Regulation of epithelial electrolyte transporters through protein-protein interactions.
Regulation of epithelial electrolyte transporters through protein-protein interactions.
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通过蛋白质-蛋白质相互作用调节上皮电解质转运蛋白。
DOI：
10.1007/0-387-23752-6_32
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发表时间：
2004
影响因子：
--
通讯作者：
Liedtke,CaroleM
中科院分区：
文献类型：
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作者：
Liedtke,CaroleM
两种Cl转运蛋白，基底外侧Na-K-2Cl（NKCC 1）协同转运蛋白和顶端Cl通道指定的囊性纤维化跨膜调节因子（CFTR），以高度协调的方式起作用以介导气道、汗腺和唾液腺内衬上皮细胞中的盐和水分泌。在气道上皮细胞中，进入传导气道的流体运动加湿吸入的空气，维持纤毛周液层，水合粘液并维持最佳粘液纤毛清除所需的最佳电解质和水稳态。电解质和液体分泌的控制是针对CFTR和NKCC 1的活性，通过细胞内信号传导机制耦合激素和环境刺激的Cl转运蛋白。我们的研究表明，NKCC 1表达在人气管上皮细胞和Calu-3气道上皮细胞系是静止的，直到激活1-肾上腺素能刺激通过效应酶蛋白激酶C（PKC）。最近的研究使用反义方法确定PKC-作为NKCC 1激活所需的PKC同种型。1，2升高cAMP水平的促分泌素迅速激活CFTR。虽然CFTR主要由蛋白激酶A（PKA）调节，但PKC在一定程度上刺激它。我们和其他人现在已经显示了PKC，3-5，特别是PKC亚型对cAMP依赖性CFTR功能的调节。6在同种型水平上，上皮Cl转运蛋白的PKC调节的高度特异性信号传导指向与蛋白质-蛋白质相互作用相关的适当细胞外和细胞内信号传导途径的保真度。在其他细胞中，衔接蛋白、锚定蛋白和支架蛋白的分子网络将激酶和磷酸酶维持在限定的亚细胞区室中。事实上，活性和非活性PKC同种型通过与锚定蛋白或支架蛋白结合而定位在其靶底物附近。8-10在这些研究中，我们研究了PKC-激活NKCC 1和PKC-激活CFTR所必需的蛋白质-蛋白质相互作用。
Two Cl transport proteins, a basolateral Na-K-2Cl (NKCC1) cotransporter and an apical Cl channel designated cystic fibrosis transmembrane regulator (CFTR), act in a highly coordinated manner to mediate salt and water secretion in epithelial cells lining the airways, sweat glands, and salivary glands. In airway epithelial cells, fluid movement into the conducting airways humidifies inspired air, maintains a periciliary fluid layer, hydrates mucus and maintains optimal electrolyte and water homeostasis necessary for optimal mucociliary clearance. Control of electrolyte and fluid secretion is directed at the activity of CFTR and NKCC1 through intracellular signaling mechanisms coupling hormonal and environmental stimuli to the Cl transporter. Our studies demonstrate that NKCC1 expressed in human tracheal epithelial cells and in a Calu-3 airway epithelial cell line is quiescent until activated by 1-adrenergic stimulation through the effector enzyme protein kinase C (PKC). More recent studies using an antisense approach identified PKC-as the PKC isotype required for NKCC1 activation. 1, 2 Secretagogues that elevate cAMP levels rapidly activate CFTR. Although CFTR is regulated primarily by protein kinase A (PKA), PKC stimulates it to a modest extent. We and others have now shown regulation of cAMP-dependent CFTR function by PKC, 3-5 specifically a PKC-isoform. 6 The highly specific signaling of PKC regulation of epithelial Cl transporters at the isotype level points to a fidelity to appropriate extracellular and intracellular signaling pathways associated with protein-protein interactions. In other cells, a molecular network of adapter, anchoring and scaffold proteins maintain kinases and phosphatases in defined subcellular compartments. 7 Indeed, active and inactive PKC isotypes have been localized near their target substrates by binding to anchoring or scaffold proteins. 8-10 In these studies, we examined protein-protein interactions necessary for activation of NKCC1 by PKC-and of CFTR by PKC-.