Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals.
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 (AsO(3) (3-); iA(III)), the pentavalent organoarsenic compounds monomethylarsonic acid (CH(3)AsO(OH)(2); MMA(V)) and dimethylarsinic acid ((CH(3))(2)AsO(OH); DMA(V)) and the trivalent compounds monomethylarsonous acid (CH(3)As(OH)(2), MMA(III)) and dimethylarsinous acid ((CH(3))(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 micromol/l and the organic arsenical compounds were tested in concentrations of 0.1-100 micromol/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 micromol/l, DMA(V) and DMA(III) significantly reduced NMDA-receptor mediated responses with threshold concentrations <0.1 micromol/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 micromol/l (MMA(III)) and <1 micromol/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.
Krüger
Katharina
K
Institut für Physiologie I, Universitätsklinikum Münster, Robert-Koch-Strasse 27a, 48149 Münster, Germany. katharina.krueger@uni-muenster.de
Gruner
Janina
J
Madeja
Michael
M
Hartmann
Louise M
LM
Hirner
Alfred V
AV
Binding
Norbert
N
Musshoff
Ulrich
U
D000818:Animals; D001152:Arsenicals / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008767:Methylmercury Compounds / Q000378:metabolism / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000378:metabolism / Q000633:toxicity*; D014982:Xenopus laevis
D001152:Arsenicals; D008767:Methylmercury Compounds; D024642:Potassium Channels, Voltage-Gated; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D013439:Sulfhydryl Reagents