Two forms of phosphodiesterase (F1 and F2) with different regulatory properties have been isolated from the soluble fraction of human brain cortex. F1 is the Ca(2+)-calmodulin-dependent phosphodiesterase and its activity is inhibited by calmodulin antagonists (W-7, TFP, tamoxifen) via a mechanism typical for the majority of Ca(2+)-calmodulin-dependent enzymes. F2 is activated by micromolar concentrations of cGMP (7-14-fold) and by Ca2+ ions (1.5-3-fold) in the absence of exogenous calmodulin. F2 contains a tightly bound Ca(2+)-binding component (apparently calmodulin) which does not dissociate from the enzyme in the presence of EGTA. The mechanism of calmodulin antagonists action on F2 is different from that for F1.