Gap junctions are specialized matched membrane domains that contain channels that allow exchange of small molecules including ions, metabolites, and second messengers (e.g., Ca2+ and IP3) between neighboring cells. These channels are necessary for proper development, and genetic linkage analyses have implicated connexins in at least 14 human diseases. The gap junction protein connexin43 (Cx43) is regulated by more than 12 phosphorylation events. The short half-life of Cx43 (~2 h) causes gap junctions to be constantly assembled, remodeled and turned over. Growth factors and wounding can further reduce Cx43's half-life and clear gap junctions from the plasma membrane within an hour in a process we term acute turnover. This proposal focuses on the role that Cx43 phosphorylation plays in gap junction stability and how acute turnover is enhanced in response to growth factors and skin wounding. We propose to: (1). determine if increased gap junction size promotes acute turnover; (2). test whether Src phosphorylation of Cx43 is necessary for GJ internalization and directs the endocytic route, and (3). determine the physiological consequences of Cx43 phosphorylation and gap junction turnover during epidermal wounding.
Cx43 phosphorylation regulates biological responses to growth factor treatment and wound repair. Our research could have a large translational impact since Cx43 is a 'drug gable' target currently being investigated for wound healing uses - the tissue on which we have chosen to focus our research. We hypothesize that more targeted drugs such as kinase activators or inhibitors could be topically applied in a manner dictated by the wound status (i.e., fresh, ulcerated, diabetic, etc.) to yield better healing and reduce the need for amputation.
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