BindingSitesonNMDAReceptor对NMDA受体的结合位点.pptxVIP

BindingSitesonNMDAReceptor对NMDA受体的结合位点第1页/共34页 Superfamilies of Ligand-Gated ChannelsCys-loop Receptors ? Nicotinic ACh ? 5HT3 ? GABAA and GABAC ? Glycine Not covered in this lecture: ATP (P2X) ReceptorsGlutamate Receptors ? NMDA receptors ? Non-NMDA receptors AMPA-type Kainate-type TRP Receptors第2页/共34页 Topologies for Ligand-Gated Ion ChannelsKandel, Schwartz Jessel, Principles of Neural Science 4th Ed. (2000)Cys-Loop Receptors第3页/共34页 Cys-Loop Channels第4页/共34页 Topology of Cys-Loop ChannelsCysCysModified from Ashcroft, Ion Channels and Disease,Academic Press (2000)Keramidas et al., Prog. Biophys. Mol. Biol.86: 161 (2004)第5页/共34页 nAChR Subunit CompositionKarlin Nature Rev. Neurosci. 3: 102 (2002)At least two a-subunits per pentamer (ACh binding sites) a1: muscle only a2 - a9: neuronalVariable stoichiometry for remaining subunits Brain: usually aabbb Muscle: aabgda3b2: 15 pS 350 μMa4b2: 20 pS 0.7 μMa7: 45 pS 110 μMChannelConductanceAChEC50第6页/共34页 nAChR: Single Channel Recording Ashcroft, Ion Channels and Disease. Academic Press (2000)第7页/共34页 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)第8页/共34页 Ion Selection: Cationic ChannelsAcidicResiduesGateRegionModified from Keramidas et al., Prog. Biophys. Mol. Biol. 86: 161 (2004)第9页/共34页 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)第10页/共34页 Atomic-Resolution Structure of nAChRMiyazawa et al., Nature 423: 949 (2003)第11页/共34页 GABA Receptor Subunit CompositionTwo GABA Binding Sites at a-b InterfacesBenzodiazepine Site at a-g InterfaceKatzung (Ed.) Basic Clinical Pharmacology, Lange (2004)第12页/共34页 Ion Selection: Chloride ChannelsBasicResiduesGateRegionModified from Keramidas et al., Prog. Biophy