TRPV1-Estradiol Stereospecific Relationship Underlies Cell Survival in Oxidative Cell Death

Abstract

Ramírez-Barrantes et al. TRPV1 Contribution in 17β-Estradiol Cell Protection GRAPHICAL ABSTRACT | TRPV1 is sufficient condition for 17β-estradiol resistance against oxidative stress-induced cell death. The cell death induced by oxidative stress could be characterized by a kinetic model of three state: alive, vulnerable and dead. In particular, the transition from alive to vulnerable state involves the depolarization of mitochondrial membrane potential, and the evolution to cell death the activation of caspases. Only in TRPV1 expressing cells, the initial application of 17β-estradiol protects against the irreversible damage triggered by oxidative stress, by inhibition of the transition from alive to vulnerable state. This mechanism includes blocking oxidative stress-dependent mitochondrial depolarization and the activation of caspases 3/7. Furthermore, 17β-estradiol potentiates TRPV1 activity associated with an increased open probability. Despite the relationship between the activation of TRPV1 and the maintenance of the mitochondrial membrane potential should be clarified, it could include the increase of the calcium buffer capacity of the mitochondria and/or the overexpression of anti-apoptotic proteins such as the Bcl-2 family as previously reported. Finally, the 17β-estradiol cell protection was independent of estrogen receptors, and was membrane started and stereospecific. These results support the role of TRPV1 as a 17β-estradiol ionotropic receptor being critical to cell survival.

Nociceptive TRP Channels and Sex Steroids

“…The discrete increase in TRPV1 activation using the non-permeable E2 is in agreement with a previous report which showed that E2 potentiated capsaicin-induced currents in rat DRG primary cultures [92]. Moreover, it was recently described that E2 potentiates TRPV1 activity in an estrogen receptor independent fashion, suggesting that TRPV1 could be an ionotropic receptor for E2 [93]. An interesting outcome from these experimental evidences is that the changes observed in TRPV1 expression are achieved using low E2 concentrations (10-100 nM) [81,83,88]; however, the effects on TRPV1 activation need supraphysiological concentrations of the steroid (1-100 μM) [93,94].…”

“…Moreover, it was recently described that E2 potentiates TRPV1 activity in an estrogen receptor independent fashion, suggesting that TRPV1 could be an ionotropic receptor for E2 [93]. An interesting outcome from these experimental evidences is that the changes observed in TRPV1 expression are achieved using low E2 concentrations (10-100 nM) [81,83,88]; however, the effects on TRPV1 activation need supraphysiological concentrations of the steroid (1-100 μM) [93,94]. This suggests that low E2 concentrations could modify TRPV1 expression through a classical genomic pathway, whereas a non-classical E2 effect on TRPV1 activation requires high E2 concentrations.…”

From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy

“…In addition, estrogen promoted the degradation of Cav1.2 through ERα in neuronal cells and in an AD mouse model, and Cav1.2 is the subunit of the L-type calcium channel, which is important in calcium overload and cell death in AD [125]. 17β-estradiol protects against oxidative stress-induced cell death in hippocampal neurons through TRPV1 [126]. In a combined bioinformatics analysis of female AD patients and AD mouse models, thioredoxin-interacting protein (TXNIP) was found specifically expressed in the hippocampus in AD.…”

TRPV1 activation induces cell death of TM3 mouse Leydig cells

“…The role of TRPV1 in testicular apoptosis remains controversial. The TRPV1 channel is known to be involved in tissue protection against oxidative damage with 17β-estradiol (Ramírez-Barrantes et al, 2020). TRPV1 KO mice have a testis phenotype with more cell death induced by oxidative stress stimuli and massive loss of germ cells from seminiferous tubules than wild-type (WT) mice Martins et al, 2014).…”

“…A recent study demonstrated that capsaicin induces apoptosis in CCL-97 Leydig cells, whereas capsazepine suppresses apoptosis, indicating that the TRPV1 channel is involved in Leydig cell apoptosis (Defo Deeh et al, 2019). Testosterone affects TRPV1 expression levels in a rat chronic inflammatory pain model (Bai et al, 2018) and inhibits TRPV1mediated currents (Ramírez-Barrantes et al, 2020). Little is known about the relationship between TRPV1 activity and testosterone secretion.…”