PKC signalling and cell-cell communication

Washington University, Saint Louis MO

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Under physiological conditions, cardiac myocytes are well coupled ensuring rapid conduction. Under pathophysiological conditions, however, myocytes become uncoupled, an adaptive response that limits the intercellular spread of noxious metabolites. PKC-epsilon null (PKCe-KO) mice, isoform-specific PKC activator and inhibitor peptides, adenoviruses expressing PKC isoforms, and phospho-specific anti-Cx43 and -PKC antibodies will be used to identify PKC isoforms and elucidate molecular events regulating gap junction channel function and Cx43 (the major ventricular gap junction protein) expression under physiological conditions and in response to ischemia. Preliminary studies show that ischemia leads to increased phosphorylation of Cx43 at the PKC site Ser368 in both wildtype and PKCe-KO hearts. Furthermore, PKCe-KO hearts show increased expression of Cx43 under basal (non-ischemic) conditions, but exhibit more dramatic loss of Cx43 in gap junctions in response to ischemia compared to wildtype. These studies will yield new insights into mechanisms of arrhythmias in patients with ischemic heart disease and contribute to efforts to develop new therapies to prevent arrhythmias in these patients. [unreadable] [unreadable] [unreadable]