Effects of lead on adenylate cyclase activity in rat cerebral cortex

Lead decreased in a dose dependent manner the basal AC activity in membrane s of rat cerebral cortex (IC50 = 2.5 +/- 0.1 mu M). In membranes preincubat ed under basal conditions, AC activity was stimulated by approximately two and fourfold by 10 mu M Gpp(NH)p or forskolin, respectively. Under basal co nditions, lead (3 mu M) inhibited enzyme activity up to 50%, but was not ab le to inhibit the Gpp(NH)p- or the forskolin-stimulated AC activity. Howeve r, in membranes preincubated with Gpp(NH)p (10 mu M). lead (3 mu M) had no significant effect on enzyme activity, but it partly blocked the stimulatio n of AC activity elicited by forskolin (10 mu M). In membranes preincubated with 10 mu M lead, the addition of 10 mu M Gpp(NH)p or forskolin in the in cubation medium did not stimulate AC activity. However, when added together in the incubation medium Gpp(NH)p + forskolin produced an increase in enzy me activity. In membranes preincubated with 10 mu M lead + 10 mu M Gpp(NH)p , Gpp(NH)p (10 mu M) or forskolin (10 mu M) added alone or in combination t o the incubation medium did not stimulate AC activity. Moreover, under thes e latter conditions lead had no further effect on enzyme activity, These re sults indicate that lead may interact with G-proteins and with the catalyti c subunit of cerebral cortical AC to produce inhibition of the enzyme activ ity.