SLC9A4 in the organum vasculosum of the lamina terminalis is a [Na+] sensor for the control of water intake
SLC9A4 in the organum vasculosum of the lamina terminalis is a [Na+] sensor for the control of water intake
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DOI：
10.1007/s00424-020-02389-y
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发表时间：
2020-05-06
影响因子：
4.5
通讯作者：
Noda, Masaharu
中科院分区：
文献类型：
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作者：
Sakuta, Hiraki;Lin, Chia-Hao;Noda, Masaharu
Na-x是一种脑内[Na+]感受器，表达于大脑的穹隆下器(SFO)和终板血管器(OVLT)。我们先前已经证明，Na-x信号通过Na-x/TRPV4途径参与控制摄水行为。脑室注射高渗氯化钠溶液(Icv)后，NA-x基因敲除小鼠的摄水量显著减少，但仍可诱导一定量的摄水量，这表明除了Na-x/TRPV4途径外，还有另一种未知的[Na+]依赖途径参与了摄水量的增加。在本研究中，我们筛选了参与摄水控制的新型[Na+]传感器，并确定了SLC9A4(也称为钠(Na+)/氢(H+)交换器4(NHE4))。SLC9A4表达于OVLT内血管紧张素II(Ang II)受体1a(AT1a)阳性神经元。用转染SLC9A4的培养细胞进行的钠成像实验表明，SLC9A4可以被细胞外[Na+]([Na+](O))的增加激活，但不能通过渗透压的增加来激活。此外，SLC9A4阳性神经元的放电活动随着[Na+](O)和Ang II浓度的增加而增强。在OVLT中敲除SLC9A4基因后，脑脊液中[Na+]浓度增加而引起的水摄入量减少，但渗透压变化不明显。脑室注射一种特定抑制剂的实验表明，SLC9A4激活引起的细胞外[H+]增加下一步刺激酸敏通道1a(AS1C1a)诱导水摄入。因此，我们的结果表明，OVLT中的SLC9A4作为[Na+]感受器来控制水的摄取，并且SLC9A4信号不依赖于Na-x/TRPV4途径。
Na-x is a brain [Na+] sensor expressed in the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT) in the brain. We previously demonstrated that Na-x signals are involved in the control of water intake behavior through the Na-x/TRPV4 pathway. Na-x gene knockout mice showed significantly attenuated water intake after an intracerebroventricular (ICV) injection of a hypertonic NaCl solution; however, the induction of a certain amount of water intake still remained, suggesting that another unknown [Na+]-dependent pathway besides the Na-x/TRPV4 pathway contributes to water intake. In the present study, we screened for novel [Na+] sensors involved in water intake control and identified SLC9A4 (also called sodium (Na+)/hydrogen (H+) exchanger 4 (NHE4)). SLC9A4 is expressed in angiotensin II (Ang II) receptor type 1a (AT1a)-positive neurons in the OVLT. Sodium-imaging experiments using cultured cells transfected with slc9a4 revealed that SLC9A4 was activated by increases in extracellular [Na+] ([Na+](o)), but not osmolality. Moreover, the firing activity of SLC9A4-positive neurons was enhanced by increases in [Na+](o) and Ang II. slc9a4 knockdown in the OVLT reduced water intake induced by increases in [Na+], but not osmolality, in the cerebrospinal fluid. ICV injection experiments of a specific inhibitor suggested that the increase in extracellular [H+] caused by SLC9A4 activation next stimulates acid-sensing channel 1a (AS1C1a) to induce water intake. Our results thus indicate that SLC9A4 in the OVLT functions as a [Na+] sensor for the control of water intake and that the SLC9A4 signal is independent of the Na-x/TRPV4 pathway.