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

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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.