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首页> 外文期刊>American Journal of Physiology >Antisense oligonucleotides against the alpha-subunit of ENaC decrease lung epithelial cation-channel activity.
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Antisense oligonucleotides against the alpha-subunit of ENaC decrease lung epithelial cation-channel activity.

机译：针对ENaC的α亚基的反义寡核苷酸会降低肺上皮阳离子通道活性。

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摘要

Amiloride-sensitive Na+ transport by lung epithelia plays a critical role in maintaining alveolar Na+ and water balance. It has been generally assumed that Na+ transport is mediated by the amiloride-sensitive epithelial Na+ channel (ENaC) because molecular biology studies have confirmed the presence of ENaC subunits alpha, beta, and gamma in lung epithelia. However, the predominant Na+-transporting channel reported from electrophysiological studies by most laboratories is a nonselective, high-conductance channel that is very different from the highly selective, low-conductance ENaC reported in other tissues. In our laboratory, single-channel recordings from apical membrane patches from rat alveolar type II (ATII) cells in primary culture reveal a nonselective cation channel with a conductance of 20.6 +/- 1.1 pS and an Na+-to-K+ selectivity of 0.97 +/- 0.07. This channel is inhibited by submicromolar concentrations of amiloride. Thus there is some question about the relationship between the gene product observed with single-channel methods and the cloned ENaC subunits. We have employed antisense oligonucleotide methods to block the synthesis of individual ENaC subunit proteins (alpha, beta, and gamma) and determined the effect of a reduction in the subunit expression on the density of the nonselective cation channel observed in apical membrane patches on ATII cells. Treatment of ATII cells with antisense oligonucleotides inhibited the production of each subunit protein; however, single-channel recordings showed that only the antisense oligonucleotide targeting the alpha-subunit resulted in a significant decrease in the density of nonselective cation channels. Inhibition of the beta- and gamma-subunit proteins alone or together did not cause any changes in the observed channel density. There were no changes in open probability or other channel characteristics. These results support the hypothesis that the alpha-subunit of ENaC alone or in combination with some protein other than the beta- or gamma-subunit protein is the major component of lung alveolar epithelial cation channels.
机译：肺上皮对阿米洛利敏感的Na +转运在维持肺泡Na +和水平衡中起关键作用。由于分子生物学研究已经证实肺上皮中存在ENaC亚基α，β和γ，因此一般认为Na +转运是由阿米洛利敏感的上皮Na +通道（ENaC）介导的。但是，大多数实验室从电生理研究中报告的主要Na +转运通道是非选择性的高电导通道，与其他组织中报道的高度选择性，低电导的ENaC截然不同。在我们的实验室中，原代培养的大鼠肺泡II型（ATII）细胞根尖膜片的单通道记录显示了一个非选择性阳离子通道，其电导率为20.6 +/- 1.1 pS，Na +-K +选择性为0.97 + /-0.07。亚微摩尔浓度的阿米洛利可抑制该通道。因此，关于通过单通道方法观察到的基因产物与克隆的ENaC亚基之间的关系存在一些疑问。我们已采用反义寡核苷酸方法来阻止单个ENaC亚基蛋白（α，β和gamma）的合成，并确定了亚基表达减少对ATII细胞顶膜斑中非选择性阳离子通道密度的影响。 。用反义寡核苷酸处理ATII细胞会抑制每个亚基蛋白的产生。然而，单通道记录显示，仅靶向α-亚基的反义寡核苷酸会导致非选择性阳离子通道密度的显着降低。单独或一起抑制β和γ亚基蛋白不会导致观察到的通道密度发生任何变化。开放概率或其他渠道特征没有变化。这些结果支持这样的假设，即单独或与除β-或γ-亚基蛋白以外的某些蛋白结合的ENaC的α-亚基是肺泡上皮阳离子通道的主要成分。

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