Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers.
Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers.
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DOI：
10.1016/j.biomaterials.2015.03.007
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发表时间：
2015-06
期刊：
影响因子：
14
通讯作者：
Christian Staat;Caroline Coisne;S. Dąbrowski;S. Stamatovic;A. Andjelkovic;H. Wolburg;B. Engelhardt
中科院分区：
文献类型：
--
作者：
Christian Staat;Caroline Coisne;S. Dąbrowski;S. Stamatovic;A. Andjelkovic;H. Wolburg;B. Engelhardt
在上皮/内皮屏障中，紧密连接蛋白形成紧密连接，密封细胞旁裂隙，并限制溶质和药物的摄取。来自claudin-1第一个细胞外环的C末端一半的肽模拟物C1C2增加了通过上皮claudin-1屏障的药物递送。然而，其分子和结构作用模式仍然未知。在本研究中，>100 μM C1C2 导致具有不同密蛋白成分（从上皮细胞到内皮细胞）的各种屏障的细胞旁开放，优先调节claudin-1和claudin-5。孵育 6 小时后，C1C2 可逆地增加了对不同大小分子的渗透性；这伴随着claudins和occludin从连接处重新分布到细胞质。 C1C2 在上皮细胞中的内化取决于claudin-1 表达和网格蛋白途径，因此大多数 C1C2 保留在 recyclosomes > 2 h 中。在冷冻断裂电子显微镜下，C1C2 将claudin-1 紧密连接链改变为更加平行的排列，并将claudin-5 链从E 面关联改为P 面——这是巨大而新颖的效果。总之，C1C2 在密蛋白存在下大部分被回收，这解释了屏障和连接损失的延迟发生、所需的高肽浓度和持久的效果。上皮/内皮屏障通过claudin-1/claudin-5进行特异性调节，可以有针对性地改善药物输送。
In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association – drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.