ER-X: A Novel, Plasma Membrane-Associated, Putative Estrogen Receptor That Is Regulated during Development and after Ischemic Brain Injury

Abstract

We showed previously in neocortical explants, derived from developing wild-type and estrogen receptor (ER)-alpha gene-disrupted (ERKO) mice, that both 17alpha- and 17beta-estradiol elicit the rapid and sustained phosphorylation and activation of the mitogen-activated protein kinase (MAPK) isoforms, the extracellular signal-regulated kinases ERK1 and ERK2. We proposed that the ER mediating activation of the MAPK cascade, a signaling pathway important for cell division, neuronal differentiation, and neuronal survival in the developing brain, is neither ER-alpha nor ER-beta but a novel, plasma membrane-associated, putative ER with unique properties. The data presented here provide further evidence that points strongly to the existence of a high-affinity, saturable, 3H-estradiol binding site (K(d), approximately 1.6 nm) in the plasma membrane. Unlike neocortical ER-alpha, which is intranuclear and developmentally regulated, and neocortical ER-beta, which is intranuclear and expressed throughout life, this functional, plasma membrane-associated ER, which we have designated "ER-X," is enriched in caveolar-like microdomains (CLMs) of postnatal, but not adult, wild-type and ERKO neocortical and uterine plasma membranes. We show further that ER-X is functionally distinct from ER-alpha and ER-beta, and that, like ER-alpha, it is re-expressed in the adult brain, after ischemic stroke injury. We also confirmed in a cell-free system that ER-alpha is an inhibitory regulator of ERK activation, as we showed previously in neocortical cultures. Association with CLM complexes positions ER-X uniquely to interact rapidly with kinases of the MAPK cascade and other signaling pathways, providing a novel mechanism for mediation of the influences of estrogen on neuronal differentiation, survival, and plasticity.

Membrane-initiated estrogen signaling in hypothalamic neurons

“…Interestingly, this E2-induced activation is not antagonized by the antiestrogen, ICI 182,780, and occurs in cortical explants from mice lacking ERα. In addition, this putative mER is particularly responsive to 17α-estradiol as compared to 17β-estradiol , Singh et al, 2000, Toran-Allerand et al, 2002. These and other findings have led to the hypothesis that ER-X is a novel ER that is ICI-insensitive (for review see (Toran-Allerand, 2004, ToranAllerand, 2005).…”

“…ER-X is a plasma membrane-associated, putative ER that is enriched in caveolar-like microdomains of postnatal, but not adult, cortical membranes , Toran-Allerand et al, 2002. In organotypic explants of the developing cerebral cortex, E2 induces tyrosine phosphorylation of both ERK1 (extracellular signal-regulated protein kinase 1) and ERK2, an action very similar to a number of growth factors including nerve growth factor (NGF) (Toran-Allerand, 2005).…”

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

“…In this sense, non-nuclear estrogen receptor has been widely described as responsible of rapid non-genomic estrogens actions (McCarthy 2008;Vasudevan and Pfaff 2008); raising the possibility that estradiol could play a neuroprotective role through a non-genomic rapid mechanism (Singer et al 1999;Wilson et al 2002). The way of its participation, among many others, could be in the increase of eNOS activity in cerebral blood vessels (McEwen 2001;Milner et al 2001;Toran-Aller et al 2002;Li et al 2003) or the downregulation of GSK3β (Glycogen Synthase Kinase 3β). The upregulation of this enzyme is responsible of the hyperphosphorylation of Tau protein, the main component of Alzheimer's disease amyloid (Goodenough et al 2003).…”

“…We cannot forget that immunohistochemistry does not allow to discern between ER67 and ER47 isoforms, and ToranAller and colleges have identified a novel plasma membrane-associated putative ER in neurons, called ER-X, different from classical estrogen receptors α and β (Toran-Aller et al 2002). The new isoform, whose apparent molecular weight is of 62-63 KDa, reacts with antibodies to ERα LBD, such as our MC-20 from Santa Cruz.…”

Male lifespan extension with 17‐α estradiol is linked to a sex‐specific metabolomic response modulated by gonadal hormones in mice

“…This study focuses on a stereoisomer of 17‐β estradiol, 17‐α estradiol (17aE2). Due to the stereochemistry of the carbon atom 17, 17aE2 has a much weaker binding affinity to the classical estrogen receptors, and in some situations has a greater binding affinity for other estrogen receptors, including the brain ER receptor ER‐X (Toran‐Allerand, Tinnikov, Singh & Nethrapalli, 2005; Toran‐Allerand et al., 2002). 17aE2 has a range of bioactive properties, including inflammatory and antioxidant effects (Moos, Dykens, Nohynek, Rubinchik & Howell, 2009), and an ability to inhibit the activity of 5‐alpha reductase enzymes (Schriefers, Wright, Rozman & Hevert, 1991), which convert testosterone to dihydrotestosterone, a more potent activator of the androgen receptor.…”