Directional coupling of oligodendrocyte connexin-47 and astrocyte connexin-43 gap junctions
Directional coupling of oligodendrocyte connexin-47 and astrocyte connexin-43 gap junctions
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DOI：
10.1002/glia.23471
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发表时间：
2018-11-01
期刊：
影响因子：
6.2
通讯作者：
Barrio, Luis C.
中科院分区：
文献类型：
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作者：
Fasciani, Ilaria;Pluta, Paula;Barrio, Luis C.
少突胶质细胞之间、星形胶质细胞之间以及这些细胞类型之间通过间隙连接通道进行的细胞间通讯对于维持中枢神经系统中髓磷脂的完整性至关重要。少突胶质细胞间隙连接连接蛋白 47 (Cx47) 是这种串扰中的关键因素，事实上，人类 Cx47 的突变会导致严重的髓鞘质疾病。然而，单独使用 Cx47 以及与星形胶质细胞 Cx43 异型组合的通道的渗透特性仍不清楚。我们在此表明，Cx47 在 5' 氨基末端含有三个额外的残基，这些残基在通道孔结构中发挥着关键作用，并解释了少突胶质细胞-少突胶质细胞 Cx47 通道相对较低的离子电导率、阳离子渗透选择性和电压门控特性。关于少突胶质细胞-星形胶质细胞耦合，Cx47 与 Cx43 形成的异型通道表现出离子和化学整流，这为离子和较大的带负电分子从表达 Cx47 的细胞到具有 Cx43 的细胞的移动创造了定向扩散屏障。 Cx47 通道的限制性通透性和 Cx47-Cx43 通道的扩散屏障被与脑白质营养不良相关的突变 Cx47P90S 消除，这表明髓鞘质疾病存在一种新的致病机制，涉及神经胶质细胞渗透性的改变。
Intercellular communication via gap junction channels between oligodendrocytes and between astrocytes as well as between these cell types is essential to maintain the integrity of myelin in the central nervous system. Oligodendrocyte gap junction connexin-47 (Cx47) is a key element in this crosstalk and indeed, mutations in human Cx47 cause severe myelin disorders. However, the permeation properties of channels of Cx47 alone and in heterotypic combination with astrocyte Cx43 remain unclear. We show here that Cx47 contains three extra residues at 5 ' amino-terminus that play a critical role in the channel pore structure and account for relative low ionic conductivity, cationic permselectivity and voltage-gating properties of oligodendrocyte-oligodendrocyte Cx47 channels. Regarding oligodendrocyte-astrocyte coupling, heterotypic channels formed by Cx47 with Cx43 exhibit ionic and chemical rectification, which creates a directional diffusion barrier for the movement of ions and larger negatively charged molecules from cells expressing Cx47 to those with Cx43. The restrictive permeability of Cx47 channels and the diffusion barrier of Cx47-Cx43 channels was abolished by a mutation associated with leukodystrophy, the Cx47P90S, suggesting a novel pathogenic mechanism underlying myelin disorders that involves alterations in the panglial permeation.