A Single Amino Acid Tunes Ca2+ Inhibition of Brain Liver Intestine Na+ Channel (BLINaC)
A Single Amino Acid Tunes Ca2+ Inhibition of Brain Liver Intestine Na+ Channel (BLINaC)
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DOI：
10.1074/jbc.m110.153064
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Gruender, Stefan
中科院分区：
文献类型：
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作者：
Wiemuth, Dominik;Gruender, Stefan
退变蛋白/上皮Na+通道基因家族的离子通道是被利尿剂阿米洛利阻断的Na+通道，并且与几种人类疾病有关。脑肝肠Na+通道（BLINaC）是变性蛋白/上皮Na+通道基因家族的一个功能未知的离子通道。在啮齿类动物中，它主要在脑、肝和肠中表达，在肾和肺中表达程度较低。大鼠BLINaC（rBLINaC）在非洲爪蟾卵母细胞中的表达导致小的非选择性电流，仅对阿米洛利弱敏感。在这里，我们表明，rBLINaC被细胞外Ca 2+的微摩尔浓度抑制。去除Ca 2+导致强大的电流，并增加离子孔的Na+选择性。引人注目的是，来自小鼠的物种直向同源物（mBLINaC）具有比rBLINaC低几乎250倍的Ca 2+亲和力，使得mBLINaC在细胞外Ca 2+的生理浓度下组成型活性。此外，mBLINaC对Na+的选择性更高，并且具有比rBLINaC高700倍的阿米洛利亲和力。我们表明，细胞外结构域中的一个氨基酸决定了这些深刻的物种差异。总的来说，我们的研究结果表明，rBLINaC是开放的未知配体，而mBLINaC是一个组成性开放的上皮Na+通道。
Ion channels of the degenerin/epithelial Na+ channel gene family are Na+ channels that are blocked by the diuretic amiloride and are implicated in several human diseases. The brain liver intestine Na+ channel (BLINaC) is an ion channel of the degenerin/epithelial Na+ channel gene family with unknown function. In rodents, it is expressed mainly in brain, liver, and intestine, and to a lesser extent in kidney and lung. Expression of rat BLINaC (rBLINaC) in Xenopus oocytes leads to small un-selective currents that are only weakly sensitive to amiloride. Here, we show that rBLINaC is inhibited by micromolar concentrations of extracellular Ca2+. Removal of Ca2+ leads to robust currents and increases Na+ selectivity of the ion pore. Strikingly, the species ortholog from mouse (mBLINaC) has an almost 250-fold lower Ca2+ affinity than rBLINaC, rendering mBLINaC constitutively active at physiological concentrations of extracellular Ca2+. In addition, mBLINaC is more selective for Na+ and has a 700-fold higher amiloride affinity than rBLINaC. We show that a single amino acid in the extracellular domain determines these profound species differences. Collectively, our results suggest that rBLINaC is opened by an unknown ligand whereas mBLINaC is a constitutively open epithelial Na+ channel.