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