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

The major female ovarian hormone, 17β-estradiol (E ₂ ), 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 ₂ , 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 ₂ and reduced by its depletion. In addition, Clic1 currents are required to mediate the E ₂ -induced rapid excitations in multiple brain ERα populations. Further, genetic disruption of Clic1 in hypothalamic ERα neurons blunts the regulations of E ₂ on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E ₂ -induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E ₂ .