BindingSitesonNMDAReceptor對(duì)NMDA受體的結(jié)合位點(diǎn)

1、1會(huì)計(jì)學(xué)BindingSitesonNMDAReceptor對(duì)對(duì)NMDA受體的結(jié)合位點(diǎn)受體的結(jié)合位點(diǎn)Cys-loop Receptors Nicotinic ACh 5HT3 GABAA and GABAC GlycineNot covered in this lecture:ATP (P2X) ReceptorsGlutamate Receptors NMDA receptors Non-NMDA receptorsAMPA-typeKainate-typeTRP ReceptorsKandel, Schwartz & Jessel, Principles of Neural Sci

2、ence 4th Ed. (2000)Cys-Loop ReceptorsCysCysModified from Ashcroft, Ion Channels and Disease,Academic Press (2000)Keramidas et al., Prog. Biophys. Mol. Biol.86: 161 (2004)Karlin Nature Rev. Neurosci. 3: 102 (2002)At least two a-subunits per pentamer (ACh binding sites)a1: muscle onlya2 - a9: neuronal

3、Variable stoichiometry for remaining subunitsBrain: usually aabbbMuscle: aabgda3b2: 15 pS 350 Ma4b2: 20 pS 0.7 Ma7: 45 pS 110 MChannelConductanceAChEC50Ashcroft, Ion Channels and Disease. Academic Press (2000)K+Na+Electron Diffraction ImageRapsynKeramidas et al., Prog. Biophys. Mol. Biol.86: 161 (20

4、04)Modified from Purves et al. (Eds.), Neuroscience, Academic Press, (1997)AcidicResiduesGateRegionModified from Keramidas et al., Prog. Biophys. Mol. Biol. 86: 161 (2004)Polar Ser or Thr (Selectivity Filter) Hydrophobic Leu (Gate)OPENCLOSEDModified from Zigmond et al. (Eds.) Fundamental Neuroscienc

5、e, Sinauer (1999)Miyazawa et al., Nature 423: 949 (2003)Two GABA Binding Sites at a-b InterfacesBenzodiazepine Site at a-g InterfaceKatzung (Ed.) Basic & Clinical Pharmacology, Lange (2004)BasicResiduesGateRegionModified from Keramidas et al., Prog. Biophys. Mol. Biol. 86: 161 (2004)Kash et al.,

6、 Nature 421: 272 (2003)Kash et al., Nature 421: 272 (2003)K279 in linker D149 in loopKash et al., Nature 421: 272 (2003) Open Time Probabilityof OpeningTwyman et al (1989) Ann. Neurol. 25: 213-220 (1989) Selectivity FilterKandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)Tetr

7、amers formed by 4 homologous subunits3 Families:NMDAAMPAKainateNR1*GluR1-4GluR5-7NR2A-D(mostlyKA1-2NR3A-BGluR1/2 & GluR2/3) *obligatoryNon-NMDA Receptors: With GluR2 subunit: permeable only to K+ and Na+ predominant Without GluR2 subunit: Ca2+-permeable NMDA Receptors: Permeable to K+, Na+, Ca2+

8、 High conductanceTranscribed codon: CAGEdited codon: CIGRight: Modified from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)Kandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)NMDA ReceptorsActivate slowlyDesensitize slowly & incompletely Prolonged Ca2+ influ

9、x in the face of sustained glutamate releaseNon-NMDA ReceptorsActivate rapidlyDesensitize within a few millisecondsNestler, Hyman, & Malenka, Molecular Neuropharmacology McGraw-Hill (2001)Glutamate&Glycine Co-Agonists Physiological glycine concentration near saturatingModified from Zigmond e

10、t al. (Eds.) Fundamental Neuroscience, Sinauer (1999)Kandel, Schwartz & Jessel, Principles of Neural Science 4th Ed. (2000)Mg2+ Blocks channel at rest Depolarization - Mg2+ ion leaves the pore Glu + depolarization = Coincidence Detector Other channel blockers: PCP, ketamine, MK801Modified from Z

11、igmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)Herron et al et al. Nature 322, 265 (1986)Lisman et al. Nature Rev. Neurosci. 3: 175 (2002)LTP (long-term potentiation): a stimulation-induced, persistent increase in synaptic efficiencyWidely studied as a physiological model for memory fo

12、rmation and storageAt many synapses, LTP involves postsynaptic NMDA receptorsCore Pathway CartoonMalenka et al. Neuron 9: 121 (1992)Morris et al. Nature 319: 774 (1986)CysCysModified from Ashcroft, Ion Channels and Disease,Academic Press (2000)Keramidas et al., Prog. Biophys. Mol. Biol.86: 161 (2004

13、)K+Na+Electron Diffraction ImageRapsynKeramidas et al., Prog. Biophys. Mol. Biol.86: 161 (2004)Modified from Purves et al. (Eds.), Neuroscience, Academic Press, (1997)Polar Ser or Thr (Selectivity Filter) Hydrophobic Leu (Gate)OPENCLOSEDModified from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (19