Effect of Chronic Exposure to Aluminium on Isoform Expression and Activity of Rat (Na+/K+)ATPase

Abstract

The ability of aluminum to inhibit the (Na(+)/K(+))ATPase activity has been observed by several investigators. The (Na(+)/K(+))ATPase is characterized by a complex molecular heterogeneity that results from the expression and differential association of multiple isoforms of both catalytic (alpha) and regulatory (beta) subunits. For instance, three main alpha (alpha(1), alpha(2) and alpha(3)) and three beta (beta(1), beta(2) and beta(3)) subunit isoforms exist in vertebrate nervous tissue, whereas only alpha(1) and beta(1) have been identified in kidney. However, no studies have focused on determining the change in (Na(+)/K(+))ATPase isoforms caused by chronic exposure to aluminum and its relation with aluminum toxicity. In this study, adult male Wistar rats were submitted to chronic dietary AlCl(3) exposure (0.03 g/day of AlCl(3) for 4 months), and the activity and protein expression of (Na(+)/K(+))ATPase isozymes were studied in brain cortex synaptosomes and in kidney homogenates. The intracellular levels of adenine nucleotides, plasma membrane integrity, and aluminum accumulation were also studied in brain synaptosomes. Aluminum accumulation upon chronic dietary AlCl(3) administration significantly decreased the (Na(+)/K(+))ATPase activity measured in the presence of nonlimiting Mg-ATP concentrations, without compromising protein expression of alpha-subunit isoforms in brain and kidney. Aluminum-induced synaptosomal (Na(+)/K(+))ATPase inhibition was due to a reduction in the activity of isozymes containing alpha(1)-alpha(2) and alpha(3)-subunits. The onset of enzyme inhibition was accompanied by a decrease of the (Na(+)/K(+))ATPase sensitivity to submicromolar concentrations of ouabain, and it preceded major damage in plasma membrane integrity and energy supply, as revealed by the analysis of lactate dehydrogenase leakage and endogenous adenine nucleotides. The data suggest that, during chronic dietary exposure to AlCl(3), brain (Na(+)/K(+))ATPase activity drops, even if no significant alterations of catalytic subunit protein expression, cellular energy depletion, and changes in cell membrane integrity are observed. Implications regarding underlying mechanisms of aluminum neurotoxicity are discussed.

Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats

“…In recent years, Al inhibitory effect on Na + /K + -ATPase has been observed in several studies (Silva et al, 2005(Silva et al, , 2013. Our results showed a decrease in Na + /K + -ATPase activity in the Al group.…”

Comparative effects of aluminum and ouabain on synaptosomal choline uptake, acetylcholine release and (Na+/K+)ATPase

“…The high-affinity choline transport by cholinergic presynaptic nerve terminals is hemicholinium-3-sensitive (K i ≈ 10 −9 to 10 −7 M) and driven by the transmembrane Na + gradient (Kuhar and Zarbin, 1978;Vickroy et al, 1985;Chatterjee et al, 1987;Saltarelli et al, 1987;Happe and Murrin, 1993;Okuda et al, 2000;Misawa et al, 2001), which is maintained by the (Na + /K + )ATPase (Stein, 1990;Nelson and Lill, 1994). During the last 20 years, a number of reports appeared to emphasize that in vivo and in vitro exposure of mammalian preparations to aluminum inhibits this P-type ATPase, a ubiquitous integral membrane pump of the plasma membrane (Lai et al, 1980;King et al, 1983;Rao, 1990Rao, , 1992Caspers et al, 1993Caspers et al, , 1994Lal et al, 1993;Sarin et al, 1997;Silva and Gonçalves, 2003;Silva et al, 2005).…”

Regulatory role of zinc during aluminium‐induced altered carbohydrate metabolism in rat brain

“…Dysregulations of carbohydrate metabolic pathways are among the most prominent features that arise in response to toxic compounds/metals. Al inhibits a large number of ATPdependent reactions and thus hampers energy-dependent processes (Silva et al, 2005;Szyperska et al, 2006). Reports have suggested that Al exposure can lead to impairment in glucose utilization, followed by altered activities of glucose-metabolizing enzymes, such as hexokinase and glutamate dehydrogenase (Yang et al, 2003;Dua et al, 2010).…”