信號轉(zhuǎn)導(dǎo)及其異常課件

AberrantCellSignalingandtheRelatedDisordersDisordersofsignaltransductionsystemsCauses

Genemutation--Functionlossorgain

ChangeofquantityofsignalproteinsChangeofactivityofsignalproteins

Autoimmunediseases

SecondarychangesAbnormality:

Ligands,Receptors,Post-receptorpathways,EffectorsDown-regulation/interruptionofsignalingSignalInsufficiencyReceptorsdown-regulation/desensitization:decreasedquantity,bindingaffinity,inhibitoryAb,cofactordisorders,functionloss,etc.DefectsinAdaptors,Signaltransducers,Effectors(Enzymes,Transcriptionfactors,etc)Up-regulation/over-activationofsignalingSignalExcessReceptorup-regulation,hypersensitivity,stimulatoryAb,etcSignaltransducers,TFs:over-expression,persistentactivationOthersPathogenesisanddiseases1.AberrantSignalViralinfectionsorotherdamagestopancreatic-cellinsulinproduction

hyperglycemia

Diabetes(TypeI)(1)AberrantSignal(SignalInsufficiency)Insulinreceptor(IR):heterotetramer(2

,2

)InsulinbindingleadstochangeinconformationActivatesIR-subunitPTKactivity

-subunitphosphorylatesTyrresiduesoncytoplasmicdomainsaswellasdownstreamsubstrates(IRS)ischemia,epilepsy,neurodegenerativediseasesextracellularglutamate/asparticacid

NMDARactivation(N-methyl-D-aspartatereceptor,IonChannelLinkedReceptor)Ca2+influx[Ca2+]i,activationofenzymesexcitatoryintoxication(2)AberrantSignal(SignalExcess)（1）ReceptorGeneMutation

—Geneticinsulin-resistantdiabetes

IRgenemutations

DisturbancesinsynthesistransfertothemembraneaffinitytoinsulinPTKactivityproteolysisTypeIIDiabetesInsulin+IRActivateRPTKIRSPI3KRas/Raf/MEK/ERKGlycogenSynthesis,CellTransportproliferation&UtilizationBindingofTSHtoR↓hypothyroidism(2)Autoimmunediseases-thyropathyBlockingAbTSH-R295~302385~395residuesGsACcAMPThyroidproliferation&secretionofthyroxine

GqPLCIP3DAGCa2+PKCTSH-R（GPCR)30~35residues

StimulatoryAbhyperthyroidismGraves病（彌漫性毒性甲狀腺腫）刺激性抗體模擬TSH的作用促進(jìn)甲狀腺素分泌和甲狀腺腺體生長女性>男性甲亢、甲狀腺彌漫性腫大、突眼橋本病(Hashimoto’sthyroditis,慢性淋巴細(xì)胞性甲狀腺炎)阻斷性抗體與TSH受體結(jié)合減弱或消除了TSH的作用抑制甲狀腺素分泌甲狀腺功能減退、黏液性水腫(3)SecondaryAbnormalityinReceptorsHeartfailure,Myocardialhypertrophy

-adrenergicreceptors(GPCR)downregulatedordesensitizedReactiontocatecholamines

Myocardialcontraction

AlleviateAcceleratemyocardiallesionheartfailure

分類累及的受體主要臨床特征遺傳性受體病

膜受體異常家族性高膽固醇血癥

LDL受體

血漿LDL升高，脂質(zhì)代謝紊亂，動(dòng)脈粥樣硬化家族性腎性尿崩癥ADHV2型受體(GPCR)男性發(fā)病，多尿、口渴和多飲

c視網(wǎng)膜色素變性視紫質(zhì)進(jìn)行性視力減退Cccccccccccccccc遺傳性色盲視錐細(xì)胞視蛋白色覺異常11111111111111嚴(yán)重聯(lián)合免疫缺陷癥IL-2受體γ鏈T細(xì)胞減少或缺失，反復(fù)感染CcccccccccccccccII型糖尿病胰島素受體(RTK)

高血糖,血漿胰島素正常或升高ccc核受體異常

ccc雄激素抵抗綜合征雄激素受體不育癥，睪丸女性化cccccccccccccccc維生素D抵抗性佝僂病維生素D受體佝僂病骨損害，禿發(fā)，繼發(fā)性甲狀旁腺素增高Cccccccccccccccc甲狀腺素抵抗綜合征β甲狀腺素受體甲狀腺功能減退，生長遲緩cccccccccccccccc雌激素抵抗綜合征雌激素受體骨質(zhì)疏松，不孕癥Ccccccccccccccc糖皮質(zhì)激素抵抗綜合征糖皮質(zhì)激素受體多毛癥,性早熟,低腎素性高血壓受體異常疾病自身免疫性受體病

cccccccccccccccc重癥肌無力

nAch受體活動(dòng)后肌無力cccccccccccccccc自身免疫性甲狀腺病刺激性TSH受體(GPCR)

抑制性TSH受體甲亢和甲狀腺腫大

甲狀腺功能減退ccccccccccccccccII型糖尿病胰島素受體高血糖，血漿胰島素正?；蛏遚ccccccccccccccc艾迪生病ACTH受體色素沉著，乏力，血壓低繼發(fā)性受體異常

ccccccccccccccc心力衰竭

腎上腺素能受體

心肌收縮力降低ccccccccccccccc帕金森病多巴胺受體肌張力增高或強(qiáng)直僵硬ccccccccccccccc肥胖胰島素受體血糖升高ccccccccccccccc腫瘤生長因子受體細(xì)胞過度增殖3.AberrantG-proteininCellSignalingGs

genemutationGTPaseactivityPersistentactivationofGs

PersistentactivationofACcAMPPituitaryproliferationandsecretionGHRHPituitaryGHRH-RGs

Ac,cAMPGHAcromegalyorGigantism(1)G-proteingenemutation—pituitary

tumor(2)G-proteinmodification——choleraCholeratoxinGs

ribosylationatArg201InactivationofGTPasePersistentactivationofGs

andAc,cAMPConformationalalterationofintestinalepitheliaCl-andH2OtolumenofintestineDiarrheaanddehydrationCirculationfailure

Theintracellularsignalinginvolvesvariousmessengers,transducers,andtranscriptionfactors.

Disorderscanoccurinanyofthesesettings.--Calciumoverloadisageneralpathologicalprocessinvariousdiseases;--ThelevelofNOispositivelycorrelatedwithischemicinjury;--StimulationofNF-

Bisseeninvariousinflammatoryresponses4.AberrantintracellularSignalingPro-carcinogenofphorbolester（diglyceride(DG)analogy）PKCpersistentactivationGrowthfactorsCancergeneexpressionNa+/H+exchange

IntracellularpH↑/K+↑Cellproliferation(Cancer)AberrantintracellularSignaling佛波酯型促癌物5.

MultipleAbnormalitiesinSignalingPathwayCancer,asetofdiseasescharacterizedbyuncontrolledorinappropriatecellgrowth,isstronglyassociatedwithdefectsinsignal-transductionproteins.Ligands(GFs):e.g.EGFReceptors(overexpression,activationofTPK):e.g.EGFRIntracellularsignaltransducers：

RasgenemutationRas-GTPaseRasactivationRafMEKERKProliferationTUMORMultifactorAberranciesandCancer---EnhancementofproliferatingsignalsMultifactorAberranciesandCancer---Deficitsinproliferation-inhibitingsignalTGF-

+TGF-RPSTKactivationSmad-phosphorylationP21/P27/P15expressionCdk4inhibitionCellcyclearrestsatG1phaseInhibitscellproliferation(pro-apoptosis)Lymphoma,livercancer,StomachcancerGenemutationNegativeregulation6.SameStimulantInducesDifferentResponses(thesamestimulicanactondifferentreceptors)7.DifferentSignalsInducestheSamePathologicResponse(differentreceptorsusethesamepathwayorbycross-talk)DifferentreceptorsusesamepathwaysGPCR,RTK,CytokinesRsPLCRasPI-3KPKCRafPKBMEKERKCrosstalk—howhypertensionleadstomyocardialhypertrophy?NE,AT-IIPLCCa2+/PKCMechanicstimuliNa+