Inhibition of amino acid transport and protein synthesis by HgCl2 and methylmercury in astrocytes: selectivity and reversibility.
The previously reported observation that submicromolar concentrations of HgCl2 inhibit glutamate uptake reversibly in astrocytes, without effect on 2-deoxyglucose uptake, suggested that elemental mercury vapor, which is oxidized to mercuric mercury in the brain, might cause neurodegenerative change through the mediation of glutamate excitotoxicity. Here, selectivity is explored further by measuring the inhibition of other amino acid transporters and protein synthesis as a function of HgCl2 concentration. The properties of MeHgCl were compared under identical conditions, and some morphological correlates of function were examined. Inhibition of amino acid transport by HgCl2 was selective, whereas MeHgCl was nonselective. The 50% inhibitory concentrations of HgCl2 for uptake of alpha-aminoisobutyric acid by system A, uptake of alpha-aminoisobutyric acid or kynurenine by a system L variant, and uptake of gamma-aminobutyric acid were all two- to fourfold greater than that for uptake of glutamate. The submicromolar concentrations of HgCl2 that inhibited glutamate transport also inhibited protein synthesis, but in a rapidly reversible fashion, and elicited only discrete ultrastructural changes (heterochromatin, increased numbers of lysosomal bodies, and increased complexity of cell surface). In contrast, inhibition of protein synthesis by MeHgCl was acutely (1-h) irreversible and became marked only at concentrations higher than those that elicited gross morphologic change in the form of "bleb"-like swellings. The results lend support to the proposed excitotoxic mediation of mercury vapor neurotoxicity and reveal a sharp contrast between the effects of HgCl2 and MeHgCl on astrocytes.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore 21201.
N
N
Brookes
D A
DA
Kristt
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D007700:Kinetics; D008627:Mercuric Chloride / Q000494:pharmacology*; D008767:Methylmercury Compounds / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D008767:Methylmercury Compounds; D009419:Nerve Tissue Proteins; D008627:Mercuric Chloride; D005680:gamma-Aminobutyric Acid; D003847:Deoxyglucose; C004925:methylmercuric chloride