Endothelin-3 Expression in the Subfornical Organ Enhances the Sensitivity of Nax, 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 similar to 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 (ETBR) signaling is involved in this modulation of Na-x gating through protein kinase C and ERK1/2 activation. ETBR agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ETBR 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.