Endothelin-3 expression in the subfornical organ enhances the sensitivity of Na_x, the brain sodium-level sensor, to suppress salt intake

Salt homeostasis is essential to survival, but brain mechanisms for salt-intake control have not been fully elucidated. Here, we found that the sensitivity of Na_x channels to [Na⁺]_o is dose-dependently enhanced by endothelin-3 (ET-3). Na_x channels began to open when [Na⁺]_o exceeded ∼150 mM without ET-3, but opened fully at a physiological [Na⁺]_o (135-145 mM) with 1 nM ET-3. Importantly, ET-3 was expressed in the subfornical organ (SFO) along with Na_x, and the level was robustly increased by dehydration. Pharmacological experiments revealed that endothelin receptor B (ET _BR) signaling is involved in this modulation of Na_x gating through protein kinase C and ERK1/2 activation. ET_BR agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ET_BR antagonist attenuated salt aversion during dehydration. These results indicate that ET-3 expression in the SFO is tightly coupled with body-fluid homeostasis through modulation of the [Na⁺]_o sensitivity of Na_x.