Inhibition of calmodulin activated adenylate cyclase in rat brain by selected insecticides.
Effect of various insecticides on basal and calmodulin (CaM) activated adenylate cyclase activity was studied in solubilized rat brain nuclear and P2 fractions. Our earlier experiments indicated that plictran, chlordecone and other insecticides affect the calcium transport across cell membranes. The present experiments were designed with the assumption that these compounds might exert their neurotoxic action by interfering with CaM (a calcium receptor protein) regulated processes. We have used detergent solubilized adenylate cyclase for our studies, since membrane bound form is not sensitive to externally added CaM. CaM significantly elevated the adenylate cyclase activity in both the fractions and a maximum stimulation of 97% in nuclear fraction and 50% in P2 fraction was observed with 1 microgram of CaM. All the insecticides studied inhibited both basal and CaM activated adenylate cyclase activity in nuclear and P2 fractions to a different extent. A significant inhibition was observed at 0.05 microM and higher concentrations of plictran. Chlordecone and toxaphene inhibited both basal and CaM activated adenylate cyclase in a concentration dependent manner. Although dieldrin and aldrin inhibited basal adenylate cyclase in a concentration dependent manner, they did not exhibit a similar pattern on CaM activated adenylate cyclase. Of all the insecticides studies, chlordecone is more potent in inhibiting both basal and CaM activated adenylate cyclase which is in agreement with the greater neurotoxic action of this compound. These results indicate that all the insecticides studied are potent inhibitors of detergent solubilized adenylate cyclase, and might exert their neurotoxic differential action by interfering with CaM regulated events in central nervous system.
Kodavanti
P R
PR
Department of Neurology, University of Mississippi Medical Center, Jackson 39216.
Mehrotra
B D
BD
Chetty
S C
SC
Desaiah
D
D
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D003902:Detergents; D004789:Enzyme Activation / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D000077423:Polidocanol; D011092:Polyethylene Glycols; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
D000067956:Adenylyl Cyclase Inhibitors; D002147:Calmodulin; D003902:Detergents; D007306:Insecticides; D000077423:Polidocanol; D011092:Polyethylene Glycols; D000262:Adenylyl Cyclases