Effects of lithium on calmodulin-stimulated adenylate cyclase activity in cortical membranes from rat brain

The influence of lithium on calmodulin-stimulated adenylate cyclase activity has been studied in vitro and after chronic treatment. Chronic lithium treatment decreased calcium-calmodulin-stimulated adenylate cyclase activity in rat cortical membranes, while no effect was observed on GTP-stimulated activity. Lithium in vitro inhibited adenylate cyclase activity stimulated by isoprenaline, GTP or calcium-calmodulin. Calcium-calmodulin-stimulated activity was more sensitive to lithium (2 mM) than isoprenaline- and GTP-stimulated activities (5 mM) and activities by these agents combined. Lithium had no effect on the unstimulated enzyme activity. The inhibitory effect of lithium in vitro on calcium-calmodulin-stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithium in vitro on the GTP-stimulated adenylate cyclase activity was increased by substituting manganese for magnesium in the assay media. Furthermore, the manganese-stimulated activity was also reduced by lithium. The latter effect was not observed in calmodulin-depleted membranes, but the inhibitory effect of lithium could be restored by addition of exogenous calmodulin. The present results suggest that lithium might influence the interaction of calmodulin with the enzyme and/or interfere with the divalent cation site(s) on the adenylate cyclase system.