Block of Lens and Neuronal Gap Junctions by Quinine

间隙连接通道提供细胞间通信的途径，允许离子和小分子通过，质量可达1kda，直径可达10- 14nm。在哺乳动物和其他脊椎动物细胞中，缝隙连接通道是由称为连接蛋白的蛋白质分子家族组成的。确定由各种连接蛋白形成的通道的作用是一个正在进行的研究领域。研究缝隙连接通道的一个问题是缺乏特异性和选择性的阻滞剂。天然阻滞剂的缺乏部分归因于细胞外间隙连接的不可接近性和这些通道的大孔径。我们最近发现，奎宁是一种天然存在的小化合物，它对某些连接蛋白形成的间隙连接通道具有显著的影响，其浓度与对其他细胞过程的影响相当。本课题提出的实验将使我们了解奎宁的作用机理及其作用于间隙连接通道的分子基础。这些研究与未来的结构-活性研究相结合，可能会导致鉴定或合成一种对间隙连接通道具有高度特异性的阻断剂。

Gap junction channels provide pathways of intercellular communication=, allowing the passage of ions and small molecules up to 1 kDa in mass or 10-14 nm in diameter. In mammalian and other vertebrate cells, gap junction channels are composed of a family of protein molecules known as connexins. Determination of the roles of channels formed by various connexins is an ongoing area of investigation. One problem with studying gap junction channels is the lack of blockers that are specific and selective. The lack of naturally occurring blockers has in part been attributed to the inaccessibility of gap junctions to extracellular space and the large pore size of these channels. We recently discovered that quinine, a small naturally occurring compound, has significant effects on gap junction channels formed of certain connexins at concentrations comparable to its effect on other cellular processes. The experiments proposed in this project will enable us to understand the mechanism of action of quinine and molecular basis for its action on gap junction channels. These studies combined with future structure-activity studies may lead to the identification or synthesis of a blocking agent that is highly specific for gap junction channels.