Summary: Researchers have discovered that estrogen’s fast action on neurons is mediated by the estrogen receptor-alpha (ER-alpha) coupling with the chloride ion channel Clic1. This interaction allows estrogen to regulate nerve impulses within milliseconds, influencing processes like mood, cognition, and body weight.
The study reveals a new mechanism beyond estrogen’s slower gene transcription activity, offering fresh insights into how this hormone affects the brain. These findings open the door to studying similar mechanisms in male physiology and other nuclear receptors.
Key Facts:
- Estrogen’s fast neural effects are mediated by the ER-alpha-Clic1 complex.
- Clic1 ion currents are critical for estrogen’s rapid influence on neurons.
- Disrupting the Clic1 gene in mice altered estrogen’s regulation of body weight.
Source: Baylor College of Medicine
Estrogen, the major female ovarian hormone, can trigger nerve impulses within milliseconds to regulate a variety of physiological processes.
At Baylor College of Medicine, Louisiana State University and collaborating institutions, researchers discovered that estrogen’s fast actions are mediated by the coupling of the estrogen receptor-alpha (ER-alpha) with an ion channel protein called Clic1.
Clic1 controls the fast flux of electrically charged chloride ions through the cell membrane, which neurons use for receiving, conducting and transmitting signals. The researchers propose that interacting with the ER-alpha-Clic1 complex enables estrogen to trigger fast neuronal responses through Clic1 ion currents.
The study appeared in Science Advances.
“Estrogen can act in the brain to regulate a variety of physiological processes, including female fertility, sexual behaviors, mood, reward, stress response, cognition, cardiovascular activities and body weight balance. Many of these functions are mediated by estrogen binding to one of its receptors, ER-alpha,” said co-corresponding author Dr. Yong Xu, professor of pediatrics – nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor.
Fast and slow
It is well known that, upon stimulation by estrogen, ER-alpha enters the cell nucleus where it mediates the transcription of genes. This classical mode of action as a nuclear receptor takes minutes to hours.
“Estrogen also can change the firing activity of neurons in a manner of milliseconds, but it was not clear how this happens,” Xu said.
In this case, it did not make sense to us that the minutes-long nuclear receptor function of ER-alpha was involved in such a rapid action. We explored the possibility that ion channels, proteins in the cell membrane that regulate the fast flux of ions, mediated estrogen’s quick actions.”
In the current study, working with cell lines and animal models, the team searched for cell membrane proteins that interact with ER-alpha. They found that protein Clic1, for chloride intracellular channel protein-1, can physically interact with ER-alpha. Clic1has been implicated in the regulation of neuronal excitability, so the researchers considered it a candidate to mediate estrogen-triggered fast actions.
“We discovered that estrogen enhances Clic1-mediated ion currents, and eliminating estrogen reduced such currents,” Xu said.
“In addition, Clic1 currents are required for estrogen to induce rapid responses in neurons. Also, disrupting the Clic1 gene in animal models blunted estrogen regulation of female body weight balance.”
The findings suggest that other nuclear receptors could also interact with ion channels, a possibility the researchers look forward to studying in the future.
“This study was conducted with female mice. However, Clic1 is also present in males. We are interested in investigating its role in male physiology,” Xu said.
Chloride channels are not as well studied as other ion channels, such as potassium, sodium or calcium channels.
“We are among the first to study the role Clic1 plays in female physiology,” Xu said. “We hope that our findings will inspire other groups in the field to expand these promising investigations.”
About this neuroscience research news
Author: Taylor Barnes
Source: Baylor College of Medicine
Contact: Taylor Barnes – Baylor College of Medicine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Identification of an ionic mechanism for ERα-mediated rapid excitation in neurons” by Yong Xu et al. Science Advances
Abstract
Identification of an ionic mechanism for ERα-mediated rapid excitation in neurons
The major female ovarian hormone, 17β-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes.
Estrogen receptor-α (ERα), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear.
Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERα with a preference to the membrane-bound ERα. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion.
In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E2 on female body weight balance.
In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2.
