Propofol modulation of [3H]flunitrazepam binding to GABAA receptors in guinea pig cerebral cortex.
Binding of the radioligand [3H]flunitrazepam to membranes prepared from the cerebral cortex of adult, male guinea pigs under equilibrium and non-equilibrium conditions was used to investigate the allosteric interaction between the intravenous general anesthetic propofol and the benzodiazepine site of the GABAA receptor. Propofol induced a potentiation of [3H]flunitrazepam binding with an EC50 of 9+/-4 microM. Propofol increased the affinity for [3H]flunitrazepam binding with no change in maximal binding. Propofol did not change the rate constant of association for [3H]flunitrazepam binding to cerebral cortical membranes. In contrast, the rate constant for dissociation of [3H]flunitrazepam was significantly decreased in the presence of propofol. These data demonstrate that propofol increases the affinity of the benzodiazepine site of the GABAA receptor via a selective decrease in the rate constant for dissociation, and suggest a mechanism for the allosteric interaction between propofol and benzodiazepines at the GABAA receptor.
Bruner
K R
KR
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Reynolds
J N
JN
D018686:Anesthetics, Intravenous; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D004357:Drug Synergism; D005445:Flunitrazepam / Q000378:metabolism*; D018757:GABA Modulators / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D014316:Tritium
D018686:Anesthetics, Intravenous; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam; D015742:Propofol