Estrogen, a primary female hormone, can initiate nerve impulses in milliseconds to regulate various physiological processes. Researchers at Baylor College of Medicine, Louisiana State University, and other institutions have found that estrogen's rapid actions are facilitated by the interaction between the estrogen receptor-alpha (ER-alpha) and an ion channel protein called Clic1. This discovery was published in Science Advances.
Clic1 is responsible for the fast movement of electrically charged chloride ions through cell membranes, which neurons use for signal transmission. The researchers suggest that estrogen triggers quick neuronal responses through Clic1 ion currents by interacting with the ER-alpha-Clic1 complex.
"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 Dr. Yong Xu, co-corresponding author and professor at Baylor.
While it is known that ER-alpha enters the cell nucleus upon estrogen stimulation to mediate gene transcription over minutes to hours, this study explores how estrogen can alter neuron firing activity within milliseconds. "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," Xu explained.
The research team investigated cell membrane proteins interacting with ER-alpha using cell lines and animal models. They identified Clic1 as a candidate for mediating estrogen-triggered fast actions due to its role in regulating neuronal excitability.
"We discovered that estrogen enhances Clic1-mediated ion currents and eliminating estrogen reduced such currents," Xu stated. "In addition, Clic1 currents are required for estrogen to induce rapid responses in neurons."
The study also suggests potential interactions between other nuclear receptors and ion channels. "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 added.
Chloride channels like Clic1 are less studied compared to potassium, sodium or calcium channels. "We hope that our findings will inspire other groups in the field to expand these promising investigations," Xu concluded.
For further details on authorship and funding support for this research, refer to the publication.
