The Na_x channel: What it is and what it does

Na_x, which is preferentially expressed in the glial cells of sensory circumventricular organs in the brain, is a sodium channel that is poorly homologous to voltage-gated sodium channels. We previously reported that Na_x is a sodium concentration ([Na⁺])-sensitive, but not a voltage-sensitive channel that is critically involved in body-fluid homeostasis. Na_x-knockout mice do not stop ingesting salt even when dehydrated and transiently develop hypernatremia. [Na⁺] in body fluids is strictly controlled at 135 to 145 mM in mammals. Although the set point must be within this range, Na_x was shown to have a threshold value of ∼150 mM for extracellular [Na⁺] ([Na⁺]_o) for activation in vitro. Therefore, the [Na⁺]_o dependency of Na_x in vivo is presumably modified by an as yet unidentified mechanism. We recently demonstrated that the [Na⁺]_o dependency of Na_x in the subfornical organ was adjusted to the physiological range by endothelin-3. Pharmacological experiments revealed that endothelin receptor B signaling was involved in this modulation of Na_x gating through protein kinase C and ERK1/2 activation. In addition, we identified a case of essential hypernatremia caused by autoimmunity to Na_x. Occurrence of a ganglioneuroma composed of Schwann-like cells that robustly expressed Na_x was likely to induce the autoimmune response in this patient. An intravenous injection of the immunoglobulin fraction of the patient's serum, which contained anti-Na_x antibodies, into mice reproduced the patient's symptoms. This review provides an overview of the physiological functions of Na_x by summarizing our recent studies.