Inhibition of calmodulin-activated Ca2(-)-ATPase by endosulfan in rat brain.

Endosulfan stereoisomer I (E-I) inhibited the activity of calmodulin-dependent Ca2+-ATPase to an extent of 15-55% in a concentration range of 1-20 microM under in vitro conditions without significantly affecting the basal enzyme activity. The less toxic isomer E-II produced no significant inhibition of Ca2+-ATPase activity up to a concentration of 40 microM. The inhibition of Ca2+-ATPase by E-I was noncompetitive with respect to substrate, free from the influence of calcium, and competitively inhibited calmodulin activation kinetics. Reconstitution with the exogenous addition of calmodulin (5 and 20 micrograms) restored the inhibited enzyme activity, indicating nonspecific binding of E-I with calmodulin. Both calmodulin-activated and basal enzyme activity was inhibited significantly in rats fed E-I (3 mg/kg body weight) for 15 d. These data suggest that endosulfan may modulate calmodulin-related events in neurons and result in its neurotoxicity.