Publication Date
10-4-2024
Journal
Science Advances
DOI
10.1126/sciadv.adp0696
PMID
39356770
PMCID
PMC11446276
PubMedCentral® Posted Date
10-2-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Neurons, Chloride Channels, Estrogen Receptor alpha, Animals, Female, Humans, Estradiol, Mice, Hypothalamus, Protein Binding
Abstract
The major female ovarian hormone, 17β-estradiol (E2), 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 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 ERα with a preference to the membrane-bound ERα. 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 ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα 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.
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Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Neurology Commons, Neurosciences Commons
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