• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.

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 beta3 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. beta3(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 beta3 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.

Pubmed ID: 12475885

Authors

  • Jurd R
  • Arras M
  • Lambert S
  • Drexler B
  • Siegwart R
  • Crestani F
  • Zaugg M
  • Vogt KE
  • Ledermann B
  • Antkowiak B
  • Rudolph U

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Data

February 29, 2003

Associated Grants

None

Mesh Terms

  • Anesthetics, Inhalation
  • Anesthetics, Intravenous
  • Animals
  • Behavior, Animal
  • Brain
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Enflurane
  • Etomidate
  • Halothane
  • Mice
  • Mice, Inbred Strains
  • Point Mutation
  • Propofol
  • Protein Subunits
  • Receptors, GABA-A