Gap junctional communication is critically ? important in many cell processes including control of cell proliferation, ? embryonic development, and cell differentiation. These pathways provide for ? cell-to-cell diffusion of small molecules (<1000 Da) including ions, ? metabolites, and second messengers. In vertebrates, gap junctions are composed ? of proteins from the connexin family, which contains over a dozen members. ? Channels composed of different connexins can be opened or closed to varying ? degrees by changes in transjunctional voltage, pH, and phosphorylation. This ? proposal is focused on connexins 43 (Cx43) and 45 for several reasons; both are ? known to be phosphorylated on multiple serines, both are positively/negatively ? regulated by kinase effectors such as TPA, however, they have very different ? conducting properties and share little sequence homology in the cytoplasmic ? tail region aside from a series of double serine repeats. This proposal ? examines the role of phosphorylation in the regulation of these gap junction ? proteins and the channels that they form. We hypothesize that in addition to ? effects on gating, phosphorylation is important for the regulation of other ? aspects of Cx43's """"""""life cycle"""""""" (i.e., connexin oligomerization, connexin ? trafficking, gap junction assembly, and protein turnover).
Our specific aims ? are to (1) determine the phosphorylation events within Cx43 and Cx45, which ? regulate connexin trafficking, gap junction assembly, gating and turnover in ? homeostatic cells. (2) Characterize kinases that bind to and regulate connexin ? function. (3) Determine the cell cycle dependent changes in connexin ? phosphorylation that allow connexin redistribution during mitosis. We plan to ? apply our knowledge of connexin phosphorylation and phosphorylation specific ? probes to the analysis of connexin status in wounded skin and the remodeling of ? gap junctions during heart disease. ? ?
Showing the most recent 10 out of 79 publications
