Potential involvement of calcium, CaM kinase II, and MAP kinases in PCB-stimulated insulin release from RINm5F cells.
Polychlorinated biphenyls (PCBs) are environmental contaminants that induce release of insulin in rat insulinoma cells, RINm5F (Fischer et al., Life Sci. (1996) 59, 2041-2049). In the present study the mechanisms of this effect were investigated using noncytotoxic concentrations (10 microg/ml) of a PCB mixture, Aroclor-1254, and the pure PCB congeners 2,2',4,4'-tetrachlorobiphenyl and 2,2',4,4',5, 5'-hexachlorobiphenyl. Treatment of RINm5F cells with each of these agents resulted in a rapid increase in intracellular free calcium. The presence of extracellular calcium was required for PCB-induced insulin release because removal of calcium from the medium attenuated the effect. In addition, pretreatment of RINm5F cells with the calcium channel blocker verapamil also blocked PCB-induced insulin release. To determine whether PCB-related insulin release could be associated with the enzyme, calcium/calmodulin-dependent kinase II (CaM kinase II), RINm5F cells were pretreated with the CaM kinase II inhibitor KN-93. PCB-induced insulin release was completely blocked by KN-93. Under similar treatment conditions, PCBs also induced the activity of mitogen-activated protein kinases (MAPK) 1 and 2. However, inhibition of MAPK activation by a specific inhibitor, PD-98059 (10.0 microM) did not prevent insulin release induced by PCBs. The results of the present investigation suggest a role for calcium and CaM kinase II in PCB-induced insulin release. Furthermore, the results suggest that insulin release by PCBs is independent of the activation of MAPKs.
Fischer
L J
LJ
Department of Pharmacology and Toxicology and Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan, 48824, USA.
Wagner
M A
MA
Madhukar
B V
BV
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D005659:Fungicides, Industrial / Q000494:pharmacology; D006581:Hexachlorobenzene / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D010766:Phosphorylation; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D014407:Tumor Cells, Cultured
D005659:Fungicides, Industrial; D007328:Insulin; C035976:2,4,2',4'-tetrachlorobiphenyl; D006581:Hexachlorobenzene; D011078:Polychlorinated Biphenyls; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium