通過膜受體的信號(hào)傳遞

通過膜受體的信號(hào)傳遞途徑SIGNALTRANSDUCTIONQUESTIONHowdovariouscellsinanmulticellurorganismcoordinatewitheachother?Howanextracellularsignal,suchasahormone,influenceintracellularevents?

Cellsignaling細(xì)胞信號(hào)傳遞:

Cellsuseavarietyofdifferentreceptor(受體）

proteinstoreceiveandrespondtosignalsfromtheexternalenvironment.Thebindingofthesignalingmolecule（suchasahormone，growthfactor，orneurotransmitter（激素、生長(zhǎng)因子、神經(jīng)遞質(zhì)等））tothereceptorresultsinacascadeofenzymaticreactions（級(jí)聯(lián)酶促反應(yīng)）

insidethecellthatconstitutestheappropriateresponsetothesignal.Definition（一）cAMP-蛋白激酶途徑

cAMP-ProteinkinasePathway

----（腺苷酸環(huán)化酶體系）adenylatecyclasesystem

SomeHormonesgothroughthispathway: eg:Glucagon(胰高血糖素)Adrenalin/Epinephrine(腎上腺素)

Antidiuretin

(抗利尿激素,ADH)

信息傳遞簡(jiǎn)式：HormoneMembranereceptorG-proteinACcAMPPKAFunctionalproteinBiologicaleffectP腺苷酸環(huán)化酶Adenylatecyclase蛋白激酶AProteinkinaseAResultchangesincAMPlevels,activatingtargetproteinssuchasproteinkinaseA（蛋白激酶A）.改變cAMP濃度，激活蛋白激酶ATheMainCharacteristic(主要特征)：Sevenmembrane-spanningαhelicsreceptorB.TrimericG-Protein（三聚體G蛋白）-subunit-subunit-subunitReceptorandThetrimericG-proteinStimulatoryGProtein(激活型G蛋白)RssGDPGTPGDP5’-AMPPhosphodiesteraseACcAMPATPPpisGTP+ActivatePKAPhospho-rylationofcellularproteinsbyPKAcausesthecellularresponseGiRiRiInhibitoryGProtein(抑制型G蛋白)IGDPGTPGDPIGTP+ACATPcAMPPpi2.cAMP和蛋白激酶A

cAMPandProteinkinaseAcAMP

cAMP(cyclicAMP)isanucleotidesecondmessengerthatparticipatesinmanyGproteinsignalingcascades.

Second-messenger

(第二信使):Thesecond-messengersystemisasetofintracellularmoleculesthatareactivatedbycellsurfacereceptorsandaffectcellfunction,producingaphysiologicalresponse.第二信使是被膜受體激活的胞內(nèi)分子，通過濃度變化傳遞信號(hào)，影響細(xì)胞功能。胞外的各種信號(hào)轉(zhuǎn)換成胞內(nèi)單一的信號(hào)，細(xì)胞只需讀取這個(gè)第二信號(hào)，作出應(yīng)答ATPcAMPAdenylatecyclasePhosphodiesterase磷酸二酯酶5’-AMPProteinkinaseA(蛋白激酶A):IsacAMP–dependentproteinkinase

依賴cAMP的蛋白激酶cAMPisitsallostericactivator

cAMP是蛋白激酶A的變構(gòu)激活劑。cAMPandProteinkinaseA

----AllostericRegulation4XcAMP4XcAMPAmplification(moleculesconverted)AdrenalinATPcAMPGlycogenGlucose1-phosphatePKAPKAProteinkinaseAPKPKPhosphorylasekinasebGPbGPaGlucogenphosphorylaseGlucoseGs1moleculesAdenylatecyclase40molecules10molecules100molecules1,00010,000（二）cGMP-蛋白激酶途徑

cGMP-Proteinkinasepathway

Somesignalmoleculesusethispathway:

Insulin(胰島素),

Atriopeptins(心房肽)，

Acetylcholine(乙酰膽堿)，

Nitricoxide(NO)

……

簡(jiǎn)圖HormoneMembranereceptorG-proteinGCcGMPPKGFunctionalproteinBiologicaleffectP鳥苷酸環(huán)化酶Guanylatecyclase蛋白激酶GProteinkinaseGGlonoin硝酸甘油NOThefunctionofcGMPisusuallytheoppositeofcAMP.CyclicGMP/cGMPcGMPisanintracellularsecondmessenger,producedfromthecyclizationofGTPinanintramolecularreactioncatalyzedbyguanylatecyclase(鳥苷酸環(huán)化酶).TherisinglevelofcGMPcanactivateacGMP-dependentproteinkinase(PKG,蛋白激酶G)thatisinvolvedinrelaxingsmoothmusclecells

Question

Wehavelearnedthatthebindingofaligandtoaproteinisthechemicalfoundationofproteinfunction.Whichstepsinthesignalingpathwaywehavejustlearnedbelongtothebindingofligandsandproteins?Isitpossiblethatchinesemedicineaffectthissignalingpathway?DrugsandToxinsThatAffect

thisCellSignalingPathwayCaffeine(咖啡因),theophylline(茶堿),andtheobromine(可可堿)arestimulants,inpart,becausetheyinhibitcAMPphosphodiesterase.Choleratoxin(霍亂毒素)

canactivateGs-protein,andthusAC.Pertussistoxin(百日咳毒素)caninhibitGi-protein,andthereforecannotinhibitAC.（三）Ca2+-依賴性蛋白激酶途徑

CalciumIon–DependentProteinKinasePathwey

1.Hormoneswhichgothroughthispathway:

促甲狀腺素釋放激素Thyrotropin-releasinghormone、去甲腎上腺素Noradrenalin血管緊張素ⅡAngiotensinⅡ加壓素Pitressin胃泌素Gastrin……

打開Ca2+通道激活PKCHormoneReceptor受體GProteinG蛋白GqPLC(磷脂酶C)PIP2IP3(肌醇三磷酸)DAG(二酰甘油)各種生物學(xué)效應(yīng)磷脂酰肌醇循環(huán)PhosphotidylinositolcyclePhosphotidylinositol磷脂酰肌醇PIIP3CH2

OCR1CH2

OHR2CO

CHOODAGCH2

OCR1CH2

OPOR2CO

CHOOOOHCH2

OCR1CH2

OPOR2CO

CHOOOOHPIP2IIPPIPPP2.磷脂酶C型G蛋白(PLCG-protein，Gp)的激活Pip+GTPpp3.第二信使的作用﹡IP3

(inositoltrisphosphate肌醇三磷酸)

：Bindthereceptorinthemembraneofthesmoothendoplasmicreticulum(內(nèi)質(zhì)網(wǎng))andmitochondria(線粒體)，opencalciumchannels.Calciumionsfloodintothecytosol,leadingtocellularresponses.

與內(nèi)質(zhì)網(wǎng)、線粒體膜特異受體結(jié)合，打開鈣庫(kù),釋放大量Ca2+,引起生物效應(yīng).如:糖原分解(glycogenolysis)↑。﹡DAG(diacylglycerol二酰甘油)：ActivatePKC,whichphosphorylatemanyotherproteins

,changingtheircatalyticactivities,leadingtocellularresponses.

激活PKC,后者使相應(yīng)的酶磷酸化而激活或抑制。如:糖原合成(glycogenesis)↓。﹡Ca2+：

(1)CooperatewithDAGinactivatingPKC(蛋白激酶C)

配合DAG激活PKC

(2)ActivateCaMkinasepathway,inwhichcalmodulin(鈣調(diào)蛋

白)bindsCa2+,undergoesachangeinconformation,and

activatesCaMkinase.Thekinasethenphosphorylates

targetenzymes,regulatingtheiractivities.

Ca2+-CaMisalsoaregulatorysubunitofadenylate

cyclase(腺苷酸環(huán)化酶)andphosphodiesterase(磷酸二酯酶).

4. 該途徑最終引發(fā)生物效應(yīng)的酶：

ProteinkinaseC(蛋白激酶C)

Ca2+

-CaMProteinkinase

(Ca2+-CaM蛋白激酶)Ca2+,鈣調(diào)蛋白與Ca2+-CaM蛋白激酶的結(jié)合

ThebindingofCa2+,calmodulinandCa2+-CaMProteinkinase小結(jié)：該途徑的信息傳遞過程簡(jiǎn)圖:Ip3

→ReleasingCa2+→Ca2+-CaM→→PIP2→DAG——→

PKC————→GqPhospho-rylationoffunctionalproteinsBiologicaleffectsPhospho-rylationoffunctionalproteinsBiologicaleffectsHormonereceptorSummary

H1HRＧ

Adenylatecyclase

cAMP

PKA

H2HRＧ

Gua