Inhibition of Rat Brain Phosphatidylinositol-Specific Phospholipase C by Aluminum: Regional Differences, Interactions with Aluminum Salts, and Mechanisms

Abstract

We have shown previously that aluminum chloride (AlCl3, 10–500 μM) inhibits hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatidylinositol-specific phospholipase C (PI-PLC) in a concentration-dependent manner. In the present study, we characterize further the effects of aluminum on PI-PLC. A comparison of different brain regions and liver revealed varying basal PI-PLC specific activities, as well as differential susceptibility to inhibition by 100 μMAlCl3. The hippocampus had the highest specific activity of PI-PLC, followed by striatum, frontal cortex, cerebellum, and liver. PI-PLC inhibition by 100 μMAlCl3was greatest in the liver, followed by cerebellum, hippocampus, cortex, and striatum. Moreover, 100 μMAlCl3or aluminum lactate (Al (lac)) were similarly effective at inhibiting PI-PLC activity in rat cortical tissue. Addition of AlCl3(100 μM) decreased PI-PLC activity at CaCl2concentrations ranging from 0 to 2 mM; however, AlCl3did not affect the shape of the calcium concentration curve, suggesting that aluminum does not inhibit PI-PLC activity by interference with the cofactor, calcium. AlCl3(100 μM) did inhibit rat cortical PI-PLC hydrolysis of PIP2in a competitive manner. These results demonstrate some regional/tissue differences in PI-PLC activity and its sensitivity to aluminum, and effects of AlCl3and Al(lac) consistent with the effects previously noted in PI turnover in brain slices. Furthermore, our results suggest that competitive inhibition of PLC-mediated PIP2hydrolysis by aluminum is a potential mechanism by which aluminum may cause the disruptions phosphoinositide signaling which have been reported followingin vivoandin vitroexposure.