Block of Lens and Neuronal Gap Junctions by Quinine

缝隙连接通道提供了细胞间通信的途径，允许质量高达1 kDa或直径10-14 nm的离子和小分子通过。在哺乳动物和其他脊椎动物细胞中，缝隙连接通道由一系列称为连接蛋白的蛋白质分子组成。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。缺乏自然产生的阻滞剂，部分原因是缝隙连接无法进入细胞外空间，以及这些通道的大孔径。我们最近发现，奎宁是一种天然存在的小化合物，对某些连接蛋白形成的缝隙连接通道有显著影响，其浓度与其对其他细胞过程的影响相当。本项目中提出的实验将使我们能够了解奎宁的作用机制及其作用于缝隙连接通道的分子基础。这些研究与未来的构效关系研究相结合，可能导致对缝隙连接通道高度特异的阻断剂的鉴定或合成。

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.