Characterization and regional distribution of adenylyl cyclase activity from human brain

Abstract

The characteristics of the human brain adenylyl cyclase complex were studied in membranes from post-mortem frontal cortex. Basal, guanine nucleotide, sodium fluoride and forskolin stimulated activities were highly magnesium-dependent. Sodium fluoride and guanine nucleotides gave bi-phasic responses, with both stimulation and inhibition of enzyme activity, the latter being more pronounced at lower magnesium concentrations. Enzyme activity was stimulated to a similar extent by GTP and its non-hydrolysable analogue Gpp(NH)p, suggesting a low GTPase activity in human post-mortem brain preparations. Guanine nucleotide stimulated enzyme activity was potently antagonized by guanosine 5?-O-(thiodiphosphate). Sodium fluoride stimulated activity was enhanced by aluminium chloride. In contrast to the effects seen with guanine nucleotides, the inhibition of sodium fluoride/aluminium chloride stimulated activity by guanosine 5?-O-(thiodiphosphate) was dependent upon pre-incubation of membranes with a neurotransmitter agonist. Basal, guanine nucleotide and sodium fluoride/aluminium chloride stimulated activities showed a marked regional distribution. Stimulated activities were highest in frontal and parietal cortex, intermediate in the nucleus caudatus and cerebellar cortex and lowest in occipital cortex, putamen, globus pallidus and ventral hippocampus. It is concluded that the regulation of human post-mortem brain adenylyl cyclase by guanine nucleotides is similar to that reported for studies on experimental animals.