Barbry P, Champigny G, Lingueglia E, Voilley N, Waldmann R, Lazdunski M
Institut de pharmacologie moléculaire et cellulaire, CNRS, Valbonne.
Nephrologie. 1996;17(7):389-93.
The amiloride-sensitive epithelial Na+ channel is formed by the assembly of three homologous subunits alpha, beta and gamma. The channel is characterized by its sensitivity to amiloride and to some amiloride derivatives, such as phenamil and benzamil, by its small unitary conductance (approximately 5pS), by its high selectivity for lithium and sodium, and by its slow kinetics. The alpha, beta, and gamma proteins share significant identity with degenerins, a family of proteins found in the mechanosensory neurons and interneurons of the nematode Caenorhabditis elegans. They are also homologous to FaNaCh, a protein from Helix aspersa nervous tissues, which corresponds to a neuronal ionotropic receptor for the Phe-Met-Arg-Phe-amide peptide. All these proteins contain a large extracellular loop, located between two transmembrane alpha-helices. The NH2 and COOH terminal segments are cytoplasmic, and contain potential regulatory segments that are able to modulate the activity of the channel. In Liddle syndrome, in which patients develop a form of genetic hypertension, mutations within the cytoplasmic COOH terminal of the beta and gamma chains of the epithelial Na+ channel lead to a hyper-activity of the channel. Epithelial Na+ channel activity is tightly controlled by several distinct hormonal systems, including corticosteroids and vasopressin. In kidney and colon, aldosterone is the major sodium-retaining hormone, acting, by stimulation of Na+ reabsorption through the epithelium. In the distal colon from steroid-treated animals, a large increase of the beta and gamma subunits transcription is observed, whereas the alpha subunit remains constitutively transcribed. In kidney, RNA levels of the three subunits are not significantly altered by aldosterone, suggesting that other mechanisms control Na+ channel activity in that tissue. In lung, the glucocorticoids are the positive regulators of the channel activity, especially around birth, and act via an increased transcription of the three subunits.
氨氯地平敏感的上皮钠通道由三个同源亚基α、β和γ组装而成。该通道的特点是对氨氯地平和一些氨氯地平衍生物（如苯甲米利和苄米利）敏感，其单通道电导较小（约5pS），对锂和钠具有高选择性，且动力学缓慢。α、β和γ蛋白与退化蛋白有显著的同源性，退化蛋白是在线虫秀丽隐杆线虫的机械感觉神经元和中间神经元中发现的一类蛋白。它们也与来自欧洲大蜗牛神经组织的蛋白FaNaCh同源，FaNaCh对应于苯丙氨酸-甲硫氨酸-精氨酸-苯丙氨酸-酰胺肽的神经元离子型受体。所有这些蛋白都包含一个位于两个跨膜α螺旋之间的大细胞外环。NH2和COOH末端片段位于细胞质中，包含能够调节通道活性的潜在调节片段。在利德尔综合征中，患者会出现一种遗传性高血压，上皮钠通道β和γ链的细胞质COOH末端内的突变会导致通道活性增强。上皮钠通道活性受到几种不同激素系统的严格控制，包括皮质类固醇和血管加压素。在肾脏和结肠中，醛固酮是主要的保钠激素，通过刺激上皮细胞对钠的重吸收发挥作用。在经类固醇处理的动物的远端结肠中，观察到β和γ亚基的转录大幅增加，而α亚基则持续转录。在肾脏中，醛固酮不会显著改变这三个亚基的RNA水平，这表明在该组织中存在其他控制钠通道活性的机制。在肺中，糖皮质激素是通道活性的正调节因子，尤其是在出生前后，通过增加这三个亚基的转录发挥作用。
