Nax signaling evoked by an increase in [Na+] in CSF induces water intake via EET-mediated TRPV4 activation

Am J Physiol Regul Integr Comp Physiol. 2016 Aug 1;311(2):R299-306. doi: 10.1152/ajpregu.00352.2015. Epub 2016 Jun 1.


Water-intake behavior is under the control of brain systems that sense body fluid conditions at sensory circumventricular organs (sCVOs); however, the underlying mechanisms have not yet been elucidated in detail. Nax is a sodium (Na(+)) level sensor in the brain, and the transient receptor potential vanilloid (TRPV) channels TRPV1 and TRPV4 have been proposed to function as osmosensors. We herein investigated voluntary water intake immediately induced after an intracerebroventricular administration of a hypertonic NaCl solution in TRPV1-, TRPV4-, Nax-, and their double-gene knockout (KO) mice. The induction of water intake by TRPV1-KO mice was normal, whereas intake by TRPV4-KO and Nax-KO mice was significantly less than that by WT mice. Water intake by Nax/TRPV4-double KO mice was similar to that by the respective single KO mice. When TRPV4 activity was blocked with a specific antagonist HC-067047, water intake by WT mice was significantly reduced, whereas intake by TRPV4-KO and Nax-KO mice was not. Similar results were obtained with the administration of miconazole, which inhibits the biosynthesis of epoxyeicosatrienoic acids (EETs), endogenous agonists for TRPV4, from arachidonic acid (AA). Intracerebroventricular injection of hypertonic NaCl with AA or 5,6-EET restored water intake by Nax-KO mice to the wild-type level but not that by TRPV4-KO mice. These results suggest that the Na(+) signal generated in Nax-positive glial cells leads to the activation of TRPV4-positive neurons in sCVOs to stimulate water intake by using EETs as gliotransmitters. Intracerebroventricular injection of equiosmolar hypertonic sorbitol solution induced small but significant water intake equally in all the genotypes, suggesting the presence of an unknown osmosensor in the brain.

Keywords: Nax; TRPV1; TRPV4; epoxyeicosatrienoic acid; water intake.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite Regulation / physiology
  • Brain / physiology
  • Cerebrospinal Fluid / metabolism*
  • Drinking / genetics*
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Ion Channel Gating / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Signal Transduction* / physiology
  • Sodium / metabolism*
  • TRPV Cation Channels* / genetics
  • TRPV Cation Channels* / metabolism
  • Voltage-Gated Sodium Channels / physiology*


  • Hydroxyeicosatetraenoic Acids
  • Scn7a protein, mouse
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Voltage-Gated Sodium Channels
  • Sodium