Related Experiment Video
Updated: Jul 18, 2026
Ovariectomy and 17β-estradiol Replacement in Rats and Mice: A Visual Demonstration
Published on: June 7, 2012
Novel sites and mechanisms of oestrogen action in the brain
1Department of Anatomy & Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Abstract:
We are investigating novel, non-transcriptionally mediated mechanisms that may contribute to the differentiative effects of oestrogen in developing forebrain neurons. Recent findings in the cerebral cortex document that 17 alpha- and 17 beta-oestradiol elicit rapid and sustained activation of the Ras-Raf-MAP kinase cascade, a major growth factor signalling pathway. Using oestrogen receptor (ER) alpha knockout (ERKO) mice, we addressed the identity of the receptor mediating activation of the MAP kinase cascade. 17 beta-oestradiol increased B-Raf activity and MEK-dependent ERK phosphorylation in explants of wild-type and ERKO cerebral cortex. Although neither the ER alpha-selective ligand, 16 alpha-iodo-17 beta-oestradiol (16 alpha-IE2) nor the ER beta-selective ligand, genistein, elicited ERK phosphorylation, as little as 0.1 nM 17 beta-oestradiol did so. Moreover, 16 alpha-IE2 acted as an inhibitory modulator of ERK activation, and the ER antagonist ICI 182 780 blocked oestradiol action only in wild-type cultures. These data suggest that neither ER alpha nor ER beta mediate activation of the MAP kinase cascade. A putative, novel, oestradiol-sensitive and ICI 182 780-insensitive receptor, designated ER-X may, rather, be involved. Association of ER-X with flotillin, the neuronal homologue of the caveolar protein, caveolin, places ER-X within plasma membrane caveolae and supports the hypothesis that a membrane-associated ER may mediate rapid oestrogen activation of the MAP kinase cascade.
Insights
Oestrogen rapidly activates brain cell signaling through a novel receptor, ER-X, independent of traditional oestrogen receptors (ER alpha and ER beta). This discovery reveals new mechanisms for oestrogen
Area of Science:
- Neuroscience
- Endocrinology
- Cell Signaling
Background:
- Oestrogen influences brain development through various mechanisms.
- Rapid, non-transcriptional signaling pathways are increasingly recognized for oestrogen's effects.
- The Ras-Raf-MAP kinase cascade is a key growth factor pathway activated by oestrogen.
Purpose of the Study:
- To investigate novel, non-transcriptional mechanisms of oestrogen action in developing forebrain neurons.
- To identify the specific oestrogen receptor mediating rapid MAP kinase cascade activation.
- To explore the role of potential novel oestrogen receptors in neuronal signaling.
Main Methods:
- Utilized oestrogen receptor (ER) alpha knockout (ERKO) mice to differentiate receptor roles.
- Examined B-Raf activity and ERK phosphorylation in response to 17 beta-oestradiol and selective ER ligands.
- Investigated the effects of ER antagonists and identified potential novel receptor interactions.
Main Results:
- 17 beta-oestradiol activated the MAP kinase cascade in both wild-type and ERKO mice.
- Neither ER alpha- nor ER beta-selective ligands elicited significant ERK phosphorylation.
- A novel oestrogen receptor, ER-X, potentially located in membrane caveolae, is implicated in this rapid signaling.
Conclusions:
- Traditional oestrogen receptors (ER alpha and ER beta) do not mediate the rapid activation of the MAP kinase cascade by oestrogen.
- A novel, membrane-associated oestrogen receptor (ER-X) is proposed to mediate these rapid, non-transcriptional signaling events.
- This finding suggests a new paradigm for oestrogen's rapid effects on neuronal development and function.
Related Concept Videos
01:26Neurochemical Transmission: Sites of Drug Action
01:20Physiology of Smell and Olfactory Pathway
The olfactory...
01:26Secondary Messengers in Hormone Action
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
01:22Hormonal Regulation of the Menstrual Cycle
At puberty, GnRH begins a pulsatile release pattern, which triggers the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The frequency and amplitude of GnRH pulses vary across the menstrual cycle, with faster pulses favoring LH release and slower pulses favoring FSH release.
01:30Hormonal Control of the Ovarian Cycle
Before puberty, the hypothalamus releases GnRH in a low frequency, low amplitude pulsatile manner. This along with the immature hypothalamic-pituitary-gonadal axis activity, results in low estrogen levels and the absence of a fully functional ovarian cycle. At puberty, GnRH secretion increases in both frequency and...
01:31Neurotransmitters