Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture
Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture
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DOI：
10.1152/ajpcell.00547.2002
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发表时间：
2003-06-01
影响因子：
5.5
通讯作者：
Anderson, JM
中科院分区：
文献类型：
--
作者：
Colegio, OR;Van Itallie, C;Anderson, JM
紧密连接（TJ）调节跨上皮细胞的细胞旁渗透性，并且其跨上皮电阻（TER）和电荷选择性变化很大。跨膜蛋白的claudin家族影响这些特性。我们以前报道过，当在低抗性的Madin-Darby犬肾（MDCK）II细胞中表达时，claudin-4使TER增加了约300%，并且使Na+的细胞旁渗透性比Cl-更低（货车Itallie C，Rahner C和安德森JM. J Clin Invest 107：1319 - 1327，2001）。相比之下，我们在此报道了claudin-2的表达仅增加了TER约20%，并且没有改变MDCK II细胞的离子选择性。为了测试密蛋白-4和-2的胞外结构域是否决定其独特的细胞旁性质，我们确定了在密蛋白-4和-2之间互换这些结构域的影响。诱导表达的野生型claudin和细胞外结构域嵌合体增加了纤维的数量和深度，但特征性的纤维形态的claudin-4或-2不改变开关细胞外结构域。像claudin-4一样，在claudin-2上表达claudin-4的第一个或两个胞外结构域的嵌合体使TER增加几倍，并显著降低Na+相对于Cl-的渗透性。相比之下，在密蛋白4上表达密蛋白2的第一个或两个胞外结构域的嵌合体分别仅使TER增加了约60%和约40%，并且仅适度地改变了电荷选择性。这些结果支持了一个模型，其中密封蛋白创建细胞旁通道和第一个胞外结构域是足以确定细胞旁电荷选择性和TER。
Tight junctions ( TJs) regulate paracellular permeability across epithelia and vary widely in their transepithelial electrical resistance (TER) and charge selectivity. The claudin family of transmembrane proteins influences these properties. We previously reported that claudin-4 increased TER similar to300% when expressed in low-resistance Madin-Darby canine kidney (MDCK) II cells and decreased the paracellular permeability for Na+ more than Cl- ( Van Itallie C, Rahner C, and Anderson JM. J Clin Invest 107: 1319 - 1327, 2001). In comparison, we report here that expression of claudin-2 increases TER by only similar to20% and does not change the ionic selectivity of MDCK II cells from their cation-selective background. To test whether the extracellular domains of claudins-4 and - 2 determine their unique paracellular properties, we determined the effects of interchanging these domains between claudins-4 and - 2. Inducible expression of wild-type claudins and extracellular domain chimeras increased both the number and depth of fibrils, but the characteristic fibril morphologies of claudin-4 or - 2 were not altered by switching extracellular domains. Like claudin-4, chimeras expressing the first or both extracellular domains of claudin-4 on claudin-2 increased TER severalfold and profoundly decreased the permeability of Na+ relative to Cl-. In contrast, chimeras expressing the first or both extracellular domains of claudin-2 on claudin-4 increased the TER by only similar to60 and similar to40%, respectively, and only modestly altered charge selectivity. These results support a model in which the claudins create paracellular channels and the first extracellular domain is sufficient to determine both paracellular charge selectivity and TER.