PDF(Pubmed)
Abstract：
Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.
摘要：
连接蛋白半通道被鉴定为真核大孔通道家族的第一个成员，该家族介导原子离子和小分子在细胞内和细胞外环境之间的渗透。常规观点是它们的孔是大的被动导管,离子和分子都以类似的方式通过其扩散。与这个概念形成鲜明对比的是，我们证明了连接蛋白半通道中离子和分子的渗透可以解偶联和差异调节。我们发现，人类连接蛋白突变会产生病理，并且以前被认为是由于缺乏离子电流而导致的功能丧失突变，仍然能够介导分子的被动运输，其动力学接近野生型通道。这种分子传输在微摩尔范围内显示出饱和度，选择性,和竞争性抑制，通过渗透分子和位于孔内的N末端结构域之间的特定相互作用来调节的特性-大孔通道的一般特征。我们建议连接蛋白半通道，很可能,其他大孔隙通道,是杂合通道/转运蛋白样蛋白，可能在这两种模式之间切换以促进健康和疾病过程中的选择性离子传导或自分泌/旁分泌分子信号传导。
