Aluminum Stimulation of Second Messenger Systems

Aluminum is reported to stimulate second messenger systems in the absence of F. McDonald and Mamrack (1988) identified an effect of A1 alone on phosphatidylinositol hydrolysis. While the phospholipase C that normally carries out this function is regulated by a G protein, their work involved the purified enzyme with no G-protein component. They found inhibition of hydrolysis of phosphatidylinositol-4,5-bisphosphate, but stimulation of the hydrolysis of phosphatidylinositol. The stimulation should therefore lead to diacylglycerol-dependent increases in intracellular Ca. Their work clearly showed that A1 and not AIF was the active factor, by using F to chelate A1 and reverse the stimulation. 

Martin has studied the effect of Al on the interaction of GTP with tubulin, a major tangle component in Al toxicity. He reports a slowing of GTP hydrolysis, which in this system causes promotion of polymerization (Martin 1988). Martin proposes that this effect is due to formation of an Al-GTP chelate in place of the normal Mg-GTP chelate. The G protein transducin, which couples the light receptor protein rhodopsin to cGMP phosphodiesterase during visual transduction, is activated by F plus Al, but inhibited by Al alone (Miller et al. 1989). Using chelators. Miller manipulated free Al to allow Al to compete with Mg for GTP and saw inhibition of GTP hydrolysis in a cell-free system. This occurred even at a 10 -fold excess of 

important since normally intracellular ionic Mg is maintained at approximately 5 X while free A1 is only in the femtomolar range (Martin 

More recently, Huang and Bittar (1991) found that GTP chelation of A1 stopped GTP stimulating the G-protein system that activates Na efflux in barnacle fibers. 

Miller et al. (1989) proposed that even if A1 and AIF both inhibit GTP hydrolysis, they could have opposite effects on the G-protein system, as he had seen in his experiments. In an attempt to reconcile his own data with those of Martin, Miller argued that, while Al was also seen to inhibit GTP hydrolysis in the GTP-transducin system that he used, the primary effect must be to slow GTP replacement of GDP on the G protein and thus inhibit the action of the G protein. Secondarily, Al replacement of Mg could inhibit GTP hydrolysis on the G protein. Miller did not consider an alternative possibility, that the GTP-Al interaction varies with Al concentration and/or free Mg so that the Al-GTP effect is biphasic, activating at low levels of Al that inhibit hydrolysis and inhibiting at levels that inhibit GTP/GDP exchange. Alternatively, the interaction of Al-GTP with one G protein may have a predominant effect on GTP/GDP exchange, while interaction with another could result predominantly in slowing hydrolysis. 

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