Sites of volatile anesthetic action on kainate (glutamate receptor 6) receptors

Kouichiro Minami, Marilee J. Wick, Yael Stern-Bach, Jo Ellen Dildy-Mayfield, Susan J. Brozowski, Elizabeth L. Gonzales, James R. Trudell, R. Adron Harris*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Molecular mechanisms of anesthetic action on neuro-transmitter receptors are poorly understood. The major excitatory neurotransmitter in the central nervous system is glutamate, and recent studies found that volatile anesthetics inhibit the function of the α-amino-3-hydroxyisoxazolepropionic acid subtype of glutamate receptors (e.g. glutamate receptor 3 (GluR3)), but enhance kainate (GluR6) receptor function. We used this dissimilar pharmacology to identify sites of anesthetic action on the kainate GluR6 receptor by constructing chimeric GluR3/GluR6 receptors. Results with chimeric receptors implicated a transmembrane region (TM4) of GluR6 in the action of halothane. Site-directed mutagenesis subsequently showed that a specific amino acid, glycine 819 in TM4, is important for enhancement of receptor function by halothane (0.2-2 mM). Mutations of Gly-819 also markedly decreased the response to isoflurane (0.2-2 mM), enflurane (0.2-2 mM), and 1- chloro-1,2,2-trifluorocyclobutane (0.2-2 mM). The nonanesthetics 1,2- dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane had no effect on the functions of either wild-type GluR6 or receptors mutated at Gly-819. Ethanol and pentobarbital inhibited the function of both wild-type and mutant receptors. These results suggest that a specific amino acid, Gly-819, is critical for the action of volatile anesthetics, but not of ethanol or pentobarbital, on the GluR6 receptor.

Original languageAmerican English
Pages (from-to)8248-8255
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number14
DOIs
StatePublished - 3 Apr 1998

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