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MECHANISMS UNDERLYING ALC13 INHIBITION OF AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION
Citation:
Shafer, T., A. Nostrandt, H. Tilson, AND W. Mundy. MECHANISMS UNDERLYING ALC13 INHIBITION OF AGONIST-STIMULATED INOSITOL PHOSPHATE ACCUMULATION. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-95/138.
Description:
Possible mechanisms of AlC13-induced inhibition of agonist-stimulated inositol phosphate (IP) accumulation were investigated using rat brain cortex slices, synaptosomes or homogenates. nder conditions in which AlC13 inhibits carbachol (CARB) stimulated IP accumulation (Gp-mediated), AlC13 did not affect CARB (100 um)-induced decreases (Gi-mediated) in 30 uM forskolin--stimulated CAMP accumulation, suggesting that AlC13 may be specific for Gp-mediated signal transduction. o determine whether AlC13 interfered with Gp function and/or phosphatidylinositol-specific phospholipase C (PiPLC) activity, effects of AlC13 on CARB-adn Ca2+-stimulated IP accumulation were examined in cortical synaptosmes, AlCl, (500 uM) decreased GARB (1 mM)- and Ca2+ (20 uM ionomycin)-stimulated IP accumulation to 77 and 75% of control, respectively, suggesting that AlC13 may not directly affect Gp activity, but does inhibit PiPLC activity. n cortical homogenates, AlC13 (10-500 uM) inhibited hydrolysis of [3H]phosphatidylinositol 4,5-bisphosphate (IPI2) by PiPLC in a concentration-dependent manner with an estimated IC50 of 100 uM. ffects of AlC13 on modulation of IP accumulation by extracellular Ca2+ and PKC were also examined as potential mechanisms. ecreasing the extracellular Ca2+ concentration ([Ca2+le) from 1.0 to 0.1 mM decreased CARB-stimulated IP accumulation in slices. lC13 (500 uM) decreased significantly 1 mM CARB-stimulated IP accumulation in 1.0 and 0.1 mMCa2+ solutions; however, the effect of AlC13 on IP accumulation did mt depend on [Ca2+le. n cortical slices, inhibition of 1 mM CARB-stimulated IP accumulation by 500 uM AlC13 was not altered by the PKC activator, phorbol 12,13-dibutyrate.