TRPV1 dependent neurotoxicity involves the mitochondrial Na+/Ca2+ exchanger in nociceptors

I Nita, Y Caspi, I Sekler, A Binshtok

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review


Background: Previous studies have demonstrated that
prolonged activation of the non-selective cationic channel
TRPV1 leads to a rise in mitochondrial calcium levels, followed by a depolarization of trans-mitochondrial potential. This
change in mitochondrial potential leads to a change in the
Na+/Ca2+ exchanger activity, from forward to reverse mode,
which further increases the levels of mitochondrial calcium.
This increase in mitochondrial calcium could underlie the well
described effect of chronically activated TRPV1 channels on
cell vitality. However, a causal link between the change in
mode of the exchanger and cell death under prolonged
S94 J Mol Neurosci (2014) 53 (Suppl 1):S1–S137
TRPV1 activity has yet to be established. Here we sought to
investigate the contribution of mitochondrial Na+/Ca2+exchanger activity to cell death. To this end, we used
HEK expressing TRPV1 cells and nociceptive neurons
that inherently express TRPV1 channels. We compared
the levels of mitochondrial calcium, mitochondrial membrane potential and cell vitality in naïve cells and in
cells transfected with small interfering RNA for modulating expression of the Na+/Ca2+ mitochondrial
Results: Capsaicin induced a steep and transient rise in intracellular and mitochondrial Ca2+. The rapid and significant
accumulation of Ca2+ in the mitochondria caused a change in
mitochondrial potential, and reversal of the mitochondrial
Na+/Ca2+exchanger. Knockdown of the mitochondrial Na+/
Ca2+exchanger leads to a decrease in the number of dead
HEK cells expressing TRPV1 compared to the control.
Conclusion: These results suggest that the change in mode of
the exchanger leads to calcium accumulation and hence calcium based toxicity. Therefore, under conditions of constant
TRPV1 activity, downregulation of the exchange is beneficial
and leads to decreased cell death.
Original languageEnglish
StatePublished - 2014


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