Toxicology and applied pharmacology

Potential involvement of calcium, CaM kinase II, and MAP kinases in PCB-stimulated insulin release from RINm5F cells.

PMID 10486306


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.