ToxSci Advance Access published online on September 14, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi324
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1 Centro de Estudos do Ambiente e Mar, Departamento de Biologia, Universidade de Aveiro, 3810-193 Aveiro, Portugal
* To whom correspondence should be addressed. The ability of aluminium 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 (
Received July 20, 2005
Accepted September 11, 2005
Neurotoxicology
Effect of Chronic Exposure to Aluminium on Isoform Expression and Activity of Rat (Na+/K+)ATPase
2 Centro de Neurociências de Coimbra, Departamento de Zoologia, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-504 Coimbra, Portugal
3 Centro de Neurociências de Coimbra, Instituto de Bioquímica, Faculdade de Medicina, Universidade de Coimbra, 3004-504 Coimbra, Portugal
Paula P. Gonçalves, E-mail: pgoncalves{at}bio.ua.pt
Abstract 
) and regulatory (
) subunits. For instance, three main (1, 2 and 3) and three (1, 2 and 3) subunit isoforms exist in vertebrate nervous tissue, whereas only 1 and 1 have been identified in kidney. However, no studies have focused on determining the change in (Na+/K+)ATPase isoforms due to chronic exposure to aluminium and its relation with aluminium toxicity. In this study, adult male Wistar rats were submitted to chronic dietary AlCl3 exposure (0.03 g/day of AlCl3, during 4 months), and the activity and protein expression of (Na+/K+)ATPase isozymes in brain cortex synaptosomes and in kidney homogenates. The intracellular levels of adenine nucleotides, plasma membrane integrity and aluminium accumulation were also studied in brain synaptosomes. Aluminium accumulation upon chronic dietary AlCl3 administration significantly decreased the (Na+/K+)ATPase activity measured in the presence of non-limiting Mg-ATP concentrations, without compromising protein expression of -subunit isoforms in brain and kidney. Aluminium-induced synaptosomal (Na+/K+)ATPase inhibition was due to a reduction in the activity of isozymes containing 1-2 and 3-subunits. The onset of enzyme inhibition was accompanied by a decrease of the (Na+/K+)ATPase sensitivity to submicromolar concentrations of ouabain and 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 AlCl3, brain (Na+/K+)ATPase activity drops down 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 aluminium neurotoxicity are discussed.
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