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

Abstract

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.

Inhibition of NHE1 transport activity and gene transcription in DRG neurons in oxaliplatin-induced painful peripheral neurotoxicity

“…Alterations in pH i have profound effects on nerve excitability and have been proposed as factors or co-factors of many dysfunctions in both the peripheral and central nervous systems 21,[26][27][28] . In mice DRG sensory neurons, we have shown that OHP induces early pH i alterations in vitro and in vivo that modify the activity of thermosensitive calcium-permeable TRPA1 and TRPV1 channels and potassium K2P channels 7,9 , key regulators of sensory neurons excitability 29 . This study presents novel findings on the OHP ability to alter NHE1 activity after short www.nature.com/scientificreports/ incubation times, as well as, the first measurement of the intrinsic buffering power and its pH i dependence in mice DRG neurons.…”

“…The reduction of the cytosolic [H + ] in neurons is caused by the formation of neuronal hemoglobin-OHP adducts, which decrease cytosolic proton buffering capacity 8 . Moreover, the intracellular pH (pH i ) change alters the electrical properties of neurons by sensitizing TRPA1 and modulating the activity of TREK channels 7,9 . On the other hand, in addition to buffering, the steady-state pH i depends on the balance between the rate of H + production from cell metabolism and the rates of acid extrusion and acid loading via alkalizing and acidifying membrane transport systems 10,11 .…”