AS160 modulates aldosterone-stimulated epithelial sodium channel forward trafficking.
AS160 modulates aldosterone-stimulated epithelial sodium channel forward trafficking.
复制标题
AS160 调节醛固酮刺激的上皮钠通道正向运输。
DOI：
10.1091/mbc.e10-01-0042
复制
发表时间：
2010-06-15
影响因子：
3.3
通讯作者：
Frizzell RA
中科院分区：
文献类型：
--
作者：
Liang X;Butterworth MB;Peters KW;Frizzell RA
AS 160有助于确定ENaC在基础条件下积聚的细胞内区室，并且醛固酮通过SGK介导的AS 160磷酸化进入该区室，以允许ENaC向前运输至顶膜。醛固酮诱导的顶端膜上皮钠通道（ENaC）密度和Na转运增加涉及14-3-3蛋白表达的诱导及其与Nedd 4 -2（血清和糖皮质激素诱导激酶（SGK 1）介导的磷酸化的底物）的相关性。在醛固酮处理的皮质集合管（CCD）细胞中寻找其他14-3-3结合蛋白，鉴定了Rab-GAP，AS 160，一种Akt/PKB底物，其磷酸化有助于响应胰岛素将GLUT 4转运蛋白募集到脂肪细胞质膜。在CCD上皮细胞中，醛固酮（10 nM，24 h）使AS 160蛋白表达增加3倍，时间过程与SGK 1表达增加相似。在缺乏醛固酮的情况下，AS 160过表达使总ENaC表达增加2.5倍，但不增加顶膜ENaC或阿米洛利敏感性钠电流（Isc）。然而，在AS 160过表达的上皮细胞中，醛固酮使顶端ENaC和Isc相对于单独的醛固酮增加2.5倍，从而将累积的ENaC募集到顶端膜。相反，AS 160敲低增加了基础条件下的顶膜ENaC和Isc至醛固酮刺激值的80%，进一步减弱了类固醇效应。醛固酮在5个位点诱导AS 160磷酸化，主要在SGK 1位点T568和S751，并诱发AS 160与类固醇诱导的14-3-3亚型β和ε结合。SGK 1磷酸化位点的AS 160突变阻断了其与14-3-3β和ε的选择性相互作用，并抑制了表达的AS 160增强醛固酮作用的能力。这些发现表明，Rab蛋白调节剂，AS 160，稳定ENaC在基础条件下的调节细胞内室，和醛固酮/SGK 1依赖性AS 160磷酸化允许ENaC向前运输到顶端膜，以增加钠的吸收。
AS160 assists in defining an intracellular compartment in which ENaC accumulates under basal conditions, and this compartment is accessed by aldosterone, via SGK-mediated phosphorylation of AS160, to permit the forward trafficking of ENaC to the apical membrane. Aldosterone-induced increases in apical membrane epithelial sodium channel (ENaC) density and Na transport involve the induction of 14-3-3 protein expression and their association with Nedd4-2, a substrate of serum- and glucocorticoid-induced kinase (SGK1)-mediated phosphorylation. A search for other 14-3-3 binding proteins in aldosterone-treated cortical collecting duct (CCD) cells identified the Rab-GAP, AS160, an Akt/PKB substrate whose phosphorylation contributes to the recruitment of GLUT4 transporters to adipocyte plasma membranes in response to insulin. In CCD epithelia, aldosterone (10 nM, 24 h) increased AS160 protein expression threefold, with a time-course similar to increases in SGK1 expression. In the absence of aldosterone, AS160 overexpression increased total ENaC expression 2.5-fold but did not increase apical membrane ENaC or amiloride-sensitive Na current (Isc). In AS160 overexpressing epithelia, however, aldosterone increased apical ENaC and Isc 2.5-fold relative to aldosterone alone, thus recruiting the accumulated ENaC to the apical membrane. Conversely, AS160 knockdown increased apical membrane ENaC and Isc under basal conditions to ∼80% of aldosterone-stimulated values, attenuating further steroid effects. Aldosterone induced AS160 phosphorylation at five sites, predominantly at the SGK1 sites T568 and S751, and evoked AS160 binding to the steroid-induced 14-3-3 isoforms, β and ε. AS160 mutations at SGK1 phospho-sites blocked its selective interaction with 14-3-3β and ε and suppressed the ability of expressed AS160 to augment aldosterone action. These findings indicate that the Rab protein regulator, AS160, stabilizes ENaC in a regulated intracellular compartment under basal conditions, and that aldosterone/SGK1-dependent AS160 phosphorylation permits ENaC forward trafficking to the apical membrane to augment Na absorption.
登录
查看更多内容
影响因子：
9.8
作者：
Gherzi R;Trabucchi M;Ponassi M;Ruggiero T;Corte G;Moroni C;Chen CY;Khabar KS;Andersen JS;Briata P
通讯作者：
Briata P
DOI：
10.1164/rccm.200708-1233oc
发表时间：
2008-04-01
影响因子：
24.7
作者：
Mall, Marcus A.;Harkema, Jack R.;Boucher, Richard C.
通讯作者：
Boucher, Richard C.
DOI：
10.1152/ajprenal.00422.2005
发表时间：
2006-09-01
影响因子：
4.2
作者：
Ergonul, Zuhal;Frindt, Gustavo;Palmer, Lawrence G.
通讯作者：
Palmer, Lawrence G.
影响因子：
4.8
作者：
Butterworth, Michael B.;Edinger, Robert S.;Frizzell, Raymond A.
通讯作者：
Frizzell, Raymond A.
影响因子：
4.1
作者：
Mîinea, CP;Sano, H;Lienhard, GE
通讯作者：
Lienhard, GE