Inhibition of rat brain adenylate cyclase activity by benzodiazepine through the effects on Gi and catalytic proteins.
The effect of benzodiazepines on adenylate cyclase system was examined in rat brain. Micromolar concentrations of diazepam inhibited the enzyme activity in synaptic membranes in dose- and time-dependent manners. The inhibitory effect of diazepam was more evident on the enzyme activity in the presence of guanylyl-5'-imidodiphosphate (GppNHp) or NaF-AlCl3 than on that in the basal state. In the pertussis toxin-treated membranes, the effect of diazepam in the presence of GppNHp or NaF-AlCl3 was markedly suppressed. In addition, other benzodiazepines, such as medazepam, flurazepam, flunitrazepam, and clonazepam, had similar effects to those of diazepam, whereas Ro15-1788, an antagonist of a high affinity receptor in the central nervous system, had no effect on adenylate cyclase activity and did not antagonize the effect of diazepam. These findings indicate that benzodiazepines inhibit rat brain adenylate cyclase activity through the effects on both a low affinity benzodiazepine receptor coupled with the inhibitory GTP-binding regulatory protein (Gi) and catalytic protein.
Dan'ura
T
T
Department of Physiological Chemistry, Hiroshima University School of Medicine, Japan.
Kurokawa
T
T
Yamashita
A
A
Yanagiuchi
H
H
Ishibashi
S
S
D000067956:Adenylyl Cyclase Inhibitors; D000535:Aluminum / Q000494:pharmacology; D000077410:Aluminum Chloride; D017607:Aluminum Compounds; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology*; D002712:Chlorides / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D013570:Synaptic Membranes / Q000201:enzymology
D000067956:Adenylyl Cyclase Inhibitors; D017607:Aluminum Compounds; D002712:Chlorides; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D006165:Guanylyl Imidodiphosphate; D000077410:Aluminum Chloride; D005442:Flumazenil; D000535:Aluminum; D019204:GTP-Binding Proteins; D003975:Diazepam