Membrane-initiated estradiol actions mediate structural plasticity and reproduction

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, ER alpha and ER beta, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ER alpha has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ER alpha 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 ER alpha interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ER alpha, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ER alpha-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 ER alpha-mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ER alpha-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 ER alpha trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity. (C) 2012 Elsevier Inc. All rights reserved.