INHIBITION OF RAT-BRAIN PHOSPHATIDYLINOSITOL-SPECIFIC PHOSPHOLIPASE-CBY ALUMINUM - REGIONAL DIFFERENCES, INTERACTIONS WITH ALUMINUM SALTS,AND MECHANISMS

We have shown previously that aluminum chloride (AlCl3, 10-500 mu M) i nhibits hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatidylinositol-specific phospholipase C(PI-PLC) in a concentrati on-dependent manner. In the present study, we characterize further the effects of aluminum on PI-PLC. A comparison of different brain region s and liver revealed varying basal PI-PLC specific activities, as well as differential susceptibility to inhibition by 100 mu M AlCl3. The h ippocampus had the highest specific activity of PI-PLC, followed by st riatum, frontal cortex, cerebellum, and liver. PI-PLC inhibition by 10 0 mu M AlCl3 was greatest in the liver, followed by cerebellum, hippoc ampus, cortex, and striatum. Moreover, 100 mu M AlCl3 or aluminum lact ate (Al(lac)) were similarly effective at inhibiting PI-PLC activity i n rat cortical tissue. Addition of AlCl3 (100 mu M) decreased PI-PLC a ctivity at CaCl2 concentrations ranging from 0 to 2 mM; however, AlCl3 did not affect the shape of the calcium concentration curve, suggesti ng that aluminum does not inhibit PI-PLC activity by interference with the cofactor, calcium. AlCl3 (100 mu M) did inhibit rat cortical PI-P LC hydrolysis of PIP2 in a competitive manner. These results demonstra te some regional/tissue differences in PI-PLC activity and its sensiti vity to aluminum, and effects of AlCl3 and Al(lac) consistent with the effects previously noted in PI turnover in brain slices. Furthermore, our results suggest that competitive inhibition of PLC-mediated PIP2 hydrolysis by aluminum is a potential mechanism by which aluminum may cause the disruptions phosphoinositide signaling which have been repor ted following in vivo and in vitro exposure. (C) 1996 Academic Press, Inc.