CFTR与囊性纤维化

26220064InternationalJournalofPathologyandClinicalMedicineVol.26No.2Apr.2006CFTR,(,100083)[](CFTR)cAMPATP,,(CF),CFTRCFTRCF,[];;ATP;F508;;[]Q71[]A[]167322588(2006)0220142204CFTRandcysticfibrosisWANGRui,LIXue2jun(DepartmentofPharmacology,SchoolofBasicMedicalSciences,PekingUniversity,Beijing100083,China)[Abstract]Thecysticfibrosistransmembraneconductanceregulator(CFTR)isacAMP2activa2tedandATP2gatedCl-channelexpressedintheapicalplasmamembraneofepithelialcellsintheair2ways,digestiveandreproductivetracts.CysticFibrosis(CF),causedbymutationsintheCFTRgene,isoneofthemostcommoninheriteddisordersofwhitepopulations.TheidentificationoftheCFgeneledustoafurtherunderstandingoftheCFTRstructureandfunction,themutationalbasisaswellasthecom2plexityofthedisease.[Keywords]cysticfibrosis(CF);cysticfibrosistransmembraneconductanceregulator(CFTR);ATPbindingcassette(ABC);deltaF508;genetherapy;drugtreatment[IntJPatholClinMed,2006,26(2):0142204](cysticfibrosis,CF),,,CF,[1]CF(cysticfibro2sistransmembraneconductanceregulator,CFTR),CFTRCF1CFTRCFTRATP(ATPbindingcassette,ABC)ABC,:,,(transmembranedomains,TMDs),6(loop),2(nucleotidebindingdomains,NBDs)NBDWalkerAB,ATPWalkerAWalkerBLSGGQ,(signatureregion)ABC,CFTR2NBDs2TMDs,,CFTRR,A(PKA)C(PKC),CFTR241:2005211209:2006203201:(19852),,,,2,:CFTR26,ATPCFTR2NBDs[2,3]CFTR,CFTRCFTR,ATP[3],CFTR2CFTR2.1CFTRCFTRcAMP,2:,cAMPR(,RCFTR);,ATPNBDs,NBD1,CFTR,,,NBD2ATP,CFTR[3,4],2NBD:NBD2ATP,CFTR,CFTR,,CFTR,,,(40mmol/L),CFTR,,[5,6]2.2CFTR,CFTR,CFTRPDZCFTR,NHE2RF(Na+/H+)/EBP250CAP70CFTRNHE2RFCAP70CFTR,NHE2RFCFTR,CFTR,NHE2RF22CFTRNHE2RFE23KARPPKACFTRCFTR[7]CFTR,CFTR2:(outwardlyrectifyingchloridechannel,ORCC)(calcium2dependentCl-channels),CFTR,CFTR,ATP,ORCC,CFTRATP,[8],CFTR,,[9],,CFTR(epithelialsodiumchannel,ENaC),CFTR(AQP)[5,8,10]CFTR3CFTRCF3.1CFTRCFCF,7qDNA250000CFTR1480,,1000CFCFTR[1]5:,,mRNA,;CFTR,,;CFTR,CFTRATP;;RNA,,,:(exonskipping)(exoninclusion)[11]70%CF341226DeltaF508,,CFTR508[1],,CFTRCFTR,[12]3.2CFTRCFCF,CFTR,,,CFTR,,,,,(),,,,[13],CFTRCF,,,CF[1]3.3CF,,,CF,[14],DeltaF508,CF[1]4CFTRCF4.1CFTR,CF,,[1],CFTR:CFTR,,:;;;[15],,CFTR;CFCFTR,;[16],,CF4.2CFTRCF2CFTR()CF,,,CFTR,[17]DeltaF508CFTR,DeltaF508CFTR,,,CFTR,42(42phenylbutyrate,42PBA),,,CFTR,CFTR[18]2:CFTR,,(xanthines),,(phenantrolines),(benzoxazoles)benzoquinolizinium[19,20]benzoquinoliziniumMPB,CFTR,CFTR,[21],CFTR,ATPUTP,,,(amiloride),,benzamil,,,CFTRCFTR4412,:CFTR26,CFTR,CF[22],CFTR01TurciosNL.Cysticfibrosis:anoverview[J].JClinGastroenterol,2005,9(4):3072317.02DorwartM,ThibodeauP,ThomasP.Cysticfibrosis:recentstruc2turalinsights[J].JCystFibros,2004,(3Suppl2):91294.03ScottOlenych.InvestigationofCFTRintermolecularstructureandprotein2proteininteraction[J].DissAbstrInt,2002,63208,SectionB:3593.04ChappeV,IrvineT,LiaoJ,etal.PhosphorylationofCFTRbyPKApromotesbindingoftheregulatorydomain[J].EMBOJ,2005,24(15):273022740.05MehtaA.CFTR:morethanjustachloridechannel[J].PediatrPul2monol,2005,39(4):2922298.06WrightAM,GongX,VerdonB,etal.Novelregulationofcysticfi2brosistransmembraneconductanceregulator(CFTR)channelgatingbyexternalchloride[J].JBiolChem,2004,279(40):41658241663.07GugginoWB,Banks2SchlegelSP.Macromolecularinteractionsandiontransportincysticfibrosis[J].AmJRespirCritCareMed,2004,170(7):8152820.08BachhuberT,KonigJ,VoelckerT,etal.ClinterferencewiththeepithelialNa+ChannelENaC[J].JBiolChem,2005,280(36):31587231594.09CuppolettiJ,TewariKP,SherryAM,etal.ClC22Cl-channelsinhumanlungepithelia:activationbyarachidonicacid,amidation,andacid2activatedomeprazole[J].AmJPhysiolCellPhysiol,2001,281(1):C46254.10BurghardtB,ElkaermL,KwonTH,etal.DistributionofaquaporinwaterchannelsAQP1andAQP5intheductalsystemofthehumanpancreas[J].Gut,2003,52(7):100821016.11KeremE.PharmacologicalinductionofCFTRfunctioninpatientswithcysticfibrosis:mutation2specifictherapy[J].PediatrPul2monol,2005,40(3):1832196.12MallM,KredaSM,MengosA,etal.TheDeltaF508mutationinlossofCFTRfunctionandmatureproteininnativehumancolon[J].Gastroenterology,2004,126(1):32241.13Nousia2ArvanitakisS.Cysticfibrosisandthepancreas:recentscien2tificadvances[J].JClinGastroenterol,1999,29(2):1382142.14LarsonJE,CohenJC.Developmentalparadigmforearlyfeaturesofcysticfibrosis[J].PediatrPulmonol,2005,40(5):3712377.15RubinBK.Emergingtherapiesforcysticfibrosislungdisease[J].Chest,1999,115(4):112021126.16GriesenbachU,GeddesDM,AltonEW.Advancesincysticfibrosisgenetherapy[J].CurrOpinPulmMed,2004,10(6):5422546.17KeremE.Pharmacologictherapyforstopmutation:howmuchCFTRactivityisenough?[J].CurrOpinPulmMed,2004,10(6):5472552.18RoomansGM.Pharmacologicalapproachestocorrectingtheiontrans2portdefectincysticfibrosis[J].AmJRespirMed,2003,2(5):4132431.19BecqF,MetteyY,GrayMA,etal.DevelopmentofsubstitutedBenzo[c]quinoliziniumcompoundsasnovelactivatorsofthecysticfibrosischloridechannel[J].JBiolChem,1999,274(39):27415227425.20DormerRL,DerandR,McNeillyCM,etal.CorrectionofdelF5082CFTRactivitywithbenzo(c)quinoliziniumcompoundsthroughfacili2tationofitsprocessingincysticfibrosisairwaycells[J].JCellSci,2001,114(Pt22):407324081.21DerandR,Bulteau2PignouxL,MetteyY,etal.Activationo