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

The major female ovarian hormone, 17β-estradiol (E ), 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 E , but...

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Published in:Science advances 2024-10, Vol.10 (40), p.eadp0696
Main Authors: Yu, Meng, Yin, Na, Feng, Bing, Gao, Peiyu, Yu, Kaifan, Liu, Hesong, Liu, Hailan, Li, Yongxiang, Ginnard, Olivia Z, Conde, Kristine M, Wang, Mengjie, Fang, Xing, Tu, Longlong, Bean, Jonathan C, Liu, Qingzhuo, Deng, Yue, Yang, Yuxue, Han, Junying, Jossy, Sanika V, Burt, Megan L, Wong, Huey Zhong, Yang, Yongjie, Arenkiel, Benjamin R, He, Yang, Guo, Shaodong, Gourdy, Pierre, Arnal, Jean-Francois, Lenfant, Francoise, Wang, Zhao, Wang, Chunmei, He, Yanlin, Xu, Yong
Format: Article
Language:English
Subjects:
Animals
Chloride Channels - genetics
Chloride Channels - metabolism
Estradiol - metabolism
Estradiol - pharmacology
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Female
Humans
Hypothalamus - cytology
Hypothalamus - metabolism
Mice
Neurons - metabolism
Neuroscience
Protein Binding
SciAdv r-articles
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Summary:The major female ovarian hormone, 17β-estradiol (E ), 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 E , 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 E and reduced by its depletion. In addition, Clic1 currents are required to mediate the E -induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E -induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E .
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adp0696