Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, 13125 Berlin, Germany.
J Biol Chem. 2010 Mar 5;285(10):7165-75. doi: 10.1074/jbc.M109.047829. Epub 2010 Jan 5.
The KCNE3 beta-subunit constitutively opens outwardly rectifying KCNQ1 (Kv7.1) K(+) channels by abolishing their voltage-dependent gating. The resulting KCNQ1/KCNE3 heteromers display enhanced sensitivity to K(+) channel inhibitors like chromanol 293B. KCNE3 was also suggested to modify biophysical properties of several other K(+) channels, and a mutation in KCNE3 was proposed to underlie forms of human periodic paralysis. To investigate physiological roles of KCNE3, we now disrupted its gene in mice. kcne3(-/-) mice were viable and fertile and displayed neither periodic paralysis nor other obvious skeletal muscle abnormalities. KCNQ1/KCNE3 heteromers are present in basolateral membranes of intestinal and tracheal epithelial cells where they might facilitate transepithelial Cl(-) secretion through basolateral recycling of K(+) ions and by increasing the electrochemical driving force for apical Cl(-) exit. Indeed, cAMP-stimulated electrogenic Cl(-) secretion across tracheal and intestinal epithelia was drastically reduced in kcne3(-/-) mice. Because the abundance and subcellular localization of KCNQ1 was unchanged in kcne3(-/-) mice, the modification of biophysical properties of KCNQ1 by KCNE3 is essential for its role in intestinal and tracheal transport. Further, these results suggest KCNE3 as a potential modifier gene in cystic fibrosis.
β亚基 KCNE3 通过消除电压依赖性门控作用，使外向整流型 KCNQ1 (Kv7.1) K(+)通道持续开放。由此产生的 KCNQ1/KCNE3 异源二聚体对 K(+)通道抑制剂（如 chromanol 293B）的敏感性增强。KCNE3 还被认为可以改变其他几种 K(+)通道的生物物理特性，并且 KCNE3 的突变被认为是人类周期性麻痹的基础。为了研究 KCNE3 的生理作用，我们现在在小鼠中敲除了其基因。kcne3(-/-) 小鼠具有活力和生育能力，既没有周期性麻痹，也没有其他明显的骨骼肌异常。KCNQ1/KCNE3 异源二聚体存在于肠道和气管上皮细胞的基底外侧膜中，它们可能通过基底外侧 K(+)离子的再循环促进跨上皮 Cl(-)分泌，并通过增加顶端 Cl(-)外排的电化学驱动力来实现。事实上，cAMP 刺激的跨气管和肠道上皮的电致 Cl(-)分泌在 kcne3(-/-) 小鼠中明显减少。由于 kcne3(-/-) 小鼠中 KCNQ1 的丰度和亚细胞定位没有改变，因此 KCNE3 对 KCNQ1 生物物理特性的修饰对于其在肠道和气管转运中的作用是必不可少的。此外，这些结果表明 KCNE3 可能是囊性纤维化的潜在修饰基因。
