Blockade of glutamatergic and GABAergic receptor channels by trimethyltin chloride.
1. Organotin compounds such as trimethyltin chloride (TMT) are among the most toxic of the organometallics. As their main target for toxicity is the central nervous system, the aim of the present study was to investigate the effects of TMT on receptor channels involved in various processes of synaptic transmission. 2. The Xenopus oocyte expression system was chosen for direct assessment of TMT effects on voltage-operated potassium channels and glutamatergic and GABAergic receptors, and hippocampal slices from rat brain for analyzing TMT effects on identified synaptic sites. 3. TMT was found to be ineffective, at 100 micromol l(-1), against several potassium- and sodium-operated ion channel functions as well as the metabotropic glutamate receptor. 4. The functions of the ionotropic glutamate and the GABA(A) receptor channels were inhibited by TMT in micromolar concentrations. Thus, at a maximum concentration of 100 micromol l(-1), around 20-30% of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and GABA(A) receptor-mediated ion currents and 35% of the N-methyl-D-aspartate receptor-mediated ion currents were blocked. 5. In the hippocampal slice model, the inhibitory effects of TMT were much stronger than expected from the results on the ion channels. Bath application of TMT significantly reduced the amplitudes of evoked excitatory postsynaptic field potentials in a concentration-dependent and nonreversible manner. 6. Induction of long-term potentiation, recorded from the CA1 dendritic region, was inhibited by TMT and failed completely at a concentration of 10 micromol l(-1). 7. In general, TMT affects the excitatory and inhibitory synaptic processes in a receptor specific manner and is able to disturb the activity within a neuronal network.
Krüger
Katharina
K
Institute of Physiology I, Robert-Koch-Str. 27a, 48149 Münster, Germany.
Diepgrond
Victoria
V
Ahnefeld
Maria
M
Wackerbeck
Christina
C
Madeja
Michael
M
Binding
Norbert
N
Musshoff
Ulrich
U
D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism*; D014298:Trimethyltin Compounds / Q000494:pharmacology*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018079:Receptors, GABA; D017470:Receptors, Glutamate; D014298:Trimethyltin Compounds; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; C040533:trimethyltin chloride