Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA.
FASEB J. 2011 Feb;25(2):727-36. doi: 10.1096/fj.10-173682. Epub 2010 Nov 17.
Targeted deletion of the Kcne2 potassium channel β subunit gene ablates gastric acid secretion and predisposes to gastric neoplasia in mice. Here, we discovered that Kcne2 deletion basolaterally reroutes the Kcnq1 α subunit in vivo in parietal cells (PCs), in which the normally apical location of the Kcnq1-Kcne2 channel facilitates its essential role in gastric acid secretion. Quantitative RT-PCR and Western blotting revealed that Kcne2 deletion remodeled fundic Kcne3 (2.9±0.8-fold mRNA increase, n=10; 5.3±0.4-fold protein increase, n=7) but not Kcne1, 4, or 5, and resulted in basolateral Kcnq1-Kcne3 complex formation in Kcne2(-/-) PCs. Concomitant targeted deletion of Kcne3 (creating Kcne2(-/-)Kcne3(-/-) mice) restored PC apical Kcnq1 localization without Kcne1, 4, or 5 remodeling (assessed by quantitative RT-PCR; n=5-10), indicating Kcne3 actively, basolaterally rerouted Kcnq1 in Kcne2(-/-) PCs. Despite this, Kcne3 deletion exacerbated gastric hyperplasia in Kcne2(-/-) mice, and both hypochlorhydria and hyperplasia in Kcne2(+/-) mice, suggesting that Kcne3 up-regulation was beneficial in Kcne2-depleted PCs. The findings reveal, in vivo, Kcne-dependent α subunit polarized trafficking and the existence and consequences of potassium channel β subunit remodeling.
靶向敲除 Kcne2 钾通道 β 亚基基因可消除胃酸分泌并使小鼠易发生胃肿瘤。在此，我们发现 Kcne2 缺失使壁细胞（PC）中 Kcnq1α 亚基基底外侧重新定向，而 Kcnq1-Kcne2 通道通常位于顶端位置，有利于其在胃酸分泌中的重要作用。定量 RT-PCR 和 Western blot 显示 Kcne2 缺失重塑了胃底的 Kcne3（mRNA 增加 2.9±0.8 倍，n=10；蛋白增加 5.3±0.4 倍，n=7），但不影响 Kcne1、4 或 5，导致 Kcne2(-/-)PC 中基底外侧 Kcnq1-Kcne3 复合物的形成。同时靶向敲除 Kcne3（产生 Kcne2(-/-)Kcne3(-/-)小鼠）恢复了 PC 顶端的 Kcnq1 定位，而没有 Kcne1、4 或 5 的重塑（通过定量 RT-PCR 评估；n=5-10），表明 Kcne3 主动地将 Kcnq1 基底外侧重新定向到 Kcne2(-/-)PC 中。尽管如此，Kcne3 的缺失加剧了 Kcne2(-/-)小鼠的胃增生，以及 Kcne2(+/-)小鼠的低胃酸分泌和增生，表明 Kcne3 的上调在 Kcne2 耗尽的 PC 中是有益的。这些发现揭示了体内 Kcne 依赖性 α 亚基极化运输以及钾通道 β 亚基重塑的存在和后果。
