ru-第5章细胞通讯20171205(1).ppt

1,CHAPTER 5 细胞通讯CELL COMMUNICATION,2,OUTLINE,5.1BASIC CHARACTERISTICS OF CELL-SIGNALING SYSTEMS 5.2 G PROTEIN COUPLED RECEPTOR5.3 SIGNALING VIA ENZYME-LINKED RECEPTORS AND OTHER SIGNALING PATHWAY5.4 SIGNAL CONVERGENT、DIVERGENT、CROSSTALK AND CELL ADAPTATION,信号出现,传递消息,决策,执行功能,信息感受,信息传递,命令传递,日常生活中的信息传递,细胞通讯：Cell Communication,4,细胞通讯：Cell Communication,5,Cell Signal：信号的产生及传送 synthesis of signal molecule release transport,Cell Communication Reaction,Signal Transduction：信号的接收、转换、应答 signal recognition transduction response,Transduction,Signal molecules,recognition(receptor),Reaction,SIGNALING COMPONENTS,Four Types of Cell CommunicationCell-Surface Receptors Fall into Three Main ClassesThe Basic Cell Signaling Process,(A)Contact-dependent:dont need secreted molecule(B)Papacrine:to nearby neighbor(C)Neuronal signaling(D)Endocrine:to long distance,From Bruce Alberts et al.,Molecular Biology of The Cell(5th edition),Signal can act over long or short range.,Four Types of Cell Communication,From Essential Cell Biology(Garland Science 2010),From Essential Cell Biology(Garland Science 2010),10,5.1.1 Cell Signaling and Signal molecule,不依赖于细胞接触：,依赖于细胞接触：,11,Transduction,Signal molecules,recognition(receptor),Reaction,5.1.2 Signal Recognition and Receptors,受体（receptor）：任何能够与信号分子结合并能引起细胞功能变化的生物大分子。,12,接收信息受体,信号分子配体(ligand),From Bruce Alberts et al.,Molecular Biology of The Cell(5th edition),1.An ion-channel-coupled opens or closes in response to binding ofits extracellular signal molecule.These channels are also calledtransmitter-gated ion channels,Cell surface receptors fall into three basic classes,From Bruce Alberts et al.,Molecular Biology of The Cell(5th edition),G-protein-coupled receptor:When a G-coupled receptor binds its extracellular signal molecule,the signal is passed first to aGTP-binding protein(G protein)that is associated with the receptor.The activated G protein then leaves the receptor and turn on a targetenzyme(or ion channel)in the membrane,From Bruce Alberts et al.,Molecular Biology of The Cell(5th edition),3.Enzyme-coupled receptors:An enzyme-linked receptor binds its extracellular signal molecule,switching on an enzyme activity,either at the other end of the enzyme or other associated enzyme,16,Cell-surface Receptors,（受体本身就是离子通道的一部分）,（GTP结合的调节蛋白偶联）,（受体本身就是酶，又称催化受体）,17,Intracellular Receptors,Two motifs,two binding sites,18,19,Generation of conditional knockout mice,ER-Cre/tamoxifen,20,Transduction,Signal molecules,recognition(receptor),Reaction,21,5.1.3 Signal Transduction,信号转导：细胞表面受体通过一定机制将外部信号转为内 部信号。,Many intracellular signaling proteins act as molecular switches:Signaling by phosphorylation:signaling proteins are activated by the addition of a phosphate group by protein kinase,and inactivated by removal of the phosphate by protein phosphatase.Protein kinase phosphates serine/threonine(called ser/thr kinase)or tyrosine(called tyrosine kinase)(B)Signaling by GTP-binding protein:a GTP-binding signaling protein is induced to exchange its bound GDT for GTP(i.e.adds aphosphate to the protein).The hydrolysis of the bound GTP to GDP Then switches the protein off,Protein kinase 2 is activated by protein kinase 1.Once activated,protein kinase 2 phosphorylates protein kinase 3,activating the enzyme.Protein kinase 3 then phosphorylates a transcription factor,increasing its affinity for a site on the DNA.Binding of a transcription factor to the DNA affects the transcription of the gene in question.Each of these activation steps in the pathway is reversed by a phosphatase.,From Gerald Karp,Cell and Molecular Biology-concepts and experiments(6th edition),Signal transduction pathway consisting of protein kinases and protein phosphatases,From Bruce Alberts et al.,Molecular Biology of The Cell(5th edition),GTPase-activating proteins(GAPs)inactivate the protein by stimulating it to hydrolyze its bound GTP to GDP.Guanine nucleotide exchange factors(GEFs)activate the inactive protein by stimulating it to release its GDP;Note that the concentration of GTP in cytosol is 10 times greater than the concentration of GDP,the protein rapidly binds GTP once it ejects GDP and is thereby activated,The regulation of a monomeric GTPases.,25,Second Messenger,第一信使：细胞外部信号。第二信使：由细胞表面受体转换而来的细胞内部信号。第一信使同其膜受体结合后最早在胞膜内侧或胞浆中出现的仅在细胞内部起作用的信号分子；能启动或调解细胞内稍晚出现的细胞应答。,26,Signal Transduction at a Glance,27,Types of Receptor-Effector Linkage,28,Transduction,Signal molecules,recognition(receptor),Reaction,Extracellular signals can act slowly or rapidly,From Essential Cell Biology(Garland Science 2010),30,Signal Cascade,Two different types of signal transduction pathways:one in which a signaling pathway is activated by a diffusible second messenger and another in which a signaling pathway is activated by recruitment of proteins to the plasma membrane.Most signal transduction pathways involve a combination of these mechanisms.signaling pathways are not typically linear tracks as depicted here,but are branched and interconnected to form a complex web.,From Gerald Karp,Cell and Molecular Biology-concepts and experiments(6th edition),The Basic Cell Signaling Process,32,5.2 G Protein-coupled Receptor,2006 Nature Review Drug Discovery,GPCR,Truly unique drugs：1,300Small molecules：1,200Major drug targets：300Drug targets in human：2664 major types of drug targets：GPCRs，nuclear receptors，ligand-gated or voltage-gated ion channelsGPCR：60,GPCR最具潜力的药靶,2006全球销量前10名的药物,35,G-蛋白:组成:一般由三个亚基组成,分别叫、,、两亚基通常紧密结合在一起,只有在蛋白变性时才分开。功能位点:亚基具有三个功能位点：GTP结合位点;鸟苷三磷酸水解酶(GTPase)活性;ADP-核糖化位点。,36,Cycling of G Protein,GDI（鸟苷解离抑制蛋白）,GEF（鸟苷交换因子）,GAP（GTPase激活蛋白）,Binding of signal molecule to receptor causes the conformation change of this receptor,which in turn alters the conformation of the G proteinThe alteration of the subunit of G protein allows it to exchange its GDP to GTPThis causes the G protein to break up into two activate components-subunit and a complex,both can regulate the activity of target proteins in the plasma membrane,From Essential Cell Biology(Garland Science 2010),38,Classification of G proteins,39,e.g.GPCR activation to opening of K+channels in the plasma membrane of heart muscle cells,activated bg complex binds toand opens a K+channelinactivation of the a subunit byhydrolysis of its bound GTP returns the G protein to itsinactive state,allowing the K+channel to close,G-protein Regulation of Ion Channels,From Essential Cell Biology(Garland Science 2010),41,PKA System,42,PKA activation,phosphorylate serine/threonine residues on their target proteins.,43,?,PKA Function(cytoplasm),1.phosphorylates key target enzymes,44,Discovery of cAMP(第二信使),1947年医学和生理学诺贝尔奖获得者,45,1971年医学和生理学诺贝尔奖获得者,Discovery of cAMP(第二信使),Earl W.Sutherland,46,Discovery of cAMP(第二信使),Earl W.Sutherland,47,Alfred G.Gilman,Martin Rodbell,1994 年医学和生理学诺贝尔奖获得者,Discovery of G protein,48,1994 年医学和生理学诺贝尔奖获得者,Discovery of G protein,49,Discovery of G protein,Martin Rodbell,50,Discovery of G protein,51,Discovery of G protein,52,PKA Function(Nuclear),2.Transcription regulation,53,cAMP途径的信号解除和抑制?,信号解除通过磷酸二酯酶将cAMP降解,形成5-AMP；信号抑制通过抑制型的信号作用于Ri,然后通过Gi起作用。,54,的合成与分解,cAMP,55,cAMP信号的抑制（Gi）,56,毒素对cAMP信号途径的影响霍乱:无痛性腹泻,“米泔水样”泻出物 传播途径：污染的水源或未煮熟的食物如海产品、蔬菜经口摄入。霍乱毒素(cholera toxin)能把NAD+上的NAD-核糖转移到Gs蛋白的亚基上，使G蛋白核糖化(ADP-ribosylation),这样将抑制亚基GTPase活性。,57,毒素对cAMP信号途径的影响百日咳：百日咳杆菌所致的急性呼吸道传染病，阵发性痉咳及阵咳终末出现的鸡鸣样吸气性吼声。多见于五岁以下的小儿。患者是唯一的传染源，通过飞沫传染。百日咳毒素(whooping couch toxin)作用机理同霍乱毒素相同，但是使Gi蛋白进行ADP核糖化,阻止Gi 亚基活化，其结果也是使cAMP的浓度增加。,58,磷脂肌醇信号途径(Phosphatidylinositol Signaling),G蛋白偶联受体系统的一种。该通路也称IP3、DAG、Ca2+信号通路,或称为PKC(Protein kinase C)系统。,