Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction

Over the past few years our understanding of estrogen signaling in the brain has expanded rapidly. Estrogens are synthesized in the periphery and in the brain, acting on multiple receptors to regulate gene transcription, neural function, and behavior. Various estrogen-sensitive signaling pathways often operate in concert within the same cell, increasing the complexity of the system. In females, estrogen concentrations fluctuate over the estrous/menstrual cycle, dynamically modulating estrogen receptor (ER) expression, activity, and trafficking. These dynamic changes influence multiple behaviors but are particularly important for reproduction. Using the female rodent model, we review our current understanding of estradiol signaling in the regulation of sexual receptivity. Membrane-initiated signaling is mediated by the classic receptors ERα and ERβ that are trafficked to the membrane as well as through novel extranuclear receptors such as GPER and Gq-mER. ERα and ERβ trafficking to the membrane requires palmitoylation and caveolin proteins. Caveolin proteins determine the mGluR associated with ERα thereby establishing whether estradiol action is stimulatory (mGluR1a/mGluR5) or inhibitory (mGluR2/3). Estradiol control of sexual receptivity requires activation of several types of ERs which are involved in cell signaling in transcriptional regulation. Control of sexual receptivity requires estradiol actions at the membrane, and involves several different activities at both ERα and GPER. Spinogenesis in the arcuate nucleus of the hypothalamus is crucial for sexual receptivity and is mediated by ERα/mGluR1a signaling.