細(xì)胞信號轉(zhuǎn)導(dǎo)與疾病課件

細(xì)胞信號轉(zhuǎn)導(dǎo)與疾病

(Extracellular,intracellular)Stimulus(Transmembrane,nuclearandorphonreceptor,etc)ReceptorIntracellularsignalingcascade(Calcium,nitricoxide,Gprotein,smallGTPases,cyclicnucleotidesphosphoinositidederivatives,proteinkinasesandphosphatases)Biologicalfunction(Growth,proliferation,apoptosis,secretion,electronicimpulse,stressresponse,etc.)SensingtheSignalsSignalTransductionSignalingtransductinreferstotheprocessinwhichcellssensetheextracellularorintracellularstimulithroughmembranousorintracellularreceptors,transducethesignalsthroughintracellularmolecules,andthusregulatethebiologicalfunctionofthecells.致病因子、神經(jīng)、體液因子鳥苷酸環(huán)化酶核受體細(xì)胞信號轉(zhuǎn)導(dǎo)途徑快慢蛋白質(zhì)細(xì)胞反應(yīng)興奮與抑制運(yùn)動、分泌代謝變化肥大、增殖分化、凋亡第二信使G蛋白膜受體蛋白激酶磷酸酶轉(zhuǎn)錄因子基因蛋白質(zhì)離子通道受體酪氨酸蛋白激酶AberrantSignalMoleculeinParkinson’sDiseasesHowdopamineandseveralotherchemicaltransmittersexerttheireffectsinthenervecell

原發(fā)性受體異常例:家族性腎性尿崩癥

ADHADHV2-RGscAMP集合管上皮細(xì)胞水通道蛋白移動入腔側(cè)膜通透性↑H2O吸收

基因突變V2R合成↓或親和力↓集合管對ADH反應(yīng)↓多尿

原發(fā)性G蛋白異常例:巨人癥腺垂體Gsα基因突變GTP酶活性↓Gsα持續(xù)激活A(yù)CcAMP垂體細(xì)胞生長、分泌

繼發(fā)性G蛋白異常例:霍亂霍亂毒素Gsα核糖化GTP酶活性↓Gsα持續(xù)激活A(yù)CcAMPCl-、水分泌↑佛波酯型促癌物PKC慢性穩(wěn)定激活生長因子、癌基因表達(dá)Na+/H+交換

胞內(nèi)pH↑、K+↑細(xì)胞增殖原發(fā)性胞內(nèi)信號轉(zhuǎn)導(dǎo)分子異常例:癌癥問:家族性高膽固醇血癥是否原發(fā)性細(xì)胞信號轉(zhuǎn)導(dǎo)障礙?R與TSH結(jié)合↓甲狀腺功能減退繼發(fā)性細(xì)胞信號轉(zhuǎn)導(dǎo)異常例:自身免疫性甲狀腺病GsACcAMP甲腺細(xì)胞生長、分泌

GqPLCIP3DAGCa2PKC阻斷性AbTSH-R295~302385~395aa殘基TSH-R30~35aa殘基刺激性AbIschemicSignalinginAstrocyte交感神經(jīng)興奮PLCGqIP3DAGCa2+CaM-PKPKCMLCKMyosin動脈收縮同一刺激引起不同病理反應(yīng)例:感染性休克腺苷酸環(huán)化酶途徑肌醇磷脂雙信使途徑KCaCa2+pump[Ca2+]i低排高阻性休克α受體高排低阻性休克β受體GsαACcAMPPKA動一靜脈短路開放（一）不同信號轉(zhuǎn)導(dǎo)途徑引起相同病理反應(yīng)例:心肌肥大NE、AT-IIPLCCa2+、PKC機(jī)械刺激Na+、Ca2+內(nèi)流Na+-H+交換MAPK靶蛋白轉(zhuǎn)錄因子c-fosc-jun靶基因生長因子TPKRaf（MAPKKK）Ras細(xì)胞信號轉(zhuǎn)導(dǎo)途徑多處異常

(例:心衰發(fā)病中交感神經(jīng)作用)心肌交感神經(jīng)密度↓；酪氨酸羥化酶↓β-R下調(diào)；pH↓→R對CA反應(yīng)↓Gs蛋白↓，功能↓；Gi蛋白

，功能

心肌肥大、心衰正常β1RcAMPGsCASR鈣泵↓H+抑Ca2+結(jié)合肌鈣蛋白SR受磷蛋白Ca2+泵[Ca2+]i↓心肌舒張

SRCa2+通道Ca2+通道Ca2+內(nèi)流[Ca2+]i心肌收縮MultipleSignalingAberrationsinDiabetesMellitusGlucose↓Insulin↓InsulinreceptorRasRafMAPKKMAPKMitogenactivityPI-3KPKB↓Glut4SignalingofGlycogenSynthaseKinase-3inAlzheimer’sDisease病理反應(yīng)中細(xì)胞信號轉(zhuǎn)導(dǎo)網(wǎng)例:缺氧性肺血管收縮缺氧DAGPKCCa2+Kv內(nèi)流Ca2+

(-)(-)[Ca2+]i↑+CaM→MLCK→MLC磷酸化收縮NOsGCcGMPPKGCa2+通道內(nèi)流Ca2+↓Ca2+泵(-)(+)GqCAPLCIP3

1GqAT-IIAT1GqETAGsPGI2ACcAMPPKA(-)SR釋Ca2+↑1、細(xì)胞信號轉(zhuǎn)導(dǎo)系統(tǒng)原發(fā)性異?？砂l(fā)生于任何環(huán)節(jié)2、細(xì)胞外來刺激引起繼發(fā)性細(xì)胞轉(zhuǎn)導(dǎo)異常3、同一刺激引起不同的病理反應(yīng)4、不同信號轉(zhuǎn)導(dǎo)途徑引起相同病理反應(yīng)5、細(xì)胞信號轉(zhuǎn)導(dǎo)途徑可有多個環(huán)節(jié)異常6、病理反應(yīng)中的信號轉(zhuǎn)導(dǎo)由多途徑、正負(fù)反饋、交叉對話構(gòu)成信號轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)

小結(jié)疾病中的細(xì)胞信號轉(zhuǎn)導(dǎo)問:通過如此復(fù)雜的信號轉(zhuǎn)導(dǎo)網(wǎng)絡(luò)引起細(xì)胞反應(yīng)的意義?

細(xì)胞信號轉(zhuǎn)導(dǎo)與疾病防治

如治缺氧性肺動脈高壓（1）病因治療——去缺氧（2）對第一信使——A