Molecular determinants of general anesthetic action: role of GABAA receptor structure.
Using receptors expressed from mouse brain mRNA in Xenopus oocytes, we found that enhancement of type A gamma-aminobutyric acid (GABAA) receptor-gated Cl- channel response is a common action of structurally diverse anesthetics, suggesting that the GABAA receptor plays an important role in anesthesia. To determine if GABAA receptor subunit composition influences actions of anesthetics, we expressed subunit cRNAs in Xenopus oocytes and measured effects of enflurane on GABA-activated Cl- currents. Potentiation of GABA-activated currents by enflurane was dependent on the composition of GABAA receptor protein subunits; the order of sensitivity was alpha 1 beta 1 > alpha 1 beta 1 gamma 2S = alpha 1 beta 1 gamma 2L > total mRNA. The results suggest that anesthetics with simple structures may act on the GABAA receptor protein complex to modulate the Cl- channel activity and provide a molecular explanation for the synergistic clinical interactions between benzodiazepines and general anesthetics.
Lin
L H
LH
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Whiting
P
P
Harris
R A
RA
D000758:Anesthesia; D000777:Anesthetics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018118:Chloride Channels; D003975:Diazepam / Q000494:pharmacology; D004357:Drug Synergism; D004553:Electric Conductivity; D004737:Enflurane / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009865:Oocytes / Q000378:metabolism; D012313:RNA / Q000235:genetics; D018075:RNA, Complementary; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000777:Anesthetics; D018118:Chloride Channels; D046911:Macromolecular Substances; D008565:Membrane Proteins; D018075:RNA, Complementary; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D012313:RNA; D004737:Enflurane; D003975:Diazepam