资源描述：
《Differential tissue and ligand-dependent signaling of GPR109A receptorl》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。
1、CellularSignalling25(2013)2003–2016ContentslistsavailableatSciVerseScienceDirectCellularSignallingjournalhomepage:www.elsevier.com/locate/cellsigDifferentialtissueandligand-dependentsignalingofGPR109Areceptor:Implicationsforanti-atherosclerotictherapeuticpotentialIbragimGai
2、darov⁎,XiaohuaChen,ToddAnthony,DominiqueMaciejewski-Lenoir,ChenLiaw,DavidJ.UnettArenaPharmaceuticals,6154NancyRidgeDrive,SanDiego,CA92121,USAarticleinfoabstractArticlehistory:Untilrecently,theanti-atheroscleroticeffectsofniacinwereattributedprimarilytoitslipidmodificationpro
3、p-Received22February2013ertiesmediatedbyadipocyteG-proteincoupledreceptorGPR109A,thoughrecentstudieshaveraisedsignificantReceivedinrevisedform7June2013doubtsaboutthismechanism.Infact,inrodentsithasrecentlybeendemonstratedthatniacininhibitsprogres-Accepted9June2013sionofather
4、osclerosisthroughactionsonimmunecells,particularlyviamacrophage-expressedGPR109A,inde-Availableonline14June2013pendentoflipid-modifyingproperties.Here,westudiedGPR109AsignaltransductioninhumanLangerhanscells,macrophagesandadipocytes.Wefindthattheconsequencesofreceptoractivat
5、ionareprofoundlyKeywords:Biasedsignalinginfluencedbycellularcontextandthatligand-biasedsignalingsignificantlyimpactsfunctionallyrelevantsignal-2+Niacining.InLangerhanscells,niacininitiatesGPR109A-mediatedsignalingpathways(Erk1/2andCa)responsibleGPR109Aforthereleaseofvasodilat
6、oryprostanoids,whilethesyntheticGPR109AagonistMK-0354failstoelicitanyAtherosclerosissignaling,providingamechanisticbasisforthelattercompound'sinabilitytocauseflushing.WhileGPR109Ame-ABCA1diatesinhibitionofcAMPinadipocytes,inmacrophagesGPR109AsignalingviaGβγsubunitsresultsinp
7、aradox-MacrophageicalaugmentationofintracellularcAMPlevels.Also,inmacrophagesniacinandGPR109Afullagonistsinduce2+Erk1/2andCasignaling,releaseofprostanoids,upregulationofcholesteroltransportersABCA1andABCG1andstimulationofreversecholesteroltransportinGPR109Adependentmanner.A
8、mechanismispresentedinwhichsignalsfromtheautocrineactionofreleasedprostanoidsandGi
