Membrane-initiated estradiol actions mediate structural plasticity and reproduction

Abstract

Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERα and ERβ, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERα has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERα is a ligand-gated transcription factor and not a typical membrane receptor, trafficking to the cell membrane requires post-translational modifications. Two necessary modifications are palmitoylation and association with caveolins, a family of scaffolding proteins. In addition to their role in trafficking, caveolin proteins also serve to determine ERα interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ERα, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ERα-mGluR interactions have been demonstrated throughout the nervous system from hippocampus to striatum to hypothalamus to dorsal root ganglion (DRG) in both neurons and astrocytes. These combinations of ER and mGluR allow estradiol to have both facilitative and inhibitory actions in neurons. In hypothalamic astrocytes, the estradiol-mediated release of intracellular calcium stores regulating neurosteroid synthesis requires ERα-mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ERα-mGluR1a signaling complex leads to the release of neurotransmitters and alteration of neuronal morphology. This review will examine estradiol membrane signaling (EMS) activating a limbic-hypothalamic lordosis regulating circuit, which involves ERα trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity.

Regulation of object recognition and object placement by ovarian sex steroid hormones

“…The beneficial effects of estrogens on hippocampal memory are likely mediated through classical ERs (ERα and ERβ), as well as non-classical membrane receptors (e.g., GPER, ER-X, Gq-mER) [41; 82; 177]. Although some evidence does implicate non-classical ERs in mediating OR and OP memory [178; 179], the involvement of specific non-classical ERs remains unclear.…”

Rapid steroid hormone actions via membrane receptors

“…In the hypothalamus, membrane signaling via ERα is involved in gonadotropin secretion [100] and sexual behavior [101], where it appears to play a vital modulatory role. The modulation of these hypothalamic homeostatic functions by E 2 is due in large part to the attenuation of the coupling of metabotropic G i/o coupled receptors and their effector systems [102,103].…”

Epigenetic regulation of estrogen-dependent memory

“…Examples of sex-specific behaviors abound in endocrinology research, perhaps none better studied than the male rat mounting behavior and the female rat lordosis posture (Blaustein and Erskine, 2002; Kow and Pfaff, 2004; Etgen et al, 2006; Dewing et al, 2007; Micevych and Christensen, 2012; Lenz et al, 2013). Sex differences in cognitive function have been documented as well, most notably the reported male advantage in spatial abilities observed in humans and rodents.…”