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.