Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
NMDA receptors comprised of different NR2 subunits exhibit strikingly unique biophysical and pharmacological properties. Here, we report that the extracellular amino-terminal domain (ATD) of the NR2 subunit controls pharmacological and kinetic properties of recombinant NMDA receptors, such as agonist potency, deactivation time course, open probability (P(OPEN)), and mean open/shut duration. Using ATD deletion mutants of NR2A, NR2B, NR2C, NR2D, and chimeras of NR2A and NR2D with interchanged ATD [NR2A-(2D-ATD) and NR2D-(2A-ATD)], we show that the ATD contributes to the low glutamate potency of NR2A-containing NMDA receptors and the high glutamate potency of NR2D-containing receptors. The ATD influences the deactivation time courses of NMDA receptors, as removal of the ATD from NR2A slows the deactivation rate, while removal of the ATD from NR2B, NR2C and NR2D accelerates the deactivation rate. Open probability also is influenced by the ATD. Removal of the ATD from NR2A or replacement of the NR2A-ATD with that of NR2D decreases P(OPEN) in single-channel recordings from outside-out patches of HEK 293 cells. In contrast, deletion of the ATD from NR2D or replacement of the NR2D ATD with that of NR2A increases P(OPEN) and mean open duration. These data demonstrate the modular nature of NMDA receptors, and show that the ATD of the different NR2 subunits plays an important role in fine-tuning the functional properties of the individual NMDA receptor subtypes.
Yuan
Hongjie
H
Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322-3090, USA. hyuan@emory.edu
Hansen
Kasper B
KB
Vance
Katie M
KM
Ogden
Kevin K
KK
Traynelis
Stephen F
SF
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry* / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000502:physiology*; D014982:Xenopus laevis
C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate