Furin Inhibition as a Mechanism to Reduce Aberrant ENaC‐Mediated Sodium Transport and Rehydrate the Airways in Cystic Fibrosis Lung Disease
Furin Inhibition as a Mechanism to Reduce Aberrant ENaC‐Mediated Sodium Transport and Rehydrate the Airways in Cystic Fibrosis Lung Disease
复制标题
弗林蛋白酶抑制作为减少囊性纤维化肺病中异常 ENaC 介导的钠转运和气道补水的机制
DOI：
10.1096/fasebj.2019.33.1_supplement.802.26
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
S. Martin
中科院分区：
文献类型：
--
作者：
L. Douglas;J. Reihill;M. Ho;J. Axten;S. Martin
上皮钠通道（ENaC）存在于包括肺上皮在内的许多组织中，并且通过其α和γ亚基的蛋白水解裂解而被激活。继发于囊性纤维化（CF）中功能性CFTR丧失的ENaC调节异常导致Na+吸收增加，这有助于气道脱水、粘液增厚和粘膜纤毛清除（MCC）受损。前蛋白转化酶如弗林蛋白酶参与了ENaC通过生物合成途径时不同池的激活（1）。弗林蛋白酶在两个位点切割α-ENaC，从细胞外环释放一个小的抑制肽，部分激活通道，随后切割γ-ENaC。这些作用“启动”了通道，以便通过细胞表面通道活化蛋白酶（如前列腺素、胰蛋白酶和中性粒细胞弹性蛋白酶）在γ亚基上的二级位点进行切割（2-4）。因此，弗林蛋白酶在ENaC介导的钠吸收的蛋白水解调节中起关键作用，并为CF肺病提供了有希望的治疗靶点。
The epithelial sodium channel (ENaC) is found in a number of tissues including lung epithelia and is activated through proteolytic cleavage of its α and γ subunits. Dysregulation of ENaC, secondary to the loss of functional CFTR in cystic fibrosis (CF), leads to increased Na+ absorption which contributes to airways dehydration, thickened mucus and impaired mucociliary clearance (MCC). Pro‐protein convertases such as furin are implicated in the activation of a distinct pool of ENaC as it passes through the biosynthetic pathway (1). Furin cleaves α‐ENaC at two sites releasing a small inhibitory peptide from the extracellular loop, partially activating the channel, and subsequently cleaves γ‐ENaC. These actions ‘prime’ the channel for cleavage at a secondary site on the γ subunit by cell‐surface channel activating proteases such as prostasin, trypsin and neutrophil elastase (2–4). Furin, therefore plays a key role in the proteolytic regulation of ENaC‐mediated sodium absorption and presents a promising therapeutic target for CF lung disease.
DOI：
10.1152/ajplung.00435.2004
发表时间：
2005-05-01
影响因子：
4.9
作者：
Caldwell, RA;Boucher, RC;Stutts, MJ
通讯作者：
Stutts, MJ