PMID- 10402203
OWN - NLM
STAT- MEDLINE
DCOM- 19990729
LR  - 20190822
IS  - 0896-6273 (Print)
IS  - 0896-6273 (Linking)
VI  - 23
IP  - 1
DP  - 1999 May
TI  - Identification and mechanism of action of two histidine residues underlying 
      high-affinity Zn2+ inhibition of the NMDA receptor.
PG  - 171-80
AB  - Zinc (Zn2+) inhibition of N-methyl-D-aspartate receptor (NMDAR) activity involves 
      both voltage-independent and voltage-dependent components. Recombinant NR1/NR2A 
      and NR1/NR2B receptors exhibit similar voltage-dependent block, but 
      voltage-independent Zn2+ inhibition occurs with much higher affinity for NR1/NR2A 
      than NR1/NR2B receptors (nanomolar versus micromolar IC50, respectively). Here, 
      we show that two neighboring histidine residues on NR2A represent the critical 
      determinant (termed the "short spacer") for high-affinity, voltage-independent 
      Zn2+ inhibition using the Xenopus oocyte expression system and site-directed 
      mutagenesis. Mutation of either one of these two histidine residues (H42 and H44) 
      in the extracellular N-terminal domain of NR2A shifted the IC50 for high-affinity 
      Zn2+ inhibition approximately 200-fold without affecting the EC50 of the 
      coagonists NMDA and glycine. We suggest that the mechanism of high-affinity Zn2+ 
      inhibition on the NMDAR involves enhancement of proton inhibition.
FAU - Choi, Y B
AU  - Choi YB
AD  - Cerebrovascular and NeuroScience Research Institute, Brigham and Women's 
      Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
FAU - Lipton, S A
AU  - Lipton SA
LA  - eng
GR  - P01 HD29587/HD/NICHD NIH HHS/United States
GR  - R01 EY05477/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuron
JT  - Neuron
JID - 8809320
RN  - 0 (Protein Isoforms)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 4QD397987E (Histidine)
RN  - J41CSQ7QDS (Zinc)
RN  - LMR3LZG146 (Diethyl Pyrocarbonate)
SB  - IM
MH  - Animals
MH  - Diethyl Pyrocarbonate/pharmacology
MH  - Female
MH  - Histidine/drug effects/genetics/*physiology
MH  - Mutation/physiology
MH  - Oocytes
MH  - Patch-Clamp Techniques
MH  - Protein Isoforms/antagonists & inhibitors
MH  - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/metabolism
MH  - Xenopus laevis
MH  - Zinc/antagonists & inhibitors/*pharmacology
EDAT- 1999/07/13 00:00
MHDA- 1999/07/13 00:01
CRDT- 1999/07/13 00:00
PHST- 1999/07/13 00:00 [pubmed]
PHST- 1999/07/13 00:01 [medline]
PHST- 1999/07/13 00:00 [entrez]
AID - S0896-6273(00)80763-1 [pii]
AID - 10.1016/s0896-6273(00)80763-1 [doi]
PST - ppublish
SO  - Neuron. 1999 May;23(1):171-80. doi: 10.1016/s0896-6273(00)80763-1.