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 neuroactivity of some polychlorinated biphenyl (PCB) congeners is associated with perturbations in cellular Ca(2+)-homeostasis. We have characterized further the neurochemical effects of PCBs on signal transduction in primary cultures of cerebellar granule cells. The present experiments found that neither 2,2'-dichlorobiphenyl (DCBP), an ortho-substituted congener, nor 3,3',4,4',5-pentachlorobiphenyl (PCBP), a non-ortho-substituted congener, affected basal phosphoinositide (PI) hydrolysis in cerebellar granule cells. However, at concentrations up to 50 microM, DCBP potentiated carbachol-stimulated PI hydrolysis, while decreasing it at 100 microM. PCBP, on the other hand, had no effect on carbachol-stimulated PI hydrolysis in concentrations up to 100 microM. [3H]Phorbol ester ([3H]PDBu) binding was used to determine protein kinase C (PKC) translocation. DCBP increased [3H]PDBu binding in a concentration-dependent manner and a twofold increase was observed at 100 microM in cerebellar granule cells. PCBP had no effect on [3H]PDBu binding at concentrations up to 100 microM. The effect of DCBP on [3H]PDBu binding was time-dependent and was also dependent on the presence of external Ca2+ in the medium. To test the hypothesis that DCBP increases [3H]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 microM) and glutamate (20 microM) were additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Kodavanti
P R
PR
Cellular and Molecular Toxicology Branch, US Environmental Protection Agency, Research Triangle Park, NC 27711.
Shafer
T J
TJ
Ward
T R
TR
Mundy
W R
WR
Freudenrich
T
T
Harry
G J
GJ
Tilson
H A
HA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid / Q000494:pharmacology; D006868:Hydrolysis; D010703:Phorbol Esters / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D010703:Phorbol Esters; D010716:Phosphatidylinositols; C012280:2,2'-dichlorobiphenyl; D018698:Glutamic Acid; D002217:Carbachol; D011078:Polychlorinated Biphenyls; D011493:Protein Kinase C; D002118:Calcium; C023035:3,4,5,3',4'-pentachlorobiphenyl