title: L-Phosphinothricin modulation of inwardly rectifying K(+) channels increased excitability in striatal medium-sized spiny neurons.
abstract: Phosphinotricin (L-PPT) is the active compound of a broad-spectrum herbicide. Acute poisoning with L-PPT has various clinical manifestations, including seizures and convulsions. However, the exact mechanism of L-PPT toxicity remains unclear. The present study addressed the role of L-PPT, in the excitability of striatal medium-sized spiny neurons (MSNs). In whole-cell current-clamp experiments, L-PPT increased the input resistance (Ri), decreased the rheobase and increased the firing frequency of action potentials. In voltage-clamp experiments, L-PPT inhibited the inward-rectifying potassium (Kir) currents. Finally, the effects of L-PPT mimicked the inhibition of Kir channels with Ba(2+) on neuronal excitability. Altogether, these results suggest that the herbicide L-PPT is a modulator of Kir channels in MSNs. Thereby, Kir channels are potent regulators of the excitability of MSNs and reduced open probability of these channels would generate a powerful upregulation of neuronal output. This effect may represent a possible mechanism for L-PPT dependent neuronal toxicity.
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Complexes métalliques et IRM pour applications biomédicales, Rue Charles Sadron, CS 80054, 45071, Orléans Cedex 2, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Domingos
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Complexes métalliques et IRM pour applications biomédicales, Rue Charles Sadron, CS 80054, 45071, Orléans Cedex 2, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Desrus
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Complexes métalliques et IRM pour applications biomédicales, Rue Charles Sadron, CS 80054, 45071, Orléans Cedex 2, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Même
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR4301, Complexes métalliques et IRM pour applications biomédicales, Rue Charles Sadron, CS 80054, 45071, Orléans Cedex 2, France. william.meme@cnrs-orleans.fr.
authors.forename: William
authors.identifier: http://orcid.org/0000-0001-7570-0851
authors.initials: W
authors.lastname: Même
mesh_terms: D000613:Aminobutyrates / Q000633:toxicity*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D006540:Herbicides / Q000633:toxicity*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*
chemical_list: D000613:Aminobutyrates; D006540:Herbicides; D024661:Potassium Channels, Inwardly Rectifying; C003121:phosphinothricin; D005974:Glutamate-Ammonia Ligase
keywords: Herbicide; Kir channels; Neurotoxicity; Patch-clamp; Striatum