Molecular design of the N-methyl-D-aspartate receptor binding site for phencyclidine and dizolcipine.
A V Ferrer-Montiel, W Sun, M Montal
Proceedings of the National Academy of Sciences of the United States of America August 15, 1995 DOI: 10.1073/pnas.92.17.8021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic molecular biology study Peer reviewed |
|---|---|
| Population | Recombinant glutamate receptor GluR1 and NMDAR constructs expressed in an experimental system |
| Key points | Three point mutations in GluR1 mimicking homologous NMDAR residues conferred PCP and MK-801 blockade with high potency, voltage dependence, and use dependence. The PCP block determinants appear confined to the putative M2 transmembrane segment, while MK-801 sensitivity requires interplay between M2 and M3 residues. The authors propose that tailored glutamate receptors could serve as models for designing and screening drugs to prevent glutamate-mediated neural damage. |
Abstract
The N-methyl-D-aspartate receptor (NMDAR), a pivotal entity for synaptic plasticity and excitotoxicity in the brain, is a target of psychotomimetic drugs such as phencyclidine (PCP) and dizolcipine (MK-801). In contrast, a related glutamate receptor, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptor GluR1, is weakly sensitive to these drugs. Three point mutations on GluR1, mimicking homologous residues on the NMDAR, confer the PCP and MK-801 blockade properties that are characteristic of the NMDAR--namely, high potency, voltage dependence, and use dependence. The molecular determinants that specify the PCP block appear confined to the putative M2 transmembrane segment, whereas the sensitivity to MK-801 requires an interplay between residues from M2 and M3. Given the plausible involvement of the NMDAR in the etiology of several neurodegenerative diseases and in excitotoxic neuronal cell death, tailored glutamate receptors with specific properties may be models for designing and screening new drugs targeted to prevent glutamate-mediated neural damage.