title: Endothelin-3 expression in the subfornical organ enhances the sensitivity of Na(x), the brain sodium-level sensor, to suppress salt intake.
abstract: 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 Nax, and the level was robustly increased by dehydration. Pharmacological experiments revealed that endothelin receptor B (ET(B)R) signaling is involved in this modulation of Na(x) gating through protein kinase C and ERK1/2 activation. ET(B)R agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ET(B)R 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).
authors.affiliation: Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki, Aichi 444-8787, Japan.
authors.forename: Takeshi Y
authors.initials: TY
authors.lastname: Hiyama
authors.forename: Masahide
authors.initials: M
authors.lastname: Yoshida
authors.forename: Masahito
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Ryoko
authors.initials: R
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuda
authors.forename: Eiji
authors.initials: E
authors.lastname: Watanabe
authors.forename: Masaharu
authors.initials: M
authors.lastname: Noda
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D065131:Endothelin B Receptor Antagonists; D019334:Endothelin-3 / Q000378:metabolism*; D005247:Feeding Behavior / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism; D013356:Subfornical Organ / Q000378:metabolism*
chemical_list: D065131:Endothelin B Receptor Antagonists; D019334:Endothelin-3; D044023:Receptor, Endothelin B; D015222:Sodium Channels; D019344:Lactic Acid; D012965:Sodium Chloride; D012964:Sodium; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose