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1、Section Section signaling pathwayssignaling pathwaysreceptorsIntracellular receptorsCytosol receptorsIntranuclear receptors Membrane receptorsIon channel receptorsG Protein coupled receptors(GPCRS)Enzyme coupled receptors(Single TMS receptors)receptorsCharacters of receptorsG Protein coupled recepto
2、rs(GPCRs)Ion channel receptors(Circle-like receptors)Enzyme coupled receptorsCharacters ligands Neurotransmitter NeurotransmitterHormonechemokineTaste/light Growth factorcytokinesstructuresingle polypeptide chainsingle polypeptide chain (catalytic/uncayalytic)Oligo-p channeltransmembrane471functionI
3、ron-channelActivate G proteinActivate PKCell responseDepolarization;hyperpolarizationDepolarization;HyperpolarizationRegulate protein function and gene expressionRegulate protein function and gene expression;proliferation.intracellular receptorstranscription activation domainCys rich, zinc fingersHi
4、nge region ligand binding, HSP binding, signal ofnucleus localization, dimerization, l2 types: cytosol receptors, intranuclear receptorslLigand: fat-soluble, enter cell lMost of receptors are transcription factorsl no hormone, inhibitory protein complex binds to DNA binding domain of receptor, preve
5、nts receptor entering cell nucleus.lthere is hormone, hormone binding changes the conformation of receptor, inhibitory protein complex dissociates and DNA binding domain and nuclear localization signal are exposed, hormone-receptor complex enters nucleus and binds to HRE in the DNA, acting as transc
6、ription regulators, modulates gene expression. Ion-channel receptorsLigand-gated receptor channelLigand is neurotransmitterTransform chemical signal into electric signalCation channels/anion channelsacetylcholine. G Protein coupled receptorslthe largest class of membrane receptorslligand: hormones,
7、neurotransmitter, stimulation of sense (optic stimulus, olfactory stimulus)lsingle polypeptide chain, glycoproteinslinvolved in vision, taste, olfaction, metabolism, cell proliferationlN terminal: outsidelC terminal: insidel7 TMS (-helix): 20-25 AA/helix TMS: transmembrane segmentlseven transmembran
8、e -helix regions form 3 circles outside and 3 circles inside.l2nd circle and 3rd circle inner side are important for interactions with G protein.GPCR-G protein mediated signaling pathwayligand +receptor（GPCR）conformation change, activatesG proteinsecond messengertarget moleculesbiological effecteffe
9、ctorsG GTP, activatesi. G protein cycleii. G-Protein effectorsAC-cAMP-PKA PLC-IP3/DAG-PKCPLC-IP3-Ca2+/CaM-PK PDE-cGMP-Na+G proteinfunctionGs(stimulatory G protein)Adenyl cyclaseCa2+ channels Gi (inhibitory G protein)Adenyl cyclaseCa2+ channelsGq (PI-PLC G protein)Phospholipase C Go (other) (brain)Ca
10、2+ channelsK+ channels Gt (transductin) (retina)cGMP specific phosphodiesterase Na+ channels Classification of G proteins according to the subunitsHormone-induced activation and inhibition of adenylyl cyclase is mediated by Gsand Gi, respectively. iii. Glucagon: AC-cAMP-PKA pathwayGlucagon regulates
11、 glycometabolismglucagonGPCR, conformational changeGs, active form: G-GTPphosphorylase b kinase / phosphorylaseglycogen synthase, glycogenolysis glycogenesis AC synthesizes cAMP cAMP bind to regulatory subunit, catalytic subunits releasePKA regulates gene transcriptionCREB: cAMP reactive element bin
12、ding proteiniv. Angiotensin :PLC-IP3/DAG-PKCGqHormonereceptor G proteinPLCPIP2IP3DAGangiotensinGPCRGq, active form: G-GTPIP3 migrate to ER, bind to IP3 receptor (Ca 2+ channel). Ca 2+ release, CaM-PKDAG remains in plasma membrane, together with Ca 2+ and PS activate PKC target proteinresponsemuscle
13、constractionHormone target protein receptordifferent cell response. enzyme linked receptor (Single TMS receptors)lhave one transmembrane segment (TMS)lcommon trait: catalytic reaction is the first step of signaling transduction pathway mediated by receptors of this kindlalso called enzyme linked rec
14、eptor. some receptors have catalytic activity, some have not and linked with enzyme.lligand: growth factors, cytokines lcellular response: regulate cell proliferation and differentiation by modulating gene expression. 表皮生长因子受体，EGFR， epidermal growth factor receptor胰岛素受体，insulin receptor干扰素受体，interfe
15、ron receptor白细胞介素受体，IL-R，interleukin receptorT细胞抗原受体，TCAR，T-cell antigen receptor转化生长因子受体，transforming growth factor receptor骨形成蛋白受体，bone morphogenetic protein（BMP) receptor心钠素受体，atrial natriuretic peptide （ANP） receptor i. EGFR: Ras-MAPK pathwaylEGFR: epidermal growth factor receptorltypical PTK (
16、protein tyrosine kinase) EGF binds to the ligand-binding domain of recptor, causes conformation of receptor change, then 2 receptors form dimer. Dimerization induce the intrinsic tyrosine kinase activation, then phosphorylates each other on tyrosine sites (autophosphorylation). EGF binds to EGFRconf
17、ormation of EGFR changeEGFR dimerizeEGFR autophosphorylate on tyrisine residueGrb2 (adaptor protein) binds tophosphorylated tyrosine residue of receptor by SH2 domainSos binds to Grb2 by proline-rich domain and SH3 domain interaction. Sos promotes dissociation of GDPfrom Ras, GTP binds and Sos disso
18、ciates from active Ras.ERK enters nucleus, phosphorylates TF, modulates gene expressionRas binds to N-terminus of Raf and activates RafRaf phosphorylates MEK on Ser/Thr residueMEK phosphorylates ERK on Tyr/Thr residueRegulation of cell proliferation and differentiation MAPKKKMAPKKMAPKii. Interferon
19、R: JAK-STAT pathwaylINF-R: enzyme linked receptor, tyrosine kinase-coupled receptorlJAK: Janus kinase, nonreceptor tyrosine kinaselJAK family: several members, JAK1,2,3, etc.lSTAT: signal transducer and activator of transcription, 6 membersInterferon binds to receptorconformation of receptor change,
20、 receptors oligomerizeactivates coupled JAK, JAK phosphorylates receptor on Tyr residueSTAT recognizes phosphotyrosine motif and binds to receptorJAK phosphorylates STAT, STAT form oligomer, enter nucleus, function as TF, regulates gene expressionCell proliferation/differation change. Common traits
21、of signaling pathwayslOccur and terminate rapidly e.g. cAMP (AC, PDE) transducer (phosphoaylation/dephosphorylation)lAmplify signal by cascade reaction e.g. AC PKA phosphorylase b kinaselUniversallCrosstalkCrosstalkWith medicine lElucidate the mechanism of diseaselFind out useful target protein for therapyCholera toxin affect the cycling of G protein.definitionlSecond messenger
