The capacity of aluminum (Al) and a group of trivalent cations that are chemically and physically related to Al (scandium, beryllium, yttrium, gallium, and lanthanum) to promote changes in membrane rheology will be discussed. These multivalent cations are recognized neurotoxicants, which have high affinity for cellular acidic molecules, especially those containing one or more phosphate groups. In negatively charged liposomes, these metals bind to membrane phospholipids establishing either trans- or cis-interactions that differentially affect the physical properties of the bilayer. As a consequence of trans-interactions, Al and related metals promote the aggregation and fusion of vesicles. cis-interactions lead to the formation of clusters of negatively charged phospholipids (phosphatidyl serine, polyphosphoinositides). In these discrete regions of the bilayer, the mobility of the acyl chains is reduced as well as the hydration of the phospholipid headgroups, resulting in an increase in the membrane permeability. In addition, the membrane surface potential is altered, due to the loss of surface negative charges. The observed alterations of membrane physical properties associated with metal-lipid interactions could have profound effects on membrane-associated processes. For example, although Al and related cations have no redox capacity in biological systems, they can stimulate Fe2+-induced lipid oxidation. We have shown that, among other possible mechanisms, Al and related metals-induced alterations on membrane fluidity and hydration create an environment that enhance the oxidant activity of Fe2+. This mechanism could occur not only in vitro but also in vivo since, in an animal model of prenatal exposure to Al, a lower fluidity of brain myelin associated with a higher content of end products of lipid oxidation was observed. In this model we found a higher myelin content of galactolipids, lipids that can also decrease membrane fluidity and favor the propagation of lipid oxidation. Independently of its effects on membranes, Al can also facilitate oxidation reactions through a direct interaction with oxidant species. Furthermore, Al-membrane interactions affect the metabolism of polyphosphoinositides. In liposomes containing a mixture of brain phosphoinositides, Al also caused membrane rigidification and lateral phase separation. Although Al did not affect the activity of the enzyme phospholipase C, a marked decrease in the activity of phosphatidyl inositol-specific phospholipase C (PI-PLC) was observed. The activity of PI-PLC was fully recovered when vesicles were disrupted by the addition of Triton X-100. The effects of Al on PI-PLC activity can be attributed to the formation of discrete clusters enriched in polyphosphoinositides that limit the accessibility of the enzyme to its substrates. In summary, in this paper we will discuss the consequences of Al and related metals interactions with membranes. These metals cause alterations in membrane physical properties, which affect lipid oxidation rates and phosphoinositide hydrolysis. However, Al-mediated changes in membrane rheology could also affect other membrane-associated processes such as signal transduction events, membrane transport, and the functionality of receptors. These mechanisms could contribute to Al neurotoxicity.
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