EFFECTS OF ALUMINUM ON THE HEPATIC INOSITOL POLYPHOSPHATE PHOSPHATASE

There is speculation that some of the toxic effects of Al3+ may originate from it perturbing inositol phosphate/Ca2+ signalling. For example, in permeabilized L1210 mouse lymphoma cells, 10-50 mu M Al3+ activated Ins(1,3,4,5)P-4-dependent Ca2+ mobilization and Ins(1,3,4,5)P-4 3-phosphatase activity [Loomis-Husselbee, Cullen,Irvine and Dawson (1991) Biochem. J. 277, 883-885]. Ins(1,3,4,5)P-4 3-phosphatase activity is performed by a multiple inositol polyphosphate phosphatase (MIPP) that also attacks Ins(1,3,4,5,6)P-5 and InsP(6), [Craxton, Ali and Shears (1995) Biochem. J. 305, 491-498] : 5-50 mu M Al3+ increased MIPP activity towards both Ins(1,3,4,5)P-4 (by 30%) and Ins(1,3,4,5,6)P-5 (by up to 500 %), without affecting metabolism of InsP(6). Higher concentrations of Al3+ inhibited metabolism of all three substrates, and in the case of InsP(6), Al3+ altered the pattern of accumulating products. When 1-50 mu M Al3+ was present, InsP(6) became a less effective inhibitor of Ins(1,3,4,5)P-4 3-phosphatase activity; this effect did not depend on the presence of cellular membranes, contrary to a previous proposal. The latter phenomenon largely explains how, in a cell-free system where Ins(1,3,4,5)P-4 3-phosphatase is inhibited by endogenous InsP(6), the addition of Al3+ can apparently increase the enzyme activity. However, there was no effect of either 10 or 25 mu M Al3+ (in either the presence or absence of apotransferrin) on inositol phosphate profiles in either Jurkat E6-1 lymphoma cells or AR4-2J pancreatoma cells.