Abstract
17β-estradiol is a neuronal survival factor against oxidative stress that triggers its protective effect even in the absence of classical estrogen receptors. The polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channel has been proposed as a steroid receptor implied in tissue protection against oxidative damage. We show here that TRPV1 is sufficient condition for 17β-estradiol to enhance metabolic performance in injured cells. Specifically, in TRPV1 expressing cells, the application of 17β-estradiol within the first 3 h avoided H2O2-dependent mitochondrial depolarization and the activation of caspase 3/7 protecting against the irreversible damage triggered by H2O2. Furthermore, 17β-estradiol potentiates TRPV1 single channel activity associated with an increased open probability. This effect was not observed after the application of 17α-estradiol. We explored the TRPV1-Estrogen relationship also in primary culture of hippocampal-derived neurons and observed that 17β-estradiol cell protection against H2O2-induced damage was independent of estrogen receptors pathway activation, membrane started and stereospecific. These results support the role of TRPV1 as a 17β-estradiol-activated ionotropic membrane receptor coupling with mitochondrial function and cell survival.
Highlights
Oxidative dynamics is involved in several physiological processes, and disruption of redox control is a general pathological condition that induces cell dysfunction and death (Ghezzi et al, 2017)
This study demonstrates that 17β-estradiol is able to induce cell protection against oxidative stress through a mechanism dependent on TRPV1 activity
Estrogens are able to induce differential physiological effects through several mechanisms, some of them depend on the interaction with nuclear estrogen receptors whereas others may result from the activation of alternative estrogen-dependent routes with differential timelines
Summary
Oxidative dynamics is involved in several physiological processes, and disruption of redox control is a general pathological condition that induces cell dysfunction and death (Ghezzi et al, 2017). Apart from classical steroid mechanism of action, a large body of evidence nowadays shows a new mechanism which appear to involve membrane-associated signaling complexes (Wu et al, 2005, 2011) Such responses could be independent or in conjunction with estrogen receptors α and β, suggesting that estrogens such as 17β-estradiol modulate neural function by direct effects on membrane receptors (Balthazart and Ball, 2006; Vega-Vela et al, 2017). In rats, the activation of TRPV1 by CAP in substancia nigra pars compacta is able to diminish cell death triggered by MPP, via reduced activation of microglia and decrease of ROS levels (Park et al, 2012) This paradoxical effect of TRPV1 points the importance of the channel in cell survival, choosing the activation of different responses depending on the cell context, the moment of activation, and transience of the signal. Can steroids differentially modulate cell viability through TRPV1? and can be the aromatic capacity relevant for paracrine and autocrine cellular protection against oxidative cell death? Here, we show that 17β-estradiol and not testosterone or 17α-estradiol, induced cell protection via modulation of TRPV1 activity during oxidative injury independently of estrogen receptor expression
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