title: The Na(x) Channel: What It Is and What It Does.
abstract: 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.
authors: Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki, Japan School of Life Science, The Graduate University for Advanced Studies, Okazaki, Japan madon@nibb.ac.jp.
authors: Masaharu
authors: M
authors: Noda
authors: Division of Molecular Neurobiology, National Institute for Basic Biology, Okazaki, Japan School of Life Science, The Graduate University for Advanced Studies, Okazaki, Japan.
authors: Takeshi Y
authors: TY
authors: Hiyama
mesh_terms: D000818:Animals; D001826:Body Fluids / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D066280:Circumventricular Organs / Q000378:metabolism / Q000502:physiology*; D019334:Endothelin-3 / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006955:Hypernatremia / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D019334:Endothelin-3; D015222:Sodium Channels; D012964:Sodium
keywords: Na-level sensor; Nax channel; autoimmune channelopathy; body-fluid homeostasis; endothelin; essential hypernatremia; paraneoplastic neurologic disorder