Effects of propofol and pentobarbital on ligand binding to GABAA receptors suggest a similar mechanism of action.
The GABAA receptor is allosterically modulated by a number of anesthetics and barbiturates. We have examined the effects of propofol and pentobarbital on the binding of the receptor agonist [3H]muscimol and the benzodiazepine modulators [3H]flunitrazepam and [3H]Ro15-4513 to bovine brain membranes. Both agents potentiated the binding of [3H]muscimol (5 nM), with EC50 values of 18.7 and 276 microM, respectively. The binding of [3H]muscimol is heterogeneous, suggesting the presence of both high (Kd approximately 10 nM) and low (Kd approximately 0.1-1.0 microM) affinity sites. The major effect of both propofol and pentobarbital was to increase the affinity of the lower affinity sites without changing the total binding capacity. In contrast, the steroid anesthetic alphaxalone did not affect the affinity of these sites, suggesting that this drug has distinct effects on the GABAA receptor. Propofol and pentobarbital also increased the binding of the benzodiazepine agonist [3H]flunitrazepam and decreased the binding of the inverse agonist [3H]Ro15-4513. The results of these studies demonstrate that propofol and pentobarbital modulate the binding of ligands to the GABAA receptor in a similar manner, suggesting that these drugs may have a common mechanism of action.
Davies
M
M
Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Canada. Martin.Davies@Ualberta.ca
Thuynsma
R P
RP
Dunn
S M
SM
D000495:Allosteric Site; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D005445:Flunitrazepam / Q000378:metabolism; D018755:GABA Agonists / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008566:Membranes; D009118:Muscimol / Q000378:metabolism; D010424:Pentobarbital / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D018686:Anesthetics, Intravenous; D001386:Azides; D018755:GABA Agonists; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D009118:Muscimol; D005445:Flunitrazepam; C042957:Ro 15-4513; D010424:Pentobarbital; D015742:Propofol