PT - JOURNAL ARTICLE AU - Jon R. Inglefield AU - William R. Mundy AU - Timothy J. Shafer TI - Inositol 1,4,5-Triphosphate Receptor-Sensitive Ca<sup>2+</sup>Release, Store-Operated Ca<sup>2+</sup> Entry, and cAMP Responsive Element Binding Protein Phosphorylation in Developing Cortical Cells following Exposure to Polychlorinated Biphenyls DP - 2001 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 762--773 VI - 297 IP - 2 4099 - http://jpet.aspetjournals.org/content/297/2/762.short 4100 - http://jpet.aspetjournals.org/content/297/2/762.full SO - J Pharmacol Exp Ther2001 May 01; 297 AB - 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 &gt;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 IP3receptor-mediated signals and 2) activation of downstream events that impact developing cortical cells. U.S. Government