Sodium sensing in the brain

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 Na x 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 Na x . Na x 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 Na x 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 Na x activation, and thereby Na x is likely to be activated in the physiological [Na + ] range. Na x stably interacts with Na + /K + -ATPase whereby Na + influx via Na x is coupled with activation of Na + /K + -ATPase associated with the consumption of ATP. The consequent activation of anaerobic glucose metabolism of Na x -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 Na x was found. In this case, the hypernatremia was considered to be induced by the complement-mediated cell death in the CVOs, where Na x specifically populates.