Cells in most tissues are interconnected by gap junction channels, which allow the passage of electrolytes and small molecules from cell to cell. In some excitable cells, these channels are involved in electrical synaptic transmission and/or synchronization of electrical activity. In other tissues, they are thought to pass signal molecules and to couple the cells metabolically. In addition, as recent evidence suggests, some gap junction proteins also form functional hemichannels, that under special circumstances, transiently connect the cytoplasm with the extracellular space. Thus, gap junction proteins may mediate extracellular communication in addition to their classical role of direct cell-to-cell communication. The objective of this research project is to understand the permeation of small ions and molecules including second messengers through gap junction channels and hemichannels formed by pannexin 1. Pannexin 1 is a member of a recently discovered small family of proteins in vertebrates including humans capable of forming hemichannels and gap junction channels in addition to the well characterized connexin family. The first specific aim tests the hypothesis that the selective permeabilities of the channels formed by connexins and pannexins are distinct and thus enable different functions of these proteins. The pore dimensions of pannexin channels will be determined and compared to those of connexin channels.
The second aim tests the hypothesis that connexins and pannexins form channels of generally similar structure with respect to membrane topology and location of pore forming moieties despite a lack of sequence homology.
The third aim i s to identify moieties in the pannexin 1 sequence mediating calcium sensitivity. Pannexin channels are activated by cytoplasmic calcium in the micromolar concentration range which contrasts the inhibition or insensitivity of connexin channels to calcium. Gap junction channels are known to be associated with a series of human diseases. Understanding their molecular function is therefore relevant to the diagnosis and therapy of the diseases. ? ?
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