Modulation of the benzodiazepine/gamma-aminobutyric acid receptor chloride channel complex by inhalation anesthetics.
Inhalation anesthetics, such as diethyl ether, halothane, and enflurane, increase 36Cl- uptake into rat cerebral cortical synaptoneurosomes in a concentration-dependent, picrotoxin-sensitive fashion. At concentrations consistent with those that stimulate 36Cl- uptake, inhalation anesthetics also inhibit the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS) to well-washed cortical membranes. Scatchard analysis of [35S]TBPS binding indicates that these agents reduce the apparent affinity of this radioligand and have little effect on the Bmax. The ability of inhalation anesthetics to directly stimulate 36Cl- uptake and inhibit [35S]TBPS binding is a property shared by nonvolatile anesthetics. Nonetheless, there are differences between nonvolatile agents (such as barbiturates and alcohols) and inhalation anesthetics, because the former compounds augment muscimol (a GABAmimetic) stimulated 36Cl- uptake, whereas the latter group (such as ether and enflurane) inhibit this effect. These findings demonstrate that therapeutically relevant concentrations of inhalation anesthetics perturb the benzodiazepine/gamma-aminobutyric acid receptor chloride channel complex, and suggest this oligomeric protein may be a common mediator of some aspects of anesthetic action.
Moody
E J
EJ
Laboratory of Neuroscience, NIDDK, Bethesda, Maryland 20892.
Suzdak
P D
PD
Paul
S M
SM
Skolnick
P
P
D000769:Anesthesia, Inhalation; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002540:Cerebral Cortex / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D004737:Enflurane / Q000494:pharmacology; D004986:Ether / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D008733:Methoxyflurane / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
D000777:Anesthetics; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D007473:Ion Channels; D011963:Receptors, GABA-A; D004986:Ether; D009118:Muscimol; D008733:Methoxyflurane; C037476:tert-butylbicyclophosphorothionate; D004737:Enflurane; D010424:Pentobarbital; D006221:Halothane