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首页> 外文期刊>American Journal of Physiology >Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.
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Defining an inhibitory domain in the gamma subunit of the epithelial sodium channel.

机译：在上皮钠通道的γ亚基中定义抑制域。

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摘要

Proteases activate the epithelial sodium channel (ENaC) by cleaving the large extracellular domains of the alpha- and gamma-subunits and releasing peptides with inhibitory properties. Furin and prostasin activate mouse ENaC by cleaving the gamma-subunit at sites flanking a 43 residue inhibitory tract (gammaE144-K186). To determine whether there is a minimal inhibitory region within this 43 residue tract, we generated serial deletions in the inhibitory tract of the gamma-subunit in channels resistant to cleavage by furin and prostasin. We found that partial or complete deletion of a short segment in the gamma-subunit, R158-N171, enhanced channel activity. Synthetic peptides overlapping this segment in the gamma-subunit further identified a key 11-mer tract, R158-F168 (RFLNLIPLLVF), which inhibited wild-type ENaC expressed in Xenopus laevis oocytes, and endogenous channels in mpkCCD cells and human airway epithelia. Further studies with amino acid-substituted peptides defined residues that are required for inhibition in this key 11-mer tract. The presence of the native gamma inhibitory tract in ENaC weakened the intrinsic binding constant of the 11-mer peptide inhibitor, suggesting that the gamma inhibitory tract and the 11-mer peptide interact at overlapping sites within the channel.
机译：蛋白酶通过切割α-和γ-亚基的大细胞外结构域并释放具有抑制特性的肽，从而激活上皮钠通道（ENaC）。弗林蛋白酶和前列素通过在43个残基抑制区（gammaE144-K186）两侧切割γ亚基来激活小鼠ENaC。为了确定在这43个残基区域中是否存在最小的抑制区域，我们在抵抗弗林蛋白酶和前列腺素裂解的通道中的γ亚基抑制区域中产生了一系列缺失。我们发现，γ-亚基R158-N171中短片段的部分或全部缺失，增强了通道活性。在γ亚基中与该段重叠的合成肽进一步鉴定了一个关键的11聚体R158-F168（RFLNLIPLLVF），其抑制非洲爪蟾卵母细胞中表达的野生型ENaC以及mpkCCD细胞和人气道上皮中的内源性通道。用氨基酸取代的肽进行的进一步研究确定了在该关键的11聚体中抑制所需要的残基。 ENaC中天然γ抑制线的存在削弱了11-mer肽抑制剂的内在结合常数，这表明γ-抑制线和11-mer肽在通道内的重叠位点相互作用。

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