Abstract
Alcohols, inhaled anesthetics, and some injectable anesthetics inhibit the function of N-methyl-d-aspartate (NMDA) receptors, but the mechanisms responsible for this inhibition are not fully understood. Recently, it was shown that ethanol inhibition of NMDA receptors was reduced by mutation of residues in the transmembrane (TM) segment 3 of the NR1 subunit (F639A) or in TM4 of the NR2A subunit (A825W), suggesting putative ethanol binding sites. We hypothesized that the actions of other anesthetics might also require these amino acids and evaluated the effects of anesthetics on the NMDA receptors expressed in Xenopus oocytes with two-electrode voltage-clamp recording. Effects of hexanol, octanol, isoflurane, halothane, chloroform, cyclopropane, 1-chloro-1,2,2-trifluorocyclobutane, and xenon were reduced or eliminated in the mutant NMDA receptors, whereas the inhibitory effects of nitrous oxide, ketamine, and benzene were not affected by these mutations. Rapid applications of glutamate and glycine by a T-tube device provided activation time constants, which suggested different properties of ketamine and isoflurane inhibition. Thus, amino acids in TM3 and TM4 are important for the actions of many anesthetics, but nitrous oxide, benzene, and ketamine seem to have distinct mechanisms for inhibition of the NMDA receptors.
Footnotes
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This study was supported by the National Institute of Health Grants GM47818 and AA06399 (to R.A.H.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.101691.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; MK-801, dizocilpine hydrogen maleate; TM, transmembrane; AP5, d-(-)-2-amino-5-phosphonopentanoic acid; F3, 1-chloro-1,2,2-trifluorocyclobutane; F6, 1,2-dichlorohexafluorocyclobutane; MAC, minimum alveolar concentration; ANOVA, analysis of variance; atm, atmosphere.
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↵1 These authors contributed equally to this work.
- Received January 20, 2006.
- Accepted April 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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