Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt

上传人(卖家):三亚风情 文档编号:3376647 上传时间:2022-08-25 格式:PPT 页数:34 大小:8.76MB
下载 相关 举报
Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt_第1页
第1页 / 共34页
Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt_第2页
第2页 / 共34页
Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt_第3页
第3页 / 共34页
Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt_第4页
第4页 / 共34页
Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt_第5页
第5页 / 共34页
点击查看更多>>
资源描述

1、Ligand-Gated Ion ChannelsRobert Blitzer,Ph.D.Depts.of Pharmacology and PsychiatryMount Sinai School of MedicineGeneral Features of LGICsMultimeric integral membrane glycoproteinsSignal by D in membrane voltage or by Ca2+entryGating(opening after ligand binds)is very fastCentral pore lined with a-hel

2、icesIon currents can be largeIon Selectivity:Cationic,often non-selective(Na+,K+,Ca2+)Cl-Often have modulatory sitesSuperfamilies of Ligand-Gated ChannelsCys-loop Receptors Nicotinic ACh 5HT3 GABAA and GABAC GlycineNot covered in this lecture:ATP(P2X)ReceptorsGlutamate Receptors NMDA receptors Non-N

3、MDA receptorsAMPA-typeKainate-typeTRP ReceptorsTopologies for Ligand-Gated Ion ChannelsKandel,Schwartz&Jessel,Principles of Neural Science 4th Ed.(2000)Cys-Loop ReceptorsCys-Loop ChannelsTopology of Cys-Loop ChannelsCysCysModified from Ashcroft,Ion Channels and Disease,Academic Press(2000)Keramidas

4、et al.,Prog.Biophys.Mol.Biol.86:161(2004)nAChR Subunit CompositionKarlin Nature Rev.Neurosci.3:102(2002)At least two a-subunits per pentamer(ACh binding sites)a1:muscle onlya2-a9:neuronalVariable stoichiometry for remaining subunitsBrain:usually aabbbMuscle:aabgda3b2:15 pS 350 Ma4b2:20 pS 0.7 Ma7:45

5、 pS 110 MChannelConductanceAChEC50nAChR:Single Channel Recording Ashcroft,Ion Channels and Disease.Academic Press(2000)Structure of nAChRK+Na+Electron Diffraction ImageRapsynKeramidas et al.,Prog.Biophys.Mol.Biol.86:161(2004)Modified from Purves et al.(Eds.),Neuroscience,Academic Press,(1997)Ion Sel

6、ection:Cationic ChannelsAcidicResiduesGateRegionModified from Keramidas et al.,Prog.Biophys.Mol.Biol.86:161(2004)Model for nAChR Gating:Twisting of M2 HelicesPolar Ser or Thr(Selectivity Filter)Hydrophobic Leu(Gate)OPENCLOSEDModified from Zigmond et al.(Eds.)Fundamental Neuroscience,Sinauer(1999)Ato

7、mic-Resolution Structure of nAChRMiyazawa et al.,Nature 423:949(2003)GABA Receptor Subunit CompositionTwo GABA Binding Sites at a-b InterfacesBenzodiazepine Site at a-g InterfaceKatzung(Ed.)Basic&Clinical Pharmacology,Lange(2004)Ion Selection:Chloride ChannelsBasicResiduesGateRegionModified from Ker

8、amidas et al.,Prog.Biophys.Mol.Biol.86:161(2004)GABA-R:Predicted Interaction Between Cys-Cys Loop and TM2-TM2 LinkerKash et al.,Nature 421:272(2003)Gating of GABA Channels:InteractionBetween the Cys-Loop and the M2-M3 Linker Kash et al.,Nature 421:272(2003)K279 in linker D149 in loopCrosslinking of

9、Substituted Cysteinesin M2-M3 Link and Signature Loop Kash et al.,Nature 421:272(2003)Benzodiazepines and Barbiturates EnhanceGABAA Currents Through Different Mechanisms Open Time Probabilityof OpeningTwyman et al(1989)Ann.Neurol.25:213-220(1989)Ionotropic Glutamate ReceptorsTopology of Glutamate Re

10、ceptorsSelectivity FilterKandel,Schwartz&Jessel,Principles of Neural Science 4th Ed.(2000)Ionotropic Glutamate Receptor SubunitsTetramers formed by 4 homologous subunits3 Families:NMDAAMPAKainateNR1*GluR1-4GluR5-7NR2A-D(mostlyKA1-2NR3A-BGluR1/2&GluR2/3)*obligatoryIon Selectivity of Glutamate Channel

11、sNon-NMDA Receptors:With GluR2 subunit:permeable only to K+and Na+predominant Without GluR2 subunit:Ca2+-permeable NMDA Receptors:Permeable to K+,Na+,Ca2+High conductanceRNA Editing Determines Ca2+-Permeability of AMPA ReceptorsTranscribed codon:CAGEdited codon:CIGRight:Modified from Zigmond et al.(

12、Eds.)Fundamental Neuroscience,Sinauer(1999)RNA Editing DeterminesCa2+-Permeability of AMPA ReceptorsKandel,Schwartz&Jessel,Principles of Neural Science 4th Ed.(2000)Kinetics of Glutamate ChannelsNMDA ReceptorsActivate slowlyDesensitize slowly&incompletely Prolonged Ca2+influx in the face of sustaine

13、d glutamate releaseNon-NMDA ReceptorsActivate rapidlyDesensitize within a few millisecondsIsolating AMPA-R and NMDA-R CurrentsWith Selective BlockersNestler,Hyman,&Malenka,Molecular Neuropharmacology McGraw-Hill(2001)NMDA Receptors Bristle with Sites for Agonists and ModulatorsGlutamate&Glycine Co-A

14、gonists Physiological glycine concentration near saturatingModified from Zigmond et al.(Eds.)Fundamental Neuroscience,Sinauer(1999)NMDAR Current:Voltage-Dependent Block by Mg2+Kandel,Schwartz&Jessel,Principles of Neural Science 4th Ed.(2000)Mg2+SiteMg2+Blocks channel at rest Depolarization-Mg2+ion l

15、eaves the pore Glu+depolarization=Coincidence Detector Other channel blockers:PCP,ketamine,MK801Modified from Zigmond et al.(Eds.)Fundamental Neuroscience,Sinauer(1999)NMDA Receptors are ActivatedDuring Intense Synaptic ActivityHerron et al et al.Nature 322,265(1986)NMDA Receptors Mediate Synaptic C

16、a2+EntryLisman et al.Nature Rev.Neurosci.3:175(2002)Synaptic Plasticity&NMDA ReceptorsLTP(long-term potentiation):a stimulation-induced,persistent increase in synaptic efficiencyWidely studied as a physiological model for memory formation and storageAt many synapses,LTP involves postsynaptic NMDA receptorsInduction of NMDAR-Dependent LTPLTP Requires a Transient NMDAR-Mediated Rise in Postsynaptic Ca2+Core Pathway CartoonMalenka et al.Neuron 9:121(1992)Morris et al.Nature 319:774(1986)

展开阅读全文
相关资源
猜你喜欢
相关搜索

当前位置:首页 > 办公、行业 > 各类PPT课件(模板)
版权提示 | 免责声明

1,本文(Binding-Sites-on-NMDA-Receptor对NMDA受体的结合位点课件.ppt)为本站会员(三亚风情)主动上传,163文库仅提供信息存储空间,仅对用户上传内容的表现方式做保护处理,对上载内容本身不做任何修改或编辑。
2,用户下载本文档,所消耗的文币(积分)将全额增加到上传者的账号。
3, 若此文所含内容侵犯了您的版权或隐私,请立即通知163文库(发送邮件至3464097650@qq.com或直接QQ联系客服),我们立即给予删除!


侵权处理QQ:3464097650--上传资料QQ:3464097650

【声明】本站为“文档C2C交易模式”,即用户上传的文档直接卖给(下载)用户,本站只是网络空间服务平台,本站所有原创文档下载所得归上传人所有,如您发现上传作品侵犯了您的版权,请立刻联系我们并提供证据,我们将在3个工作日内予以改正。


163文库-Www.163Wenku.Com |网站地图|