JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Brimecombe, J. C.
Right arrow Articles by Aizenman, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brimecombe, J. C.
Right arrow Articles by Aizenman, E.

Vol. 286, Issue 2, 627-634, August 1998

An NR2B Point Mutation Affecting Haloperidol and CP101,606 Sensitivity of Single Recombinant N-Methyl-D-Aspartate Receptors1

Jessica C. Brimecombe, Michael J. Gallagher, David R. Lynch and Elias Aizenman

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh (J.C.B., E.A.), and the Department of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Children's Seashore House, Philadelphia (M.J.G., D.R.L.), Pennsylvania

Haloperidol and ifenprodil are N-methyl-D-aspartate (NMDA) receptor (NR) antagonists with preference for the NR1/NR2B subunit combination. Previous investigations utilizing 125I-MK801 binding assays with recombinant receptors distinguished certain structural determinants on the NR2B subunit for these two drugs, with glutamate 201 being critical for haloperidol sensitivity and arginine 337 being important for ifenprodil block. Other studies, however, suggested that these two sites pharmacologically overlap. In an attempt to resolve these discrepancies, we have characterized the actions of haloperidol and CP101,606, an ifenprodil analog, on the single-channel properties of NR1/NR2B(E201R) receptors transiently expressed in Chinese hamster ovary cells, because receptors formed by NR1/NR2B(R337K) appear to be nonfunctional. Haloperidol (10 µM) inhibited wild-type NR1/NR2B channels by decreasing the frequency of channel opening, whereas CP101,606 (0.5 µM) antagonized NR1/NR2B channel activity by decreasing both the open dwell time and the frequency of channel opening. The inhibitory actions of both drugs were virtually absent in the mutant NR1/NR2B(E201R) receptors. These results suggest that glutamate 201 is critical for both haloperidol and CP101,606 inhibition, thus demonstrating common features in the action of these two antagonists.

0022-3565/98/2862-0627$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 NeuroscientistHome page
C. Villmann and C.-M. Becker
On the Hypes and Falls in Neuroprotection: Targeting the NMDA Receptor
Neuroscientist, December 1, 2007; 13(6): 594 - 615.
[Abstract] [PDF]

Home page
 J. Neurophysiol.Home page
A. B. Alex, A. J. Baucum, and K. S. Wilcox
Effect of Conantokin G on NMDA Receptor-Mediated Spontaneous EPSCs in Cultured Cortical Neurons
J Neurophysiol, September 1, 2006; 96(3): 1084 - 1092.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
P. Malherbe, V. Mutel, C. Broger, F. Perin-Dureau, J. A. Kemp, J. Neyton, P. Paoletti, and J. N. C. Kew
Identification of Critical Residues in the Amino Terminal Domain of the Human NR2B Subunit Involved in the RO 25-6981 Binding Pocket
J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 897 - 905.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. D. Sinor, S. Du, S. Venneti, R. C. Blitzblau, D. N. Leszkiewicz, P. A. Rosenberg, and E. Aizenman
NMDA and Glutamate Evoke Excitotoxicity at Distinct Cellular Locations in Rat Cortical Neurons In Vitro
J. Neurosci., December 1, 2000; 20(23): 8831 - 8837.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
J. C. Brimecombe, W. K. Potthoff, and E. Aizenman
A Critical Role of the N-Methyl-D-aspartate (NMDA) Receptor Subunit (NR) 2A in the Expression of Redox Sensitivity of NR1/NR2A Recombinant NMDA Receptors
J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 785 - 792.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
N. W. Kleckner, J. C. Glazewski, C. C. Chen, and T. D. Moscrip
Subtype-Selective Antagonism of N-Methyl-D-Aspartate Receptors by Felbamate: Insights into the Mechanism of Action
J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 886 - 894.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.