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General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit
Author(s) -
Jurd Rachel,
Arrasa Margarete,
Lambert Sachar,
Drexler Berthold,
Siegwart Roberta,
Crestani Florence,
Zaugg Michael,
Vogt Kaspar E.,
Ledermann Birgit,
Antkowiak Bernd,
Rudolph Uwe
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0611fje
Subject(s) - etomidate , anesthetic , propofol , halothane , gabaa receptor , chemistry , pharmacology , enflurane , in vivo , isoflurane , general anesthetics , receptor , protein subunit , electrophysiology , neuroscience , anesthesia , medicine , biology , biochemistry , gene , genetics
General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene‐targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the β3 subunit of the GABA A receptor. In these mice, the suppression of noxious‐evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. β3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA A receptor‐mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA A receptor β3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.