Researchers have identified a way in which estrogen can cause quick neuron responses.
Estrogen, the primary hormone produced by the ovaries in females, is capable of stimulating nerve signals in just milliseconds to manage several bodily functions. At Baylor College of Medicine, Louisiana State University, and other partner institutions, scientists found that the rapid effects of estrogen are due to its interaction with a protein known as Clic1, which is linked to the estrogen receptor-alpha (ER-alpha).
Clic1 is responsible for regulating the swift movement of electrically charged chloride ions across the cell membrane, a process that neurons use to receive, carry, and relay signals. The researchers suggest that by interacting with the ER-alpha-Clic1 complex, estrogen can initiate rapid neuronal reactions via Clic1 ion currents. This research was published in Science Advances.
“Estrogen plays a role in the brain by influencing various physiological functions such as female fertility, sexual behavior, mood, reward systems, stress responses, cognitive abilities, cardiovascular functions, and body weight regulation. Many of these actions are facilitated when estrogen binds to its receptor, ER-alpha,” explained Dr. Yong Xu, a co-author of the study and professor of pediatrics and nutrition at the USDA/ARS Children’s Nutrition Research Center at Baylor.
Rapid vs. Slow Actions
It is well understood that when estrogen is activated, ER-alpha moves into the cell nucleus and influences gene transcription. This traditional nuclear receptor function takes anywhere from minutes to hours.
“Estrogen can alter the firing activity of neurons in just milliseconds, but the mechanism behind this was unclear,” Xu remarked. “It seemed illogical to us that the traditional nuclear receptor action of ER-alpha, which takes minutes, could be responsible for such a swift effect. We investigated whether ion channels, which are proteins in the cell membrane that control quick ion flow, might be responsible for estrogen’s rapid effects.”
In the present study, using cell lines and animal models, the researchers searched for membrane proteins that could interact with ER-alpha. They discovered that Clic1, which stands for chloride intracellular channel protein-1, can physically bind to ER-alpha. Since Clic1 is known to influence neuronal excitability, the researchers considered it a prime candidate for mediating estrogen’s quick actions.
“We found that estrogen boosts Clic1-mediated ion currents, and removing estrogen decreased these currents,” Xu commented. “Moreover, Clic1 currents are essential for estrogen to elicit quick neuron responses. Additionally, disrupting the Clic1 gene in animal models weakened estrogen’s influence on regulating female body weight.”
The results imply that other nuclear receptors might also interact with ion channels, a potential avenue the researchers are eager to explore in future studies.
“This investigation was done using female mice, but Clic1 is also found in males. We are keen to study its function in male physiology,” Xu added.
Chloride channels haven’t been as thoroughly examined as other types of ion channels like potassium, sodium, or calcium channels. “We are one of the pioneering groups to investigate the role of Clic1 in female physiology,” Xu stated. “We hope our findings will motivate other researchers in this area to broaden these beneficial studies.”
