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《Profiling of FSHR Negative Allosteric Modulators on LHCGR RevealsFHSR负变构调节剂对LH_CGR的研究 类固醇拮抗作用中的有偏拮抗作用》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、ProfilingofFSHRNegativeAllostericModulatorsonLH/CGRRevealsBiasedAntagonismwithImplicationsinSteroidogenesis1,2,*113MohammedAkliAyoub,RomainYvinec,GwenhaëlJégot,JamesA.Dias,4111Sonia-MariaPoli,AnnePoupon,PascaleCrépieux,andEricReiter1PRC,INRA,CNRS,IFCE,UniversitédeTou
2、rs,37380,Nouzilly,France.2®LESTUDIUMLoireValleyInstituteforAdvancedStudies,45000,Orléans,France.3DepartmentofBiomedicalSciences,StateUniversityofNewYorkatAlbany,Albany,NewYork.4AddexPharmaS.A,Plan-les-Ouates,Geneva,Switzerland.*Correspondence:InstitutNationaldelaRech
3、ercheAgronomique(INRA)UMR85,CNRS-UniversitéFrançois-RabelaisUMR7247,PhysiologiedelaReproductionetdesComportements-Nouzilly37380,France-Email:Mohammed.Ayoub@tours.inra.frAbstractBiasedsignalinghasrecentlyemergedasaninterestingmeanstomodulatethefunctionofmanyGprotein-c
4、oupledreceptors(GPCRs).Previousstudiesreportedtwonegativeallostericmodulators(NAMs)offollicle-stimulatinghormonereceptor(FSHR),ADX68692andADX68693,withdifferentialeffectsonFSHR-mediatedsteroidogenesisandovulation.Inthisstudy,weattemptedtopharmacologicallyprofilethese
5、NAMsonthecloselyrelatedluteinizinghormone/chorionicgonadotropinhormonereceptor(LH/CGR)withregardstoitscanonicalGs/cAMPpathwayaswellastoß-arrestinrecruitmentinHEK293cells.TheNAMs’effectsoncAMP,progesteroneandtestosteroneproductionwerealsoassessedinmurineLeydigtumorcel
6、lline(mLTC-1)aswellasprimaryratLeydigcells.WefoundthatbothNAMsstronglyantagonizedLH/CGRsignalinginthedifferentcellmodelsusedwithADX68693morepotentthanADX68692toinhibithCG-inducedcAMPproductioninHEK293,mLTC-1andLeydigcellsaswellasß-arrestin2recruitmentinHEK293cells.In
7、terestingly,differentialantagonismofthetwoNAMsonhCG-promotedsteroidogenesisinmLTC-1andLeydigcellswasobserved,eventhoughbothNAMsinhibitedcAMPpathways.Indeed,whileasignificantinhibitionoftestosteroneproductionbythetwoNAMswasobservedinbothcelltypes,progesteroneproductio
8、nwasonlyinhibitedbyADX68693inprimaryratLeydigcells.Inaddition,whileADX68693totallyabolishedtestosteroneproductionat10µM,ADX68692had
