Sodium sensing in the brain.

Masaharu Noda,Takeshi Y Hiyama

doi:10.1007/s00424-014-1662-4

Abstract

Sodium (Na) homeostasis is crucial for life, and the Na+ level ([Na+]) of body fluids is strictly maintained at a range of 135–145 mM. However, the existence of a [Na+] sensor in the brain has long been controversial until Nax was identified as the molecular entity of the sensor. This review provides an overview of the [Na+]-sensing mechanism in the brain for the regulation of salt intake by summarizing a series of our studies on Nax. Nax is a Na channel expressed in the circumventricular organs (CVOs) in the brain. Among the CVOs, the subfornical organ (SFO) is the principal site for the control of salt intake behavior, where Nax populates the cellular processes of astrocytes and ependymal cells enveloping neurons. A local expression of endothelin-3 in the SFO modulates the [Na+] sensitivity for Nax activation, and thereby Nax is likely to be activated in the physiological [Na+] range. Nax stably interacts with Na+/K+-ATPase whereby Na+ influx via Nax is coupled with activation of Na+/K+-ATPase associated with the consumption of ATP. The consequent activation of anaerobic glucose metabolism of Nax-positive glial cells upregulates the cellular release of lactate, and this lactate functions as a gliotransmitter to activate GABAergic neurons in the SFO. The GABAergic neurons presumably regulate hypothetic neurons involved in the control of salt intake behavior. Recently, a patient with essential hypernatremia caused by autoimmunity to Nax was found. In this case, the hypernatremia was considered to be induced by the complement-mediated cell death in the CVOs, where Nax specifically populates.

Highlights

Terrestrial animals are exposed to considerable risks of dehydration and salt deficiency, and their life depends on the maintenance of water and salt in the body fluids [3, 4]
The behavioral phenotype of Nax-KO mice was completely recovered by a site-directed transfer of the Nax gene with an adenoviral vector into the subfornical organ (SFO) (Fig. 1c) [33]. These data clearly indicate that the SFO is the primary locus of [Na+] sensing in the brain for the control of salt intake behavior and that Nax plays a critical role in the sensing mechanism
We examined the effects of ET-3 on the [Na+]o dependency of Nax by using the patch clamp method [35]. [Na+]o-sensitive inward currents were observed when the “high Na+ solution” ([Na+]o=170 mM) was applied to Nax-positive SFO cells derived from WT mice [35]

Summary

Introduction

Terrestrial animals are exposed to considerable risks of dehydration and salt deficiency, and their life depends on the maintenance of water and salt in the body fluids [3, 4]. Among the CVOs, only three loci, the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), and area postrema (AP), harbor neuronal cell bodies that have efferent neural connections to many other areas of the brain. Because Nax-KO mice have a normal tasting ability, including that for salt, the behavioral defects in the NaxKO mice were supposed to be attributable to some internal sensing mechanisms for [Na+] in body fluids [65] Consistent with this view, infusion of a hypertonic Na+ solution into the cerebral ventricle did not induce aversion to salt in Nax-KO mice, in contrast to wildtype animals [33]. These data clearly indicate that the SFO is the primary locus of [Na+] sensing in the brain for the control of salt intake behavior and that Nax plays a critical role in the sensing mechanism

Molecular properties of Nax in vitro

Drop counter

Ependymal cell

Lactate signaling from glial cells to neurons

Findings

Future directions