期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1995
卷号：92
期号：17
页码：8021-8025
DOI：10.1073/pnas.92.17.8021
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
