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Vol. 297, Issue 2, 762-773, May 2001

Inositol 1,4,5-Triphosphate Receptor-Sensitive Ca2+ Release, Store-Operated Ca2+ Entry, and cAMP Responsive Element Binding Protein Phosphorylation in Developing Cortical Cells following Exposure to Polychlorinated Biphenyls

Jon R. Inglefield, William R. Mundy and Timothy J. Shafer

Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

The present study assessed intracellular Ca2+ signaling pathways sensitive to polychlorinated biphenyls (PCBs), xenobiotics that perturb neural development and plasticity. Mobilization of intracellular Ca2+ stores after acute exposure to a PCB mixture, Aroclor 1254 (A1254), as well as selected PCB congeners, was studied in P0 rat cortical neuronal culture using fluorescence microscopy. Ca2+ responses to A1254 progressed from a transient intracellular Ca2+ increase (lasting 3-5 min) at 1 to 2 µM (0.3-0.6 ppm) to a Ca2+ transient with store-operated Ca2+ influx and later disturbances of basal Ca2+ concentration; this latter pattern occurred more often with 10 to 20 µM (3-6 ppm) A1254. Thapsigargin, xestospongin C, and carbachol/Ca2+-free buffer blocked significantly the PCB-induced Ca2+ transient, whereas both ryanodine (to deplete ryanodine-sensitive stores) and the L-type Ca2+ channel blocker nifedipine were without effect on the A1254 initial Ca2+ transient. Both thapsigargin and xestospongin also blocked latent elevations (at 0.5 h) in Ca2+, disturbances that depend upon extracellular Ca2+ entry via ion channels. Two possible consequences were explored. Phosphorylation of cAMP responsive element binding protein, a Ca2+-activated nuclear transcription factor (CREB), occurred in an A1254 concentration-dependent manner and persisted at least 1 h. Cell viability following a 24-h exposure to A1254 (2-20 µM) was decreased at 20 µM, but only in cells cultured >6 days. This cell death did not occur via an apoptotic mechanism. These results indicate that Ca2+ disturbances following PCB exposure are associated with 1) discrete alterations in IP3 receptor-mediated signals and 2) activation of downstream events that impact developing cortical cells.

0022-3565/01/2972-0762$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by U.S. Government


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