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 appears 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 matter 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.”