Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction

Paul E. Micevych, Paul G. Mermelstein, Kevin Sinchak

Research output: Contribution to journalReview articlepeer-review

45 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)654-666
Number of pages13
JournalTrends in Neurosciences
Issue number11
StatePublished - Nov 2017

Bibliographical note

Funding Information:
The authors gratefully acknowledge the editorial support of Dr Melinda Mittelman-Smith, Dr Lauren Rudolph, and Katherine Tonn. Experiments from our laboratories were supported by National Institutes of Health grants DA013185 and HD042635 to P.E.M., DA035008 and DA041808 to P.G.M., and HD058638 to K.S. Caveolin (CAV) proteins a family of integral membrane proteins that act as scaffolding proteins to compartmentalize and concentrate signaling proteins. There are three members: CAV1, CAV2, and CAV3. They appear to act as chaperones for nuclear steroid hormone receptors, especially ERα and ERβ. Estrous cycle in rodents the ovarian cycle is composed of four stages, diestrus I, diestrus II, proestrus, and estrus. In diestrus, developing ovarian follicles produce primarily estrogen which feeds back onto the hypothalamus to inhibit the release of GnRH, and onto the pituitary to inhibit FSH and LH release. On the afternoon of proestrus, the rising levels of estrogen stimulate the synthesis of progesterone in the hypothalamus, and together these steroids stimulate the surge release of GnRH leading to the release of LH and ovulation of an ovum from the ovary. On estrus, release of progesterone from the corpus luteum inhibits the hypothalamus, resulting in low levels of GnRH as well as low levels of LH and FSH release from the pituitary, leading to low circulating levels of estrogen and progesterone. Lordosis reflex the naturally occurring body posture for sexual receptivity/copulation that is present in most mammals including rodents. Primary characteristics include raising of the hips, ventral arching of the back, lateral deviation of the tail, which present the vagina to the male and allow intromission. Palmitoylation the covalent attachment of the fatty acid palmitate to proteins, which increases their hydrophobicity. Palmitoylation contributes to the trafficking of proteins between intracellular compartments and to the cell membrane. Finally, palmitoylation modulates protein–protein interactions such as between estrogen receptors and metabotropic glutamate receptors.

Publisher Copyright:
© 2017 Elsevier Ltd


  • ERα
  • GPER
  • caveolin
  • estrogen feedback
  • lordosis behavior
  • mGluR


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