Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals.
Pentavalent and trivalent organoarsenic compds. belong to the major metabolites of inorg. arsenicals detected in humans. Recently, the question was raised whether the org. arsenicals represent metabolites of a detoxification process or methylated species with deleterious biol. effects. In this study, the effects of trivalent arsenite (AsO33-; iAIII), the pentavalent organoarsenic compds. monomethylarsonic acid (CH3AsO(OH)2; MMAV) and dimethylarsinic acid ((CH3)2AsO(OH); DMAV) and the trivalent compds. monomethylarsonous acid (CH3As(OH)2, MMAIII) and dimethylarsinous acid ((CH3)2As(OH); DMAIII) 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 concns. of 1-1,000 mmol/l and the org. arsenical compds. were tested in concns. of 0.1-100 mmol/l. We found no significant effects on voltage-operated ion channels; however, the arsenicals exert different effects on glutamate receptors. While MMAV and MMAIII significantly enhanced ion currents through N-methyl-d-aspartate (NMDA) receptor ion channels with threshold concns. <10 mmol/l, DMAV and DMAIII significantly reduced NMDA-receptor mediated responses with threshold concns. <0.1 mmol/l; iAIII had no effects on glutamate receptors of the NMDA type. MMAIII and DMAV significantly reduced ion currents through a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor ion channels with threshold concns. <10 mmol/l (MMAIII) and <1 mmol/l (DMAV). MMAV and iAIII had no significant effects on glutamate receptors of the AMPA type. The effects of MMAV, MMAIII, DMAV and DMAIII on glutamate receptors point to a neurotoxic potential of these substances.
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