title: Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog.
abstract: The NMDA ionotropic glutamate receptor is ubiquitous in mammalian central neurons. Because partial agonists bind to the same site as glutamate but induce less channel activation, these compounds provide an opportunity to probe the mechanism of activation of NMDA-type glutamate receptors. Molecular dynamics simulations and site-directed mutagenesis demonstrate that the partial agonist homoquinolinate interacts differently with binding pocket residues than glutamate. Homoquinolinate and glutamate induce distinct changes in the binding pocket, and the binding pocket exhibits significantly more motion with homoquinolinate bound than with glutamate. Patch-clamp recording demonstrates that single-channel activity induced by glutamate or by homoquinolinate has identical single-channel current amplitude and mean open-channel duration but that homoquinolinate slows activation of channel opening relative to glutamate. We hypothesize that agonist-induced conformational changes in the binding pocket control the efficacy of a subunit-specific activation step that precedes the concerted global change in the receptor-channel complex associated with ion channel opening.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, USA. kevin.erreger@vanderbilt.edu
authors.forename: Kevin
authors.initials: K
authors.lastname: Erreger
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Geballe
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011805:Quinolinic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D018690:Excitatory Amino Acid Agonists; D011805:Quinolinic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C040632:homoquinolinic acid