Involvement of the inhibitory GTP-binding regulatory protein and a low-affinity benzodiazepine receptor in the inhibitory effect of diazepam on rat brain adenylate cyclase system.
The effect of diazepam on the adenylate cyclase system was studied in rat synaptosomal membranes. Micromolar concentrations of diazepam inhibited the cyclase activities in the presence or absence of guanylyl-5'-imidodiphosphate (GppNHp). The inhibitory effect of diazepam was greater on the cyclase activity in the presence of GppNHp than on that in the basal state. This effect of diazepam was not antagonized by Ro15-1788, an antagonist of a high affinity benzodiazepine receptor in the central nervous system. Furthermore, micromolar concentrations of Ro15-1788 had no inhibitory effect on cyclase activities in the presence or absence of GppNHp. In addition, the bromide ion enhanced the inhibition by diazepam of the cyclase activity in the presence of GppNHp, but not the basal activity, although the bromide ion had no effect on both activities in the absence of diazepam. On the other hand, the pretreatment of synaptosomal membranes with GppNHp increased the KD value for [3H]diazepam binding from 98 microM to 198 microM. These data led us to conclude that diazepam inhibits rat brain adenylate cyclase through the effects on both a low affinity benzodiazepine receptor coupled with the inhibitory GTP-binding regulatory protein (Gi) and the catalytic protein.
Kurokawa
T
T
Department of Physiological Chemistry, Hiroshima University School of Medicine, Japan.
Dan'ura
T
T
Yamashita
A
A
Une
Y
Y
Ishibashi
S
S
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D001965:Bromides / Q000494:pharmacology; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism*; D013570:Synaptic Membranes / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D001965:Bromides; D011963:Receptors, GABA-A; D006165:Guanylyl Imidodiphosphate; D005442:Flumazenil; D019204:GTP-Binding Proteins; D003975:Diazepam