title: Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
abstract: Fast desensitization is an important regulatory mechanism of neuronal NMDA receptor function. Only recombinant NMDA receptors composed of NR1/NR2A exhibit a fast component of desensitization similar to neuronal NMDA receptors. Here we report that the fast desensitization of NR1/NR2A receptors is caused by ambient zinc, and that a positive allosteric interaction occurs between the extracellular zinc-binding site located in the amino terminal domain and the glutamate-binding domain of NR2A. The relaxation of macroscopic currents reflects a shift to a new equilibrium due to increased zinc affinity after binding of glutamate. We also show a similar interaction between the ifenprodil binding site and the glutamate binding site of NR1/NR2B receptors. These data raise the possibility that there is an allosteric interaction between the amino terminal domain and the ligand-binding domain of other glutamate receptors. Our findings may provide insight into how zinc and other extracellular modulators regulate NMDA receptor function.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA. fzheng@emory.edu
authors.forename: F
authors.initials: F
authors.lastname: Zheng
authors.forename: K
authors.initials: K
authors.lastname: Erreger
authors.forename: C M
authors.initials: CM
authors.lastname: Low
authors.forename: T
authors.initials: T
authors.lastname: Banke
authors.forename: C J
authors.initials: CJ
authors.lastname: Lee
authors.forename: P J
authors.initials: PJ
authors.lastname: Conn
authors.forename: S F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D004492:Edetic Acid / Q000494:pharmacology; D004553:Electric Conductivity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D010446:Peptide Fragments / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D010446:Peptide Fragments; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D004492:Edetic Acid; D015032:Zinc; C010739:ifenprodil