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Article

Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification

1
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy
2
Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy
3
Biología Molecular y Celular, Universidad Miguel Hernández de Elche, 03202 Elche (Alicante), Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7164; https://doi.org/10.3390/ijms21197164
Received: 11 September 2020 / Accepted: 27 September 2020 / Published: 28 September 2020
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na+/H+ exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability. View Full-Text
Keywords: oxaliplatin; TREK channels; neuropathic pain; pH; DRG neurons; Na+/H+ exchanger; electrophysiology; TRPV1 oxaliplatin; TREK channels; neuropathic pain; pH; DRG neurons; Na+/H+ exchanger; electrophysiology; TRPV1
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MDPI and ACS Style

Dionisi, M.; Ruffinatti, F.A.; Riva, B.; Lim, D.; Canta, A.; Meregalli, C.; Fumagalli, G.; Monza, L.; Ferrer-Montiel, A.; Fernandez-Carvajal, A.; Cavaletti, G.; Genazzani, A.A.; Distasi, C. Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification. Int. J. Mol. Sci. 2020, 21, 7164. https://doi.org/10.3390/ijms21197164

AMA Style

Dionisi M, Ruffinatti FA, Riva B, Lim D, Canta A, Meregalli C, Fumagalli G, Monza L, Ferrer-Montiel A, Fernandez-Carvajal A, Cavaletti G, Genazzani AA, Distasi C. Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification. International Journal of Molecular Sciences. 2020; 21(19):7164. https://doi.org/10.3390/ijms21197164

Chicago/Turabian Style

Dionisi, Marianna, Federico A. Ruffinatti, Beatrice Riva, Dmitry Lim, Annalisa Canta, Cristina Meregalli, Giulia Fumagalli, Laura Monza, Antonio Ferrer-Montiel, Asia Fernandez-Carvajal, Guido Cavaletti, Armando A. Genazzani, and Carla Distasi. 2020. "Early Stimulation of TREK Channel Transcription and Activity Induced by Oxaliplatin-Dependent Cytosolic Acidification" International Journal of Molecular Sciences 21, no. 19: 7164. https://doi.org/10.3390/ijms21197164

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