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 Ba2+ 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.
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Acknowledgments
We are grateful to Professor T. Gefflault (University of Clermont-Ferrand) for providing us with L-PPT. This work was funded by the French National Research Agency (ANR) and the National Center for Scientific Research (CNRS). As part of the PhD studies of L.D., it was also supported by the French Ministry of Education and Research.
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Domingos, L., Desrus, A., Même, S. et al. L-Phosphinothricin modulation of inwardly rectifying K+ channels increased excitability in striatal medium-sized spiny neurons. Arch Toxicol 90, 1719–1727 (2016). https://doi.org/10.1007/s00204-016-1721-z
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DOI: https://doi.org/10.1007/s00204-016-1721-z