Abstract
Our understanding of estrogen signaling in the nervous system has undergone a significant shift in recent years. For over three decades, the idea that all estradiol actions were explained by direct regulation of transcription held sway. Within the past decade, the idea that in addition to classical effects, membrane-initiated actions of estradiol are important has gained traction. While several novel putative membrane estrogen receptors (ERs) have been described, a large fraction of measured responses appear to be due to membrane-localized estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta), the same proteins that regulate gene expression. These membrane-localized ERs participate in the regulation of the synthesis of neuroprogesterone, dorsal root ganglion (DRG) neuron excitation, and female sexual receptivity. This is achieved by the modulation of intracellular cell signaling pathways usually associated with the activation of G protein-coupled receptors (GPCRs). ER alpha and ER beta are themselves not GPCRs that directly activate G proteins to regulate physiological responses, but rather interact with traditional GPCRs to initiate cell signaling. This review presents results that support a direct protein-protein interaction between ER alpha and ER beta with metabotropic glutamate receptors (mGluRs), allowing estradiol to signal through mGluRs. This ER/mGluR hypothesis explains how estradiol can activate a wide-range of intracellular pathways and provides an underlying mechanism for the hitherto seemingly unrelated rapid membrane actions in the nervous system.