Identification of an ionic mechanism for ERa-mediated rapid excitation in neurons

Authors: YU, MENG - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); FENG, BING - Pennington Biomedical Research Center; GAO, PEIYU - Pennington Biomedical Research Center; YU, KAIFAN - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); LI, YONGXIANG - Children'S Nutrition Research Center (CNRC); GINNARD, OLIVIA - Children'S Nutrition Research Center (CNRC); CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); FANG, XING - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); BEAN, JONATHAN - Children'S Nutrition Research Center (CNRC); LIU, QINGZHUO - Children'S Nutrition Research Center (CNRC); DENG, YUE - Children'S Nutrition Research Center (CNRC); YANG, YUXUE - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); JOSSY, SANIKA - Children'S Nutrition Research Center (CNRC); BURT, MEGAN - Children'S Nutrition Research Center (CNRC); WONG, HUEY ZHONG - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); RENKIEL, BENJAMIN - Baylor College Of Medicine; HE, YANG - Baylor College Of Medicine; GUO, SHAODONG - Texas A&M University; GOURDY, PIERRE - University Of Toulouse; ARNAL, JEAN-FRANCOIS - University Of Toulouse; LENFANT, FRANCOISE - University Of Toulouse; WANG, ZHAO - Baylor College Of Medicine; WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Pennington Biomedical Research Center; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/26/2024
Publication Date: 10/2/2024
Citation: Yu, M., Yin, N., Feng, B., Gao, P., Yu, K., Liu, H., Liu, H., Li, Y., Ginnard, O.Z., Conde, K.M., Wang, M., Fang, X., Tu, L., Bean, J.C., Liu, Q., Deng, Y., Yang, Y., Han, J., Jossy, S.V., Burt, M.L., Wong, H., Yang, Y., Renkiel, B.R., He, Y., Guo, S., Gourdy, P., Arnal, J., Lenfant, F., Wang, Z., Wang, C., He, Y., Xu, Y. 2024. Identification of an ionic mechanism for ERa-mediated rapid excitation in neurons. Science Advances. 10. Article eadp0696. https://doi.org/10.1126/sciadv.adp0696.
DOI: https://doi.org/10.1126/sciadv.adp0696

Interpretive Summary: The hormone 17ß-estradiol (E2), produced by the ovaries, can quickly change how nerve cells function, affecting various body processes. Estrogen receptor-a (ERa), which is usually known for its role inside the cell nucleus, also exists on cell membranes and helps carry out these rapid effects of E2. However, the exact way this happens is still unclear. Our study found that a protein called chloride intracellular channel protein-1 (Clic1) interacts with ERa, especially with the membrane-bound version. E2 increases Clic1-related electrical activity in cells, while reducing E2 levels decreases it. We also discovered that Clic1 is necessary for the quick nerve cell responses triggered by E2 in different parts of the brain that contain ERa. Additionally, when Clic1 is removed from certain brain cells in the hypothalamus, E2 loses its ability to help regulate body weight in females. In summary, we identified the Clic1 channel as a crucial link in how E2 rapidly excites nerve cells, which could play a role in many brain functions controlled by this hormone.

Technical Abstract: The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-a (ERa), 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 ERa with a preference to the membrane-bound ERa. 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 ERa populations. Further, genetic disruption of Clic1 in hypothalamic ERa 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.