Endothelin-3 Expression in the Subfornical Organ Enhances the Sensitivity of Nax, the Brain Sodium-Level Sensor, to Suppress Salt Intake
Endothelin-3 Expression in the Subfornical Organ Enhances the Sensitivity of Nax, the Brain Sodium-Level Sensor, to Suppress Salt Intake
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DOI：
10.1016/j.cmet.2013.02.018
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发表时间：
2013-04-02
期刊：
影响因子：
29
通讯作者：
Noda, Masaharu
中科院分区：
文献类型：
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作者：
Hiyama, Takeshi Y.;Yoshida, Masahide;Noda, Masaharu
盐的体内平衡对生存至关重要，但盐摄入控制的大脑机制尚未完全阐明。在此，我们发现Na-x通道对[Na+]（o）的敏感性被内皮素-3（ET-3）剂量依赖性地增强。Na-x通道在[Na+]（o）超过类似于150 mM而没有ET-3时开始打开，但在生理[Na+]（o）（135-145 mM）下与1 nM ET-3完全打开。重要的是，ET-3在穹窿下器官（SFO）中与Na-x沿着表达，并且其水平在脱水时显著增加。药理学实验表明，内皮素受体B（ETBR）信号转导通过蛋白激酶C和ERK 1/2激活参与这种Na-x门控的调节。ETBR激动剂通过SFO中的乳酸增加GABA能神经元的放电率，ETBR拮抗剂减弱脱水期间的盐厌恶。这些结果表明，ET-3在SFO中的表达通过调节Na-x的[Na+]（o）敏感性与体液稳态紧密耦合。
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.