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Chap16NeurotrophicFactor
神经营养因子
HistoryItwasknownthatextracellularsignalscanpromotethegrowthanddifferentiationofnervecellsinmorethanhalfacenturyago.Nervegrowthfactor(NGF)wasfirstdiscoveredbyBuekerin1948.RitaLevi-MontalciniandVictorHamburgerdemonstratedNGFisnecessaryforsympatheticandsensoryneuronsNGFtokeeptheirsurvival.Neurite(神经突起)Neuriticbranchisdescribedaxonanddendrite.Especially,itisavailableforgrowingneuritewhichdidnotassuredaxonordendrite.TheeffectofNGFonculturedspinalneurons(Levi-MontalciniR.1987.Science237:1157)Neurotrophicfactor(NTF)influencesthegrowth,differentiationandsurvivalofneuronsduringdevelopment.NTFsarealso
re-activatedinadulthoodintissuerenewalorregeneration.ThesignalingfailureofNTFmayunderlieneurodegenerativedisorderssuchasAlzheimerdisease(AD),Parkinsondisease(PD),huntingtondisease(HD)andamyotrophiclateralsclerosis(ALS).ThetermofNeurotrophicfactorThetermNeurotrophicFactorreferstoanymoleculethataffectsthenervessystembyinfluencingthegrowth,differentiation,orcellcyclesofneuronsorglia.
ThedifferencebetweenofNTFsandNeuropeptides:1)NTFsarelargemolecularproteins,butneuropeptidesarethesmallmolecularproteins(<30-40peptides).2)Differencemolecularsignalingpathway.
ThedifferencebetweenofNTFsandnonpeptides:NTFsaredistinguishedfrommanynonpeptidemolecules,includingsteroidhormones,retinoicacidandneurotransmitters,thatalsocaninfluencethegrowthandintegrityofthenervoussystem.
NPNTFThelifecyclesofNTFBiosynthesis
:synthesizedmainlyinthenervalcellbody,includingneuronandglia.Storage:storedinthelargedensecorevesicles,andwastransportedtonerveterminalorextendeddendrite.ThelifecyclesofNTFRelease:
SomeNTFs,includingBDNFandGDNF,wereproducedfromimmediate-earlygenes,therefore,theirreleasewasdependonactive-dependentsynthesis.Theothersweredependontheirdepolarization.Breakdown:
BrokendownbymembranepeptidasesBDNFwasdetainedbyfunctional-inactivereceptorandthenitsdispersionwasbaffled.Simultaneitythepersistence-actionwindowwasalsorestricted.Thepartnershipofactivation-synthesisresultstoNTFshigh-complicatedformsinintercellularinformationofneuronsandglia.ModesofintercellularcommunicationsubservedbyNTFRetogradetransmission
Paracrinetransmission
AutocrinetransmissionAnterogradetramsmissionNTF与神经肽的区别NTFNPMolecularweight
Synthesislarge,>14kDaNTFisproducedincellbody.small,<kDaNPisproducedincellbody
StoragelargedensecoredvesicleslargedensecoredvesiclesReleaseactive-dependentsynthesis.depolarization.electricstimulation,hyperpotassiumcauseddepolarization.Breakdownproteasehydrolyzation,detained
byinactivation-receptorproteasehydrolyzationSignalingThebindingtoTrkreceptorleadtomanyofthebiologiceffectsThebindingG-proteincouplereceptorandthesecondmessengerleadtothebiologiceffects.Actionsretograde,anterograde,autocrine,paracrinetransmission.anterograde,autocrine,paracrinetransmission.NTF与神经递质的区别NTFClassicaltransmittersMolecularweightLarge,>14kDa<1kDaSynthesisproductedincellbodyproducedattheterminalStoragelargedensecoredvesiclesSynapticvesiclesReleaseactive-dependentsynthesis.depolarization.Low-frequencystimulationdepolarization.breakdownproteasehydrolyzation,enshroudbyincativation-receptorreuptake,re-use,SignalingthebindingtoTrkreceptorleadtomanyofthebiologiceffectsThebindingG-proteincouplereceptorandthesecondmessengerleadtothebiologiceffects.Actionretograde,anterograde,autocrine,paracrinetransmission.anterograde,autocrine,paracrinetransmission.actingas‘quick’transmitter.
NeurotrophicFactors Receptors
NeurotrophinsTrk(R-PTKs)
NGF、BDNF、NT-3、NT-4TrkA、TrkB、TrkC1 GDNFfamilyCoupledtoRetGDNF、neurturin、persephinGFR
1、GFR
2、nu-known CNTFfamilyCoupledtoJanuskinase(JAK)
CNTF、LIF、IL-6 GP130、CNTFR
、LIFR
Ephrins Eph(R-PTKs) EGFfamilyErbB(R-PTKs)EGF,TGF
,neuregulns2
OthergrowthfactorsR-PTKs Insulin,IGF,FGF,PDGF interleukinsandrelatedcytokinesIL-IRcoupledtoPS/TK,R-PTKIL-1,IL-2,IL-3,IL-5,TNF
,TNF
CoupledtoJAK,Relatedtop753TGFfamilyTGF
R-PS/TRs OthercytokinesCoupledtoJAK,R-PTKsinterferons(IFN
,
,
),m-CSF,gm-CSFCoupledtoJAKChemokinesGprotein-coupledreceptorsCCchemokines(IL-8)CC1-CC8RCXCchemokines(MIP,MCP)CXC1-CXC4RCX3Cchemokines(neurotactin) Cx3C1R 分类NeurotrophinsNeurotrophinsaresmallproteins.TheyproducetheirphysiologiceffectsbymeansoftheTrkreceptorfamily.Familymenbers:NGF、BDNF、NT-3、NT-4/5。EffectionssurvivalofneuronsPreventingtodeathofneuronsneurogenesisPromoteaxonsanddendritesgrowth.neuritePromoteneuriteofaxonsanddendrites.AnabolismEnhancethesizeofneuronalbody.differentiationProteinsarenecessaryforneuronaldifferentiation.RegulatingthetransmitionIncreasethesynthesisofneurotransmittors,neuropeptidesandtheirsyntheticalenzymesElectricalexcitabilityAltertheactivationandlevelofionchannelsNGFBDNFNT-3composingofaminoacides
1163disulfidebonds1193disulfidebonds1193disulfidebondsMW13kDa13kDa13kDadistributionWidelydistrubutionCNS,PNSandperipheraltissuesInCNS:
hypothalamus,cortex,hippocampusindeveloping;
Inperipheraltissues:BDNFmRNAwashighlyexpressedinmuscletissuesWidelydistrubutinCNS,PNSreceptorsTrkATrkBTrkCsignalingpathwayTrkreceptorsignalingpathway.CharacteristicofneurotrphinsNeurotrophinsreceptor——Trk-RTransmembrancereceptorGlycoproteinswhosemolecularweightrangefrom140to145kDa.DifferenttypesofTrk-RNeurotrophinsandreceptorsDistributionofTrkRinnervalcellsThemostofTrkAswerefoundinsensoryandsympatheticneurons,afewinbrainneurons.TrkBandTrkCexpressinthemostofneurons.Trktruncationwasexistedinastrocytesandoligodendrocytes.P75receptora75-kDaproteinasthelow-affinityneurotrophinreceptor.alsoappearstomodulateTrksignaling;theincreasesphosphorylationofTrkandthenenhancestheactivationofTrk.mayallowTrk-RtoresponsetothelessconcentrationofNGFandtheotherneurotrophinsIt’sbelievedtobeakeyplayerincelldeathpathways.ThesignalingpathwayofNeurotrophins
TrkwasactivatedbyautophosphorylationofTry(Y490、Y785)intheintracellulardomainandsubsequentlyformtodimer,andthenenablesphosphorylationtheintracellularsignalingproteinbyinteractingwithitsSH2domain,e.g.ShcandPLC
.Threesignalingpathways:Ras/MAPKcascadesPI3K/AKTPLC/IP3-dependentCa2+releaseIP3DAGCa2+释放
ThesignalingpathwayofNeurotrophinsRas/MAPK
Rasprotein:①.21kDphosphorylatingprotein;asmallG-protein;
②
switchbetweeninactivationofGDP-boundformandactivationofGTP-boundform
③
GTP-boundformkeepstheactivationofcellgrowthandactivatesthecellstooverproliferationacascadeofTrkAactivatesRasShcSosRasGrb2AcascadeofRas/Raf/MEK/ERKRafERKTheeffectofRas/Raf/MEKcascadeinneuritegrowthPC12originatesfrompheochromocytomaTrkAandp75areexpressedinmembraneofPC12NGFtreatmentmaystimulatetheneuritegrowthonPC12cells.TheeffectofRas/Raf/MEKcascadeinneuritegrowthDiseaseofRassignalingpathwayDefectsoftheintracellularsignalingpathways,whichwereactivatedbyNTFs,canleadtotheoverproliferationofcells,subsequentlygiverisetovariousdisorders.NeurofibromatosisisaninheriteddiseasecausedbymutationoftheRas-modulatoryprotein.OncogenicRasgeneisamutationformthatcauseRastoremaininitsactivestatebytwoRasforms:1)reducedtheintrinsicGTPaseactivityofRas;2)inhibitedthesensitivityofRastoGAPs(GTPaseactivatingproteins).NeurotrophinsandTrk-Rknockoutmice
Mice,inwhichthegenesencodingNGForTrkAhavebeeninactivated,showedalossofsympatheticneuronsaswellassensoryneuronsindorsalrootgangliaofthetrigeminalsystem.NGForTrkAKOmicealsoshowedpartiallossofthecholinergicneuronsinthebasalforebrainthatprojecttothehippocampusandcerebralcortex.TrkBKOmiceshowedthedeathofcranialmotorneuronsandtrigeminalganglionneurons.BDNFKOmiceshowednoalossoffacialorspinalmotorneurons.Incontrast,TrkBKOmiceshowedsignificantmotorneuronsloss.TheeffectsofNeurotrophinsNGFactivatedneuritegrowth.BDNFmaintainssurvivalofmotorneurons.NT-4isimportantforsupportingsurvivalofmotorneuronsindevelopment.TheeffectofNT-3,maintainingsurvivalofmotorneurons,islessthanBDNFandNT-4.TheeffectsofNGFFasteffect:Regulatingorparticipatinginthereleaseofneurotransmitter:alteringtheactivationofionchannels;enhancingthesynthesisoftransmitters,peptidesanditssyntheticalenzymes.Sloweffect:Preventingagainstdeathofneurons;
Maintainingdevelopmentofsympatheticneurons;Maintainingneuronalfunctionandplasticityinadult.Topromotesurvivalofcholinergicneurons:TopromotesurvivalofneuronsAsthesameofNGF,BDNFalsocanpromotesurvivalofcholinergicneuronsanddifferentiationoftheirphenotypeinvitro.Butbotheffectindifferentgrowthphasesofcholingergicneurons,BDNFinforepartbutNGFinanaphase.BDNF、NT-3andNT-4canpromotesurvivalofsomemotorcorticalneuronsandhippocampalneurons.NeurotrophinscanpromotesurvivaloftheneuronsofNE-activated,DA-activated,5-HT-activatiedinbrainstem.ToregulatesynapticplasticityStudiesoftheformationofoculardominancecolumnsinthedevelopingvisualcortexhavebeconfirmedthatneurotrophinsmediateformsofsynapticplasticity.Neurotrophinsalsoareinvolvedinregulatingsynapticplasticityinthefullydifferentiatedadultbrain.Neurotrophinscanmodulatesynaptictransmissionandregulatetheformationandstrengtheningofsynapses.Neurotrophinsalsoregulatesynaptictransmissioninthehippocampus,althoughsuchaccountsremaincontroversy.GDNFFamilyGDNFwasfirstisolatedfromaglialcelllinethatmaintainssurvivalofdopaminergicneuronsformthemidbraininculture.Glialcellline-DerivedNeurotrophicFactorGDNF,aglycosylatedproteinof18kDa.GDNFfamilyincludesNeurturin、persphinGDNFreceptorsanditssignalingpathwayGDNFeffectsviatheactivationofaproteintyrosinekinase,butsuchactivationisachievedindirectlythroughaninterveningreceptorprotein.AGDNFdimerbindstoaspecificreceptor,termedGFR
1,aproteinof40kDa,whichisanchoredtotheplasmamembranebyGPI.GDNFbindingtriggersGFR
1tocombinewithRet.Retisatransmembraneproteintyrosinekinaseofabout150kDa.ThisbindingresultsinRettoactivate,whichisbelievedthatleadingtomanyofthebiologiceffectsofGDNFviatriggeringthephosphorylationofspecificsubstrates.Theautophosphorylatedc-Retinturnactivatesseveralintracellularsignalingproteinsthatregulatecellsurvival,differentiation,proliferation,migration,neuriticgrowthandsynapticmodulation.Thesesignalingproteins,belongingtoproteinandlipidkinasesandphospholipases,actonseveralsignaltransductionpathways.PLC-
Ca2+byincreasingthelevelofIP3MAPkinaseneuritegrowthneuronalsurvivalPI3KneuronalsurvivalneuritegrowthSeveralsignaltransductionpathways:GDNFmediatedc-RetsignalingcaninteractwithandactivatetheSrc-familykinaseselicitingoptimalneuriteoutgrowthandneuronalsurvival.InRetdeficientcelllinesandprimaryneurons,GDNFtriggersSrc-familykinaseactivationandphosphorylationofERK/MAPkinase,PLC-
andthetranscriptionfactorCREB,andinductionofFosGDNFfamilyreceptorscomplexTheeffectsofGDNFfamily1.DopamineNeurons
GDNFselectivelyenhancedthesurvivalanddevelopmentofdopaminergicneurons.Invitro,GDNFprotectedmesencephalicdopaminergiccellsagainstthedeleteriouseffectsoftheneurotoxinMPP1.GDNFimprovedthesurvivalofcells,preventedfurthercelldeath,andstimulatedtheregrowthofdopaminergicfibersdamagedbyMPP1.Invivo,
InPDmodelinducedbytheadministrationofthe6-OHDAintothemedialforebrainbundle,GDNFhasbeenshowntoreverseapomorphine-inducedrotationandrescuelesioneddopaminergicneuronsGDNFmaybeavaluabletherapeuticagentintreatingParkinson’sdisease.NeurturinisalsoafactorfortreatmentofPD.TheeffectsofGDNFfamily2.Motorneurons
GDNFwasshowntoprotectfacialmotoneuronsfrominjury-inducedcelldeath.GDNFcanaffectmotoneurondevelopmentandmotoneuronsurvivalafteraxotomy,novelapproachesformotorneurondiseasearesuggested.GDNFcanrescuesomespinalmotoneuronfromprogrammedcelldeathindevelopmentandpromoteitssurvival.GDNFcanpreventtheneuronaldegenerationwhichwascausedbyaxonbroken.TheeffectsofGDNFfamily3.PNSneurons
GDNF
promotesthesurvivalandneuriticoutgrowthofcultured
sympatheticneurons,parasympatheticciliaryganglion
neuronsandsensorydorsalrootganglionneurons.GDNFisimportantforthedevelopingofentericneuronsandrenalneurons.Ret(loss-of-function)mutationhasthesamesymptonashumanHirschsprungdesease.Ret(gain-of-function)mutationhasthesamesymptomasneuralcrestmaligntumor,e.g.multadenomatosis,medullarthyroidcancer.CNTFfamily(Ciliaryneurotriphicfactor)CNTFfamilyReceptors(JAK-coupledreceptors)CNTFGp130
LIFR
CNTFR
LIF(leukemiainhibitoryfactor)IL-6,prolactin,growthhormone,leptinIL-11、OSM(oncostatinM)
CNTFfamilyCNTF,aproteinapproximately24kDainsize,wasstudiedasasurvivalfactorforchickciliarygenglionneurons.CNTFisonesuchcytokinethatplaysaroleamongseveralprocesseswithinthehumanbodyfromendogenousneuroprotectiontoregulationofenergyexpenditure.CNTFisamult-functionalocytokine,expressedinglialcellsofperipheralnervesandCNS.ThefamilymembersincludeLIF,IL-6,OSM,IL-1,prolactin,growthhormone,leptin,andinterferons.CNTFreceptorcomplexConsistsofthreecomponents:
CNTFR
signaltransducingreceptorcomponent:
LIFR,gp130,TheeffectsofCNTFCNTFhasbeenproventoregulatethesurvivalordifferentiationofmanyneuronalcells,includingsympatheticneurons,sensoryneurons,motorneurons,culturedhippocampalneuronsanddopaminergicneuronsinthemidbrain.Itseffectonmotorneuronsareperhapsthemostframatic:CNTFnotonlysupportsthesurvivalofthesneuronsinvitro,italsopreventstheirdegenerationafteraxotomyandimprovessomemotordefectsinmurineofmotorneurondisease.LIFandIL-6mayregulatethesurvivalordifferentiationofneurons.IL-6promotesthesurvivalofseptalcholinergic,mesencephaliccatecholaminerfic,andhypothalamicneuronsinculture.CNTFandCNTFR
CNTFKOnicedevelopnormally,exhibitingonlymildmotorneurondefectsduringadulthood.Approximately2.5%oftheJapanesepopulationarehomozygousforinactivatingmutationsofCNTFandthustheyarehumanCNTF“knockouts”,likeCNTFKOmice.Incontrast,micelackingtheCNTFRlosealmostalloftheirmotorneuronsanddiewithin24hoursofbirth.
ItsuggestedtheexistenceofanotherendogenousligandforCNTFR,butthathasnotbeendiscoveredyet.TherapeuticagentsdirectedatNTFTreatmentwithBDNF,CNTF,orcombinationofthesefactorshasbeenshowntoslowdownorattesttheprogressionofmotorneurondegengrationinthewobblermouse.BecauseBDNF,GDNG,andotherfactorshaveenhancedthesurvivalo
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