升高的氧化应激有助于晶状体白内障,和间隙连接在保持透镜透明度方面起着重要作用。除了形成间隙连接,连接蛋白(Cx)蛋白也形成半通道。这里,我们报道了一个新的机制,通过这个机制,半通道介导还原性谷胱甘肽向晶状体纤维细胞的转运,并保护细胞免受氧化应激。我们发现Cx50(也称为GJA8)半通道响应于晶状体纤维细胞中的H2O2而打开,但是通过通道的运输被Cx50中的两个显性阴性突变体Cx50P88S抑制,抑制通过缝隙连接和半通道的运输,和Cx50H156N,仅抑制通过半通道而不是缝隙连接的运输。用H2O2处理增加了经历凋亡的成纤维细胞的数量,这种增加被显性阴性突变体增强,这些突变体破坏了由Cx46(也称为GJA3)和Cx50形成的半通道,而Cx50E48K,这只会损害间隙连接,没有这样的效果。此外,半通道介导谷胱甘肽的摄取,这种摄取保护晶状体纤维细胞免受氧化应激,而运输受损的半通道对谷胱甘肽的保护作用较小。一起来看,这些结果表明,氧化应激激活晶状体纤维细胞中的连接蛋白半通道,半通道可能通过转运细胞外还原剂保护晶状体细胞免受氧化损伤。
Elevated oxidized stress contributes to lens cataracts, and gap junctions play important roles in maintaining lens transparency. As well as forming gap junctions, connexin (Cx) proteins also form hemichannels. Here, we report a new mechanism whereby hemichannels mediate transport of reductant glutathione into lens fiber cells and protect cells against oxidative stress. We found that Cx50 (also known as GJA8) hemichannels opened in response to H2O2 in lens fiber cells but that transport through the channels was inhibited by two dominant-negative mutants in Cx50, Cx50P88S, which inhibits transport through both gap junctions and hemichannels, and Cx50H156N, which only inhibits transport through hemichannels and not gap junctions. Treatment with H2O2 increased the number of fiber cells undergoing apoptosis, and this increase was augmented with dominant-negative mutants that disrupted both hemichannels formed from Cx46 (also known as GJA3) and Cx50, while Cx50E48K, which only impairs gap junctions, did not have such an effect. Moreover, hemichannels mediate uptake of glutathione, and this uptake protected lens fiber cells against oxidative stress, while hemichannels with impaired transport had less protective benefit from glutathione. Taken together, these results show that oxidative stress activates connexin hemichannels in the lens fiber cells and that hemichannels likely protect lens cell against oxidative damage through transporting extracellular reductants.