Differential effects of triorganotins on calmodulin activity

Abstract

In vitro effects of three triorganotins--tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT)--on calmodulin (CaM) activity were studied. Stimulation of Ca2(+)-ATPase of rat brain synaptic membranes and phosphodiesterase (PDE) of bovine brain were assayed as indicators of CaM activity. The rat synaptic membranes were prepared and CaM was depleted by washing with 1 mM EGTA. All the three organotins inhibited the basal as well as CaM-stimulated Ca2(+)-ATPase in a concentration-dependent manner, suggesting their interaction with calcium pump. However, CaM-stimulated Ca2(+)-ATPase was more sensitive than the basal enzyme. The order of potency of the three organotin compounds was TBT greater than TET greater than TMT. The IC50 values of Ca2(+)-ATPase (basal) were 0.63, 35, and approximately 800 microM, respectively, whereas the values for CaM-stimulated Ca2(+)-ATPase were 0.05, 0.8, and 18 microM for TBT, TET, and TMT, respectively. CaM-deficient PDE did not show any sensitivity to these three organotin compounds, while TBT and TET significantly decreased the CaM-stimulated PDE activity. TMT, which was the least effective inhibitor of Ca2+ pump, did not alter PDE activity. Further, the inhibition of CaM-stimulated Ca2(+)-ATPase activity by these organotins could be reversed by excess addition of CaM. These results suggest that the organotins interact with CaM activity, as evidenced by their potent effect on CaM-dependent Ca2(+)-ATPase and PDE activities.