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.