Abstract:The influence of lithium on calmodulin‐stimulated adenylate cyclase activity has been studiedin vitroand 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. Lithiumin vitroinhibited 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 lithiumin vitroon calcium‐calmodulin‐stimulated adenylate cyclase activity was antagonized by magnesium. The inhibition induced by lithiumin vitroon 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 t