Aluminum interaction with phosphoinositide-associated signal transduction.
Concerning molecular and cellular mechanisms of aluminum toxicity, recent studies support the hypothesis that interactions of aluminum ions with elements of signal transduction pathways are apparently primary events in cells. In the case of the phosphoinositide-associated signalling pathway of neuroblastoma cells, guanine nucleotide-binding proteins (G proteins) and a phosphatidylinositol-4,5-diphosphate (PIP2)-specific phospholipase C are probable interaction sites for inhibitory actions of aluminum ions. Following interiorization of aluminum by the cell, metal interactions decrease the accumulation of inositol phosphates, especially that of inositol-1,4,5-triphosphate (IP3), concomitant with derangements of intracellular Ca2+ homeostasis. In the presence of high concentrations of Ca2+, formation of IP3 is also diminished in aluminum-pretreated cells, presumably involving a process not requiring Mg(2+)-dependent G proteins. At higher aluminum doses, metal-induced changes in the lipid milieu of the membrane-bound phospholipase may play a role. These types of primary interactions of aluminum ions with elements of cellular communication channels are probably crucial in the manifestation of the multifacetted aluminum toxicity syndrome. If present as a phosphate-like fluoro-aluminate, a stimulatory role of aluminum ions is displayed in G protein-coupled transmembrane signalling.
Haug
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A
Department of Microbiology, Michigan State University, East Lansing 48824.
Shi
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B
Vitorello
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V
D000535:Aluminum / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D004347:Drug Interactions; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D010716:Phosphatidylinositols / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D015220:Calcium Channels; D010716:Phosphatidylinositols; D000535:Aluminum; D019204:GTP-Binding Proteins; D002118:Calcium