Regulation of neuronal gap junctions turnover by LNX-mediated ubiquitination of the neuronal gap junction protein connexin36

一种名为连接蛋白的蛋白质家族在细胞质膜之间的接触处形成通道，允许离子和小分子在细胞之间流动。这些通道聚集在一起形成称为缝隙连接的结构，在人体许多器官的广泛细胞功能中发挥着重要作用。当可电兴奋的细胞之间发生缝隙连接时，包括大脑中的神经元，这些连接由连接蛋白36组成，它们形成所谓的电突触。与化学突触不同，电突触调节神经元之间的直接电通讯。虽然长期以来人们认为高等动物中存在的电突触很少，但最近的研究揭示了在哺乳动物大脑的许多区域中形成这些突触的缝隙连接的普遍性和功能重要性。因为现在人们已经接受了电子突触在大脑认知功能中起着关键作用，所以很容易想象这些突触的故障可能会导致精神障碍。Nagy团队的研究重点是获取有关生化过程的知识，这些过程控制神经元缝隙连接的形成和维持，并调节它们传递电信号的能力。这包括旨在确定与神经元缝隙连接物理相关的蛋白质，并阐明其中一些蛋白质有助于缝隙连接组装和拆卸的机制的研究。一种特殊的蛋白质叫做LNX1，Nagy的研究小组认为，它可能有助于从神经元缝隙连接中移除连接蛋白36。他们已经设计了策略来测试这种移除是通过LNX1与连接蛋白36的物理相互作用发生的，然后修改连接蛋白36的结构，导致连接蛋白的分解或降解。这项工作将提供对控制电突触运行的基本生化机制的理解，这将使人们能够考虑这些突触可能发生故障导致疾病的方式。

A family of proteins called connexins form channels at contacts between cellular plasma membranes and allow the flow of ions and small molecules from cell to cell. These channels aggregate to form structures called gap junctions, which play essential roles in a broad range of cellular functions in many organs of the body. When gap junctions occur between electrically excitable cells, including neurons in the brain where these junctions are composed of connexin36, they form what are called electrical synapses. Unlike chemical synapses, electrical synapses mediate direct electrical communication between neurons. Although it was thought for a long time that very few electrical synapses exist in higher animals, recent studies have revealed both the prevalence and functional importance of gap junctions forming these synapses in many regions of mammalian brain. Because it is now accepted that electrical synapses play a crucial role in brain cognitive functions, it is easy to imagine that malfunction of these synapses could contribute to mental disorders. Research in Nagy's group is focused on acquiring knowledge about biochemical processes that control the formation and maintenance of neuronal gap junctions, and that regulate their capacity to transmit electrical signals. This includes studies aimed to identify proteins that are physically associated with neuronal gap junctions and to elucidate mechanisms whereby some of these proteins contribute to the assembly and disassembly of gap junctions. One protein of particular focus is called LNX1, which Nagy's group believes may contribute to the removal of connexin36 from neuronal gap junctions. They have devised strategies to test the idea that this removal occurs by physical interaction of LNX1 with connexin36, followed by modification of connexin36 structure, leading to the breakdown or degradation of this connexin. This work will provide understanding of the basic biochemical machinery that governs the operation of electrical synapses, which will allow considerations of ways these synapses could malfunction to cause diseases.