Heitzmann Dirk, Koren Viktoria, Wagner Michael, Sterner Christina, Reichold Markus, Tegtmeier Ines, Volk Tilmann, Warth Richard
Institute of Physiology, University of Regensburg.
Cell Physiol Biochem. 2007;19(1-4):21-32. doi: 10.1159/000099189.
BACKGROUND/AIMS: Heteromeric KCNEx/KCNQ1 (=KvLQT1, Kv7.1) K(+) channels are important for repolarization of cardiac myocytes, endolymph secretion in the inner ear, gastric acid secretion, and transport across epithelia. They are modulated by pH in a complex way: homomeric KCNQ1 is inhibited by external acidification (low pH(e)); KCNE2/KCNQ1 is activated; and for KCNE1/KCNQ1, variable effects have been reported.
The role of KCNE subunits for the effect of pH(e) on KCNQ1 was analyzed in transfected COS cells and cardiac myocytes by the patch-clamp technique.
In outside-out patches of transfected cells, hKCNE2/hKCNQ1 current was increased by acidification down to pH 4.5. Chimeras with the acid-insensitive hKCNE3 revealed that the extracellular N-terminus and at least part of the transmembrane domain of hKCNE2 are needed for activation by low pH(e). hKCNE1/hKCNQ1 heteromeric channels exhibited marked changes of biophysical properties at low pH(e): The slowly activating hKCNE1/hKCNQ1 channels were converted into constitutively open, non-deactivating channels. Experiments on guinea pig and mouse cardiac myocytes pointed to an important role of KCNQ1 during acidosis implicating a significant contribution to cardiac repolarization under acidic conditions.
External pH can modify current amplitude and biophysical properties of KCNQ1. KCNE subunits work as molecular switches by modulating the pH sensitivity of human KCNQ1.
背景/目的：异聚体KCNEx/KCNQ1（=KvLQT1，Kv7.1）钾通道对心肌细胞复极化、内耳内淋巴分泌、胃酸分泌以及上皮细胞转运具有重要作用。它们受pH以复杂方式调节：同聚体KCNQ1受细胞外酸化（低pH(e)）抑制；KCNE2/KCNQ1被激活；而对于KCNE1/KCNQ1，已报道有不同的效应。
采用膜片钳技术在转染的COS细胞和心肌细胞中分析KCNE亚基对pH(e)作用于KCNQ1的影响。
在转染细胞的外向膜片中，hKCNE2/hKCNQ1电流在酸化至pH 4.5时增加。与酸不敏感的hKCNE3构建的嵌合体表明，hKCNE2的细胞外N端和至少部分跨膜结构域是低pH(e)激活所必需的。hKCNE1/hKCNQ1异聚通道在低pH(e)时表现出明显的生物物理特性变化：缓慢激活的hKCNE1/hKCNQ1通道转变为组成性开放、不失活的通道。豚鼠和小鼠心肌细胞实验表明，KCNQ1在酸中毒期间起重要作用，这意味着在酸性条件下对心脏复极化有显著贡献。
细胞外pH可改变KCNQ1的电流幅度和生物物理特性。KCNE亚基通过调节人KCNQ1的pH敏感性发挥分子开关的作用。
