Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals

Kruger K, Gruner J, Madeja M, Hartmann LM, Hirner AV, Binding N, Musshoff U

Abstract

Pentavalent and trivalent organoarsenic compounds belong to the major metabolites of inorganic arsenicals detected in humans. Recently, the question was raised whether the organic arsenicals represent metabolites of a detoxification process or methylated species with deleterious biological effects. In this study, the effects of trivalent arsenite (AsO33-; iA(III)), the pentavalent organoarsenic compounds monomethylarsonic acid (CH3AsO(OH)(2); MMA(V)) and dimethylarsinic acid ((CH3)(2)AsO(OH); DMA(V)) and the trivalent compounds monomethylarsonous acid (CH3As(OH)(2), MMA(III)) and dimethylarsinous acid ((CH3)(2)As(OH); DMA(III)) were tested on glutamate receptors and on voltage-operated potassium and sodium channels heterologously expressed in Xenopus oocytes. Membrane currents of ion channels were measured by conventional two-electrode voltage-clamp techniques. The effects of arsenite were tested in concentrations of 1-1,000 mu mol/l and the organic arsenical compounds were tested in concentrations of 0.1-100 mu mol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMA(V) and MMA(III) significantly enhanced ion currents through N-methyl-D-aspartate (NMDA) receptor ion channels with threshold concentrations < 10 mu mol/l, DMA(V) and DMA(III) significantly reduced NMDA-receptor mediated responses with threshold concentrations < 0.1 mu mol/l; iA(III) had no effects on glutamate receptors of the NMDA type. MMA(III) and DMA(V) significantly reduced ion currents through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concentrations < 10 mu mol/l (MMA(III)) and < 1 mu mol/l (DMA(V)). MMA(V) and iA(III) had no significant effects on glutamate receptors of the AMPA type. The effects of MMA(V), MMA(III), DMA(V) and DMA(III) on glutamate receptors point to a neurotoxic potential of these substances.