Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
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.
Zheng
F
F
Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA. fzheng@emory.edu
Erreger
K
K
Low
C M
CM
Banke
T
T
Lee
C J
CJ
Conn
P J
PJ
Traynelis
S F
SF
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
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