DIFFERENTIAL-EFFECTS OF POLYCHLORINATED BIPHENYL CONGENERS ON PHOSPHOINOSITIDE HYDROLYSIS AND PROTEIN-KINASE-C TRANSLOCATION IN RAT CEREBELLAR GRANULE CELLS

Previous reports from our laboratory have suggested that the neuroacti vity of some polychlorinated biphenyl (PCB) congeners is associated wi th perturbations in cellular Ca2+-homeostasis. We have characterized f urther the neurochemical effects of PCBs on signal transduction in pri mary cultures of cerebellar granule cells. The present experiments fou nd that neither 2,2'-dichlorobiphenyl (DCBP), an ortho-substituted con gener, nor 3,3',4,4',5-pentachlorobiphenyl (PCBP), a non-ortho-substit uted congener, affected basal phosphoinositide (PI) hydrolysis in cere bellar granule cells. However, at concentrations up to 50 mu M, DCBP p otentiated carbachol-stimulated PI hydrolysis, while decreasing it at 100 mu M. PCBP, on the other hand, had no effect on carbachol-stimulat ed PI hydrolysis in concentrations up to 100 mu M. [H-3]Phorbol ester ([H-3]PDBu) binding was used to determine protein kinase C (PKC) trans location. DCBP increased [H-3]PDBu binding in a concentration-dependen t manner and a twofold increase was observed at 100 mu M in cerebellar granule cells. PCBP had no effect on [H-3]PDBu binding at concentrati ons up to 100 mu M. The effect of DCBP on [H-3]PDBu binding was time-d ependent and was also dependent on the presence of external Ca2+ in th e medium. To test the hypothesis that DCBP increases [H-3]PDBu binding by acting on receptor-activated calcium channels, the effects of DCBP were compared to those of L-glutamate. The effects of DCBP (50 mu M) and glutamate (20 mu M) were additive. MK-801, a non-competitive NMDA antagonist, blocked the effects of glutamate, but had no effect on the DCBP-induced increase in [H-3]PDBu binding. Other pharmacological pre treatments such as incubations with 3-(2-carboxypiperazin-4-yl)-propyl -1-phosphonic acid (CPP; competitive NMDA antagonist), 6-cyano-7-nitro quinoxaline-2,3-dione (CNQX; AMPA antagonist), verapamil (Ca2+-channe l antagonist) or tetrodotoxin (Na+ channel antagonist) also had no eff ect on DCBP-induced increases in [H-3]PDBu binding. These studies indi cate that DCBP, a putative neuroactive PCB congener, has a biphasic ef fect on receptor-mediated PI hydrolysis and causes translocation of PK C in cerebellar granule cells.