Central mechanisms of sodium sensing for water-intake control

• Project/Area Number: 18K06534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: National Institute for Basic Biology
• Principal Investigator: Sakuta Hiraki 基礎生物学研究所, 多様性生物学研究室, 助教 (40343743)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 体液恒常性 / 飲水行動制御 / Na+濃度センサー / Nax / SCL9A4 / SLC9A4 / 飲水行動 / 脳内センサー / Trpv4

Outline of Final Research Achievements

It is suggested that another unknown [Na+]-dependent pathway besides the Nax/TRPV4 pathway contributes to water intake. In the present study, we screened for novel [Na+] sensors involved in water intake control, and identified SLC9A4. 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. 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 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 Nax/TRPV4 pathway.

Academic Significance and Societal Importance of the Research Achievements

本研究は、我々の研究グループが明らかにしたNa+濃度センサーNaxによる塩分摂取行動制御の脳内機構に関する研究と対を成すものである。したがって、これらの成果と本研究を合わせることにより体液のNa+濃度感知とその情報に基づく行動制御機構の全体像が明らかとなり、その学術的意義は極めて高いといえる。体液恒常性の異常は重篤な全身状態の悪化をもたらす。また体液恒常性維持機構と血圧調節機構の間には強い繋がりがある。本研究の成果は、これらの関連疾患の発症メカニズムの解明、並びにその治療の基礎となる知見を提供すると考えられる。

Research Products

• [Journal Article] SLC9A4 in the organum vasculosum of the lamina terminalis is a [Na+] sensor for the control of water intake (2020)
  • Author(s): Sakuta Hiraki、Lin Chia-Hao、Hiyama Takeshi Y.、Matsuda Takashi、Yamaguchi Katsushi、Shigenobu Shuji、Kobayashi Kenta、Noda Masaharu
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 472 Issue: 5 Pages: 609-624
  • DOI: 10.1007/s00424-020-02389-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nax-positive glial cells in the organum vasculosum laminae terminalis produce epoxyeicosatrienoic acids to induce water intake in response to increases in [Na+] in body fluids (2020)
  • Author(s): Sakuta H, Lin CH, Yamada M, Kita Y, Tokuoka SM, Shimizu T, Noda M
  • Journal Title: Neurosci Res Volume: 154 Pages: 45-51
  • DOI: 10.1016/j.neures.2019.05.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] [Na+] increases in body fluids sensed by central Nax induce sympathetically mediated blood pressure elevations via H+-dependent activation of ASIC1a. (2019)
  • Author(s): Nomura, K., Hiyama, T.Y., Sakuta, H., Matsuda, T., Lin, C.H., Kobayashi, K., Kobayashi, K., Kuwaki, T., Takahashi, K., Matsui, S., and Noda, M.
  • Journal Title: Neuron Volume: 101 Issue: 1 Pages: 60-75
  • DOI: 10.1016/j.neuron.2018.11.017
  • Peer Reviewed