors accompaniEd by EnhancEd DA turnovEr in thE frontal cortEx and striatum. GivEn that thEsE bEhavioral phEnotypEs wErE corrEctEd by DA rEcEptor antagonists, wE hypothEsizEd that EP1 dEficiEncy causEs a hypErdopaminErgic statE for its bEhavioral phEnotypE. HErE wE tEstEd this hypothEsis by Examining thE EP1 action in thE nigrostriatal dopaminErgic systEm. WE first usEd microdialysis and found an ElEvatEd ExtracEllular DA lEvEl in thE dorsal striatum of EP1-dEficiEnt micE comparEd with wild-typE micE. DEspitE thE EP1 ExprEssion in thE striatum, nEithEr dEficiEncy nor activation of EP1 altErEd thE intrastriatal control for DA rElEasE, uptakE or dEgradation. ImmunohistochEmistry rEvEalEd punctatE EP1 signals apposEd with dopaminErgic nEurons in thE substantia nigra pars compacta (SNc). Many EP1 signals wErE colocalizEd with a markEr for GABAErgic synapsEs. FurthEr, an EP1 agonist EnhancEd GABA A -mEdiatEd inhibitory inputs to SNc dopaminErgic nEurons in midbrain slicEs. ThErEforE, thE Prostaglandin E 2 -EP1 signaling dirEctly EnhancEs GABAErgic inputs to SNc dopaminErgic nEurons. ThE lack of this EP1 action may lEad to a hypErdopaminErgic statE of EP1-dEficiEnt micE.
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Prostaglandin E rEcEptor Ep1 EnhancEs gaba mEdiatEd inhibition of dopaminErgic nEurons in thE substantia nigra pars compacta and rEgulatEs dopaminE lEvEl in thE dorsal striatum
European Journal of Neuroscience, 2009Co-Authors: Yasuhiro R. Tanaka, Tomoyuki Furuyashiki, Toshihiko Momiyama, Hisaaki Namba, Akira Mizoguchi, Tomoyuki Mitsumori, Tetsuro Kayahara, Hitoshi Shichi, Kazushi Kimura, Toshiyuki MatsuokaAbstract:DopaminE (DA) is a nEuromodulator that is critical for sEnsory-motor, cognitivE and Emotional functions. WE prEviously found that micE lacking Prostaglandin E rEcEptor EP1 showEd impulsivE Emotional bEhaviors accompaniEd by EnhancEd DA turnovEr in thE frontal cortEx and striatum. GivEn that thEsE bEhavioral phEnotypEs wErE corrEctEd by DA rEcEptor antagonists, wE hypothEsizEd that EP1 dEficiEncy causEs a hypErdopaminErgic statE for its bEhavioral phEnotypE. HErE wE tEstEd this hypothEsis by Examining thE EP1 action in thE nigrostriatal dopaminErgic systEm. WE first usEd microdialysis and found an ElEvatEd ExtracEllular DA lEvEl in thE dorsal striatum of EP1-dEficiEnt micE comparEd with wild-typE micE. DEspitE thE EP1 ExprEssion in thE striatum, nEithEr dEficiEncy nor activation of EP1 altErEd thE intrastriatal control for DA rElEasE, uptakE or dEgradation. ImmunohistochEmistry rEvEalEd punctatE EP1 signals apposEd with dopaminErgic nEurons in thE substantia nigra pars compacta (SNc). Many EP1 signals wErE colocalizEd with a markEr for GABAErgic synapsEs. FurthEr, an EP1 agonist EnhancEd GABA A -mEdiatEd inhibitory inputs to SNc dopaminErgic nEurons in midbrain slicEs. ThErEforE, thE Prostaglandin E 2 -EP1 signaling dirEctly EnhancEs GABAErgic inputs to SNc dopaminErgic nEurons. ThE lack of this EP1 action may lEad to a hypErdopaminErgic statE of EP1-dEficiEnt micE.
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facilitation of th1 mEdiatEd immunE rEsponsE by Prostaglandin E rEcEptor Ep1
Journal of Experimental Medicine, 2007Co-Authors: Miyako Nagamachi, Toshiyuki Matsuoka, Tomoyuki Furuyashiki, Daiji Sakata, Kenji Kabashima, Takahiko Murata, Eri Seginishida, Kitipong Soontrapa, Yoshiki Miyachi, Shuh NarumiyaAbstract:Prostaglandin E2 (PGE2) ExErts its actions via four subtypEs of thE PGE rEcEptor, EP1–4. WE show that micE dEficiEnt in EP1 ExhibitEd significantly attEnuatEd Th1 rEsponsE in contact hypErsEnsitivity inducEd by dinitrofluorobEnzEnE (DNFB). This phEnotypE was rEcapitulatEd in wild-typE micE by administration of an EP1-sElEctivE antagonist during thE sEnsitization phasE, and by adoptivE transfEr of T cElls from sEnsitizEd EP1−/− micE. ConvErsEly, an EP1-sElEctivE agonist facilitatEd Th1 diffErEntiation of naivE T cElls in vitro. Finally, CD11c+ cElls containing thE induciblE form of PGE synthasE incrEasEd in numbEr in thE draining lymph nodEs aftEr DNFB application. ThEsE rEsults suggEst that PGE2 producEd by dEndritic cElls in thE lymph nodEs acts on EP1 in naivE T cElls to promotE Th1 diffErEntiation.
Yukihiko Sugimoto - One of the best experts on this subject based on the ideXlab platform.
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Prostaglandin E rEcEptor subtypE EP4 agonist protEcts cochlEaE against noisE-inducEd trauma.
Neuroscience, 2009Co-Authors: Ryusuke Hori, Yukihiko Sugimoto, Takayuki Nakagawa, Tatsunori Sakamoto, Norio Yamamoto, Kiyomi Hamaguchi, Juichi ItoAbstract:Abstract Prostaglandin E 1 is frEquEntly usEd for thE clinical trEatmEnt of acutE sEnsorinEural hEaring loss. HowEvEr, thE mEchanisms undErlying thE EffEcts of Prostaglandin E 1 on thE innEr Ear havE not yEt bEEn ElucidatEd. ThE physiological EffEcts of Prostaglandin E 1 arE mEdiatEd by thE prostanoid rEcEptors Prostaglandin I rEcEptor and thE Prostaglandin E rEcEptor subtypEs EP1, EP2, EP3, and EP4, thE rEspEctivE agonists for which havE bEEn purifiEd. In thE currEnt study, wE ExaminEd thE Efficacy of a local EP4 agonist application for thE trEatmEnt of sEnsorinEural hEaring loss. WE ExaminEd EP4 ExprEssion in thE mousE cochlEa using thE rEvErsE transcription–polymErasE chain rEaction and immunohistochEmistry. ThE protEctivE EffEcts of local EP4 agonist trEatmEnt bEforE or aftEr noisE ExposurE wErE tEstEd in guinEa pigs using mEasurEmEnts of auditory brain-stEm rEsponsEs and histological analysis. ThE rEsults dEmonstratEd EP4 ExprEssion in thE cochlEa, and showEd that prE- and post-trEatmEnt with an EP4 agonist significantly attEnuatEd thrEshold shifts of auditory brain stEm rEsponsEs, and significant attEnuation in thE loss of outEr hair cElls was found in local EP4 agonist trEatmEnt bEforE noisE ExposurE. ThEsE findings indicatE that EP4 is involvEd in mEchanisms for Prostaglandin E 1 actions on thE cochlEa, and local EP4 agonist trEatmEnt could attEnuatE acutE sEnsorinEural hEaring loss.
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SupprEssion of allErgic inflammation by thE Prostaglandin E rEcEptor subtypE EP3
Nature immunology, 2005Co-Authors: Tomonori Kunikata, Hana Yamane, Eri Segi, Toshiyuki Matsuoka, Yukihiko Sugimoto, Satoshi Tanaka, Hiroyuki Tanaka, Hiroichi Nagai, Atsushi Ichikawa, Shuh NarumiyaAbstract:Prostaglandins, including PGD(2) and PGE(2), arE producEd during allErgic rEactions. Although PGD(2) is an important mEdiator of allErgic rEsponsEs, aspirin-likE drugs that inhibit Prostaglandin synthEsis arE gEnErally inEffEctivE in allErgic disordErs, suggEsting that anothEr Prostaglandin-mEdiatEd pathway prEvEnts thE dEvElopmEnt of allErgic rEactions. HErE wE show that such a pathway may bE mEdiatEd by PGE(2) acting at thE Prostaglandin E rEcEptor EP3. MicE lacking EP3 dEvElopEd allErgic inflammation that was much morE pronouncEd than that in wild-typE micE or micE dEficiEnt in othEr Prostaglandin E rEcEptor subtypEs. ConvErsEly, an EP3-sElEctivE agonist supprEssEd thE inflammation. This supprEssion was EffEctivE whEn thE agonist was administErEd 3 h aftEr antigEn challEngE and was associatEd with inhibition of allErgy-rElatEd gEnE ExprEssion. Thus, thE PGE(2)-EP3 pathway is an important nEgativE modulator of allErgic rEactions.
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downrEgulation of Prostaglandin E rEcEptor subtypE Ep3 during colon cancEr dEvElopmEnt
Gut, 2004Co-Authors: Yutaka Shoji, Tomohiro Kitamura, Kouji Watanabe, Mami Takahashi, Toshihiko Kawamori, Shuh Narumiya, Yukihiko Sugimoto, Manabu Negishi, Toshihiko Maruyama, Takashi SugimuraAbstract:Background and aims: InvolvEmEnt of Prostaglandin E2 (PGE2) rEcEptors EP1, EP2, and EP4 in thE formation of abErrant crypt foci (ACF) and/or intEstinal polyps has bEEn suggEstEd. In contrast, EP3 appEars to havE no influEncE on thE Early stagEs of colon carcinogEnEsis. In thE prEsEnt study, wE ExaminEd ExprEssion of PGE2 rEcEptor subtypEs EP1, EP2, EP3, and EP4 in normal colon mucosa and colon cancErs, and assEssEd thE contribution of EP3 to colon cancEr dEvElopmEnt. MEthods: mRNA ExprEssion of PGE2 rEcEptor subtypEs EP1, EP2, EP3, and EP4 in normal colon mucosa and colon cancErs in azoxymEthanE (AOM) trEatEd micE and rats, and in humans, wErE ExaminEd by rEvErsE transcription-polymErasE chain rEaction (RT-PCR), quantitativE rEal timE RT-PCR, and immunohistochEmical analysEs. Evaluation of thE rolE of EP3 was pErformEd by intrapEritonEal injEction of AOM, using EP3 rEcEptor knockout micE. EffEcts of EP3 rEcEptor activation on cEll growth of human colon cancEr cEll linEs wErE ExaminEd using ONO-AE-248, an EP3 sElEctivE agonist. MorEovEr, EP3 ExprEssion in colon cancEr cEll linEs was analysEd with or without 5-aza-2′-dEoxycytidinE (5-aza-dC) trEatmEnt. REsults: ExprEssion lEvEls of EP1 and EP2 mRNA wErE incrEasEd in cancEr tissuEs. EP4 mRNA was constantly ExprEssEd in normal mucosa and cancErs. In contrast, ExprEssion of EP3 mRNA was markEdly dEcrEasEd in colon cancEr tissuEs, bEing 5% in micE, 9% in rats, and 28% in humans comparEd with normal colon mucosa, analysEd by quantitativE rEal timE RT-PCR. ImmunohistochEmical staining dEmonstratEd thE rat EP3 rEcEptor protEin to bE ExprEssEd in EpithElial cElls of normal mucosa and somE parts of small carcinomas but hardly dEtEctablE in largE carcinomas of thE colon. Colon cancEr dEvElopmEnt inducEd by AOM in EP3 rEcEptor knockout micE was EnhancEd comparEd with wild-typE micE, with a highEr incidEncE of colon tumours (78% v 57%) and mEan numbEr of tumours pEr mousE (2.17 (0.51) v 0.75 (0.15); p<0.05). ExprEssion of EP3 mRNA was dEtEctEd in only onE of 11 human colon cancEr cEll linEs tEstEd. TrEatmEnt with 5 μM of an EP3 sElEctivE agonist, ONO-AE-248, rEsultEd in a 30% dEcrEasE in viablE cEll numbErs in thE HCA-7 human colon cancEr cEll linE in which EP3 was ExprEssEd. TrEatmEnt with 5-aza-dC rEstorEd EP3 ExprEssion in CACO-2, CW-2, and DLD-1 cElls but not in WiDr cElls, suggEsting involvEmEnt of hypErmEthylation in thE downrEgulation of EP3 to somE ExtEnt. Conclusion: ThE PGE2 rEcEptor subtypE EP3 plays an important rolE in supprEssion of cEll growth and its downrEgulation EnhancEs colon carcinogEnEsis at a latEr stagE. HypErmEthylation of thE EP3 rEcEptor gEnE could occur and may contributE towards downrEgulating EP3 ExprEssion to somE ExtEnt in colon cancErs.
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IdEntification and charactErization of a novEl progEstEronE rEcEptor-binding ElEmEnt in thE mousE Prostaglandin E rEcEptor subtypE EP2 gEnE
Genes to cells : devoted to molecular & cellular mechanisms, 2003Co-Authors: Sohken Tsuchiya, Yukihiko Sugimoto, Satoshi Tanaka, Masato Katsuyama, Reiko Ikegami, Atsushi IchikawaAbstract:Background: GEnE ExprEssion of Prostaglandin E rEcEptor EP2 is inducEd in thE luminal EpithElium of thE mousE utErus during pEri-implantation pEriod (day-5 of psEudoprEgnancy), suggEsting thE involvEmEnt of progEstEronE and its rEcEptor (PR) in this ExprEssion. HowEvEr it rEmains unclEar whEthEr PR affEcts EP2 gEnE ExprEssion through its binding. REsults: WE invEstigatEd transcriptional rEgulation of EP2 gEnE ExprEssion with rEportEr gEnE analysis using HELa cElls with or without ExprEssion of thE PR. ThE 5′-flanking rEgion (−3260 to −27, upstrEam of thE translation initiation sitE) ExhibitEd progEstEronE-inducEd promotEr activation and basal promotEr activity in thE prEsEncE of PR. Using succEssivE dElEtion analysis, wE dEtErminEd thE six rEgulatory rEgions in thE EP2 gEnE. ThrEE rEgions wErE found to bE involvEd in progEstEronE-inducEd promotEr activation, whErEas thE othEr thrEE rEgions wErE involvEd in basal promotEr activity in thE prEsEncE of PR. WE idEntifiEd a novEl PR-binding sEquEncE, 5′-G(G/A)CCGGA-3′, in thE two basal promotEr rEgions and Sp1- and Sp3-binding in thE othEr basal promotEr rEgion. Conclusions: WE idEntifiEd a novEl PR-binding sEquEncE, which may bE involvEd in thE rEgulation of basal promotEr activity in thE EP2 gEnE.
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impairEd bonE rEsorption to Prostaglandin E2 in Prostaglandin E rEcEptor Ep4 knockout micE
Journal of Biological Chemistry, 2000Co-Authors: Fumitaka Ushikubi, Shuh Narumiya, Yukihiko Sugimoto, Atsushi Ichikawa, Chisato Miyaura, Masaki Inada, Tetsuo Suzawa, Tatsuo SudaAbstract:Abstract Prostaglandin E2(PGE2) acts as a potEnt stimulator of bonE rEsorption. In this study, wE first clarifiEd in normal ddy micE thE involvEmEnt of protEin kinasE A and induction of matrix mEtalloprotEinasEs (MMPs) in PGE2-inducEd bonE rEsorption, and thEn idEntifiEd PGE rEcEptor subtypE(s) mEdiating this PGE2 action using micE lacking Each subtypE (EP1, EP2, EP3, and EP4) of PGE rEcEptor. In calvarial culturE obtainEd from normal ddy micE, both PGE2and dibutyryl cyclic AMP (Bt2cAMP) stimulatEd bonE rEsorption and inducEd MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protEin kinasE A, H89, or an inhibitor of MMPs, BB94, significantly supprEssEd bonE-rEsorbing activity inducEd by PGE2. In calvarial culturE from EP1-, EP2-, and EP3-knockout micE, PGE2 stimulatEd bonE rEsorption to an ExtEnt similar to that found in calvaria from thE wild-typE micE. On thE othEr hand, a markEd rEduction in bonE rEsorption to PGE2 was found in thE calvarial culturE from EP4-knockout micE. ThE impairEd bonE rEsorption to PGE2 was also dEtEctEd in long bonE culturEs from EP4-knockout micE. Bt2cAMP grEatly stimulatEd bonE rEsorption similarly in both wild-typE and EP4-knockout micE. Induction of MMP-2 and MMP-13 by PGE2 was grEatly impairEd in calvarial culturE from EP4-knockout micE, but Bt2cAMP stimulatEd MMPs induction similarly in thE wild-typE and EP4-knockout micE. ThEsE findings suggEst that PGE2 stimulatEs bonE rEsorption by a cAMP-dEpEndEnt mEchanism via thE EP4 rEcEptor.
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downrEgulation of Prostaglandin E rEcEptor subtypE Ep3 during colon cancEr dEvElopmEnt
Gut, 2004Co-Authors: Yutaka Shoji, Tomohiro Kitamura, Kouji Watanabe, Mami Takahashi, Toshihiko Kawamori, Shuh Narumiya, Yukihiko Sugimoto, Manabu Negishi, Toshihiko Maruyama, Takashi SugimuraAbstract:Background and aims: InvolvEmEnt of Prostaglandin E2 (PGE2) rEcEptors EP1, EP2, and EP4 in thE formation of abErrant crypt foci (ACF) and/or intEstinal polyps has bEEn suggEstEd. In contrast, EP3 appEars to havE no influEncE on thE Early stagEs of colon carcinogEnEsis. In thE prEsEnt study, wE ExaminEd ExprEssion of PGE2 rEcEptor subtypEs EP1, EP2, EP3, and EP4 in normal colon mucosa and colon cancErs, and assEssEd thE contribution of EP3 to colon cancEr dEvElopmEnt. MEthods: mRNA ExprEssion of PGE2 rEcEptor subtypEs EP1, EP2, EP3, and EP4 in normal colon mucosa and colon cancErs in azoxymEthanE (AOM) trEatEd micE and rats, and in humans, wErE ExaminEd by rEvErsE transcription-polymErasE chain rEaction (RT-PCR), quantitativE rEal timE RT-PCR, and immunohistochEmical analysEs. Evaluation of thE rolE of EP3 was pErformEd by intrapEritonEal injEction of AOM, using EP3 rEcEptor knockout micE. EffEcts of EP3 rEcEptor activation on cEll growth of human colon cancEr cEll linEs wErE ExaminEd using ONO-AE-248, an EP3 sElEctivE agonist. MorEovEr, EP3 ExprEssion in colon cancEr cEll linEs was analysEd with or without 5-aza-2′-dEoxycytidinE (5-aza-dC) trEatmEnt. REsults: ExprEssion lEvEls of EP1 and EP2 mRNA wErE incrEasEd in cancEr tissuEs. EP4 mRNA was constantly ExprEssEd in normal mucosa and cancErs. In contrast, ExprEssion of EP3 mRNA was markEdly dEcrEasEd in colon cancEr tissuEs, bEing 5% in micE, 9% in rats, and 28% in humans comparEd with normal colon mucosa, analysEd by quantitativE rEal timE RT-PCR. ImmunohistochEmical staining dEmonstratEd thE rat EP3 rEcEptor protEin to bE ExprEssEd in EpithElial cElls of normal mucosa and somE parts of small carcinomas but hardly dEtEctablE in largE carcinomas of thE colon. Colon cancEr dEvElopmEnt inducEd by AOM in EP3 rEcEptor knockout micE was EnhancEd comparEd with wild-typE micE, with a highEr incidEncE of colon tumours (78% v 57%) and mEan numbEr of tumours pEr mousE (2.17 (0.51) v 0.75 (0.15); p<0.05). ExprEssion of EP3 mRNA was dEtEctEd in only onE of 11 human colon cancEr cEll linEs tEstEd. TrEatmEnt with 5 μM of an EP3 sElEctivE agonist, ONO-AE-248, rEsultEd in a 30% dEcrEasE in viablE cEll numbErs in thE HCA-7 human colon cancEr cEll linE in which EP3 was ExprEssEd. TrEatmEnt with 5-aza-dC rEstorEd EP3 ExprEssion in CACO-2, CW-2, and DLD-1 cElls but not in WiDr cElls, suggEsting involvEmEnt of hypErmEthylation in thE downrEgulation of EP3 to somE ExtEnt. Conclusion: ThE PGE2 rEcEptor subtypE EP3 plays an important rolE in supprEssion of cEll growth and its downrEgulation EnhancEs colon carcinogEnEsis at a latEr stagE. HypErmEthylation of thE EP3 rEcEptor gEnE could occur and may contributE towards downrEgulating EP3 ExprEssion to somE ExtEnt in colon cancErs.
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cEllular localization of mrnas for Prostaglandin E rEcEptor subtypEs in mousE gastrointEstinal tract
American Journal of Physiology-gastrointestinal and Liver Physiology, 1997Co-Authors: Kimiko Morimoto, Yukihiko Sugimoto, Manabu Negishi, Masato Katsuyama, Hiroji Oida, Kazuhito Tsuboi, Kiyohiko Kishi, Yoshikazu Kinoshita, Tsutomu Chiba, Shuh NarumiyaAbstract:REgional and cEllular distribution of mRNAs for Prostaglandin E (PGE) rEcEptor subtypEs was invEstigatEd in thE mousE gastrointEstinal tract by in situ hybridization. Strong signals for EP1 transcripts wErE dEtEctEd in cElls of thE muscularis mucosaE layEr, EspEcially in thE body of thE stomach. IntEnsE signals for EP3 transcripts wErE dEtEctEd in nEurons of thE myEntEric ganglia throughout thE tract. ModEratE EP3 mRNA ExprEssion was also obsErvEd in fundic gland EpithElial cElls, ExcEpt for surfacE mucous cElls in thE stomach. ExprEssion of EP4 mRNA was modEratE in surfacE EpithElial cElls of thE corpus and in glands from thE surfacE to thE basE of thE antrum. Strong EP4 signals wErE obsErvEd in thE EpithElium in thE duodEnum, jEjunum, and ilEum. In thE ilEum, signals wErE only obsErvEd in thE uppEr part of thE villi. HowEvEr, no or wEak signals for EP2 transcripts wErE dEtEctEd. ThEsE findings suggEst that PGE2 modulatEs various gastric or intEstinal functions via at lEast thrEE diffErEnt PGE rEcEptors.
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Prostaglandin E REcEptor EP3 SubtypE InducEs NEuritE REtraction via Small GTPasE Rho
The Journal of biological chemistry, 1996Co-Authors: Hironori Katoh, Manabu Negishi, Atsushi IchikawaAbstract:Abstract Prostaglandin E rEcEptor EP3 subtypE is widEly distributEd in thE nErvous systEm and is spEcifically localizEd to nEurons, suggEsting that thE EP3 rEcEptor plays important rolEs in thE nErvous systEm. WE EstablishEd a PC12 cEll linE that stably ExprEssEs thE EP3B rEcEptor isoform isolatEd from bovinE adrEnal chromaffin cElls and ExaminEd thE EffEct of agonist stimulation on thE nEuronal morphology of thE PC12 cElls. In thE diffErEntiatEd cElls, M&B28767, an EP3 agonist, causEd nEuritE rEtraction in a pErtussis toxin-insEnsitivE mannEr. 12-O-TEtradEcanoylphorbol-13-acEtatE (TPA) also inducEd nEuritE rEtraction. HowEvEr, whEn protEin kinasE C was down-rEgulatEd by long tErm ExposurE to TPA, TPA failEd to inducE nEuritE rEtraction, whilE thE EP3B rEcEptor-mEdiatEd rEtraction occurrEd normally. Clostridium botulinum C3 ExoEnzymE complEtEly inhibitEd both EP3 agonist- and TPA-inducEd nEuritE rEtraction whEn microinjEctEd into thE cElls, indicating that thE morphological EffEct of thE EP3B rEcEptor is dEpEndEnt on Rho activity. Thus, thE activation of thE EP3B rEcEptor inducEd nEuritE rEtraction through a protEin kinasE C-indEpEndEnt Rho-activation pathway.
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Two Isoforms of thE Prostaglandin E REcEptor EP3 SubtypE DiffErEnt in Agonist-indEpEndEnt ConstitutivE Activity
The Journal of biological chemistry, 1996Co-Authors: Hiroshi Hasegawa, Manabu Negishi, Atsushi IchikawaAbstract:Abstract WE prEviously idEntifiEd two isoforms of thE mousE Prostaglandin E rEcEptor EP3 subtypE, EP3α and EP3β, with diffErEnt carboxyl-tErminal tails, producEd through altErnativE splicing and showing diffErEnt EfficiEncy in inhibition of adEnylatE cyclasE (Sugimoto, Y., NEgishi, M., Hayashi, Y., Namba, T., Honda, A., WatabE, A., Hirata, M., Narumiya, S., and Ichikawa, A.(1993) J. Biol. ChEm. 268, 2712-2718). To assEss thE rolE of thE carboxyl-tErminal tails in thE G protEin coupling propErtiEs of thE EP3 rEcEptor, wE ExaminEd thE G activitiEs of EP3α, EP3β, and thE mutant rEcEptor, in which thE carboxyl-tErminal tail was truncatEd at thE splicing sitE. ThE EP3α rEcEptor showEd markEd agonist-indEpEndEnt constitutivE inhibition of adEnylatE cyclasE, whilE EP3β rEcEptor had no agonist-indEpEndEnt inhibition. On thE othEr hand, thE truncatEd rEcEptor showEd only agonist-indEpEndEnt constitutivE inhibition. ThE constitutivE activity of thEsE rEcEptors on thE stimulation of GTPasE activity of G was also obsErvEd. Thus, altErnativE splicing producEd two isoforms with diffErEnt carboxyl-tErminal tails and with diffErEnt constitutivE activity, and thE truncation of thE carboxyl-tErminal tail causEd full constitutivE activity.
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thE mousE Prostaglandin E rEcEptor Ep2 subtypE cloning ExprEssion and northErn blot analysis
FEBS Letters, 1995Co-Authors: Masato Katsuyama, Shuh Narumiya, Yukihiko Sugimoto, Manabu Negishi, Nobuhiro Nishigaki, Kimiko Morimoto, Atsushi IchikawaAbstract:A functional cDNA clonE for thE mousE Prostaglandin (PG) E rEcEptor EP2 subtypE was isolatEd from a mousE cDNA library. ThE mousE EP2 rEcEptor consists of 362 amino acid rEsiduEs with sEvEn putativE transmEmbranE domains. [3H]PGE2 bound spEcifically to thE mEmbranE of ChinEsE hamstEr ovary cElls stably ExprEssing thE clonEd rEcEptor. This binding was displacEd by unlabElEd prostanoids in thE ordEr of PGE2 = PGE1 >> iloprost, a stablE PGI2 agonist > PGF2 alpha > PGD2. Binding was also inhibitEd by butaprost (an EP2 agonist) and to a lEssEr ExtEnt by M&B 28767 (an EP3 agonist), but not by sulprostonE (an EP1 and EP3 agonist) or SC-19220 (an EP1 antagonist). PGE2 and butaprost incrEasEd thE cAMP lEvEl in thE ChinEsE hamstEr ovary cElls in a concEntration-dEpEndEnt mannEr. NorthErn blot analysis rEvEalEd that EP2 mRNA is ExprEssEd most abundantly in thE utErus, followEd by thE splEEn, lung, thymus, ilEum, livEr, and stomach.
