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. Here we show that TRPV1 mediated 17β-estradiol cell protection in primary culture of hippocampal-derived neurons against H2O2-induced damage was independent of estrogen receptors pathway activation. 17β-estradiol-mediated cell protection was reproduced in TRPV1-expressing heterologous systems. Whereas the protective effect was mimicked by membrane-impermeable 17β-estradiol-BSA, it was not induced by its epimer, 17α-estradiol or testosterone. Specifically, in TRPV1 expressing cells, the application of 17β-estradiol within the first three hours avoided H2O2-dependent mitochondrial depolarization and the activation of caspase 3/7 protecting against the irreversible damage triggered by H2O2. 17β-estradiol promoted a leftward shift in the conductance versus potential (G/V) relationship, indicating that the steroid hormone potentiates TRPV1 activity. In single channel recordings, we observed an increase in TRPV1 activity associated with an increased channel open probability. This effect was not observed after the application of α-estradiol. Actually, α-estradiol behaves as a TRPV1 antagonist. These results support the role of TRPV1 as a membrane receptor that can be activated by steroids as 17β-estradiol via ‘non-classical’ membrane mechanisms, improving mitochondrial function, and contributing to cell protection against oxidative stress.