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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
2、a-helicesIon 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 re
3、ceptors Non-NMDA 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 Pr
4、ess (2000)Keramidas 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: aabgd
5、a3b2: 15 pS 350 Ma4b2: 20 pS 0.7 Ma7: 45 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 a
6、l. (Eds.), Neuroscience, Academic Press, (1997)Ion Selection: 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
7、from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)Atomic-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, Lang
8、e (2004)Ion Selection: Chloride ChannelsBasicResiduesGateRegionModified from Keramidas 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
9、the M2-M3 Linker Kash et al., Nature 421: 272 (2003)K279 in linker D149 in loopCrosslinking of 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 OpeningT
10、wyman et al (1989) Ann. Neurol. 25: 213-220 (1989) Ionotropic Glutamate ReceptorsTopology of Glutamate ReceptorsSelectivity FilterKandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)Ionotropic Glutamate Receptor SubunitsTetramers formed by 4 homologous subunits3 Families:NMDAAMPAKa
11、inateNR1*GluR1-4GluR5-7NR2A-D(mostlyKA1-2NR3A-BGluR1/2 & GluR2/3) *obligatoryIon Selectivity of Glutamate ChannelsNon-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 Edit
12、ing Determines Ca2+-Permeability of AMPA ReceptorsTranscribed codon: CAGEdited codon: CIGRight: Modified from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)RNA Editing DeterminesCa2+-Permeability of AMPA ReceptorsKandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)K
13、inetics of Glutamate ChannelsNMDA ReceptorsActivate slowlyDesensitize slowly & incompletely Prolonged Ca2+ influx in the face of sustained glutamate releaseNon-NMDA ReceptorsActivate rapidlyDesensitize within a few millisecondsIsolating AMPA-R and NMDA-R CurrentsWith Selective BlockersNestler, Hyman
14、, & Malenka, Molecular Neuropharmacology McGraw-Hill (2001)NMDA Receptors Bristle with Sites for Agonists and ModulatorsGlutamate&Glycine Co-Agonists Physiological glycine concentration near saturatingModified from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)NMDAR Current: Voltage-
15、Dependent Block by Mg2+ Kandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)Mg2+ SiteMg2+ Blocks channel at rest Depolarization - Mg2+ ion leaves the pore Glu + depolarization = Coincidence Detector Other channel blockers: PCP, ketamine, MK801Modified from Zigmond et al. (Eds.) Fun
16、damental Neuroscience, Sinauer (1999)NMDA Receptors are ActivatedDuring Intense Synaptic ActivityHerron et al et al. Nature 322, 265 (1986)NMDA Receptors Mediate Synaptic Ca2+ EntryLisman et al. Nature Rev. Neurosci. 3: 175 (2002)Synaptic Plasticity & NMDA ReceptorsLTP (long-term potentiation): a st
17、imulation-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)
Binding Sites on NMDA Receptor对NMDA受体结合位点
