Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes.
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.
Ogata
Junichi
J
University of Texas, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, Austin, TX 78712-0159, USA, and Department of Anesthesia, Kyoto University Hospital, Japan.
Shiraishi
Munehiro
M
Namba
Tsunehisa
T
Smothers
C Thetford
CT
Woodward
John J
JJ
Harris
R Adron
RA
D019943:Amino Acid Substitution / Q000235:genetics; D000777:Anesthetics / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D009154:Mutation; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000235:genetics*; D014982:Xenopus laevis
D000777:Anesthetics; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D016194:Receptors, N-Methyl-D-Aspartate