Inhibition of brain adenylate cyclase by barbiturates through the effect on the interaction between guanine nucleotide-binding stimulatory regulatory protein and catalitic unit.

The effect of barbiturates on an adenylate cyclase system in rat brain was examined. The activity of the catalytic unit of this system isolated from the synaptic membrane was inhibited by phenobarbital in dose- and time-dependent manners. The mode of the inhibition was non-competitive with respect to Mg-adenosine triphosphate (ATP). The activity of the synaptic membrane-bound adenylate cyclase was also inhibited by phenobarbital in a similar manner. The inhibitory effect of phenobarbital was more potent on the activation of the enzyme by 5'-guanylylimidodiphosphate (GppNHp) than on the basal enzyme activity. The inhibitory effect, however, was not observed in the synaptic membrane preparation in which the guanine nucleotide-binding stimulatory regulatory protein (Ns) and the catalytic unit of adenylate cyclase system had been functionally coupled by pretreatment with GppNHp. Similar results were obtained with other pharmacologically active barbiturates. These findings indicate that barbiturates primarily affect the activation of the catalytic unit by an interaction with Ns resulting in the inhibition of the enzyme activity.