Brief periods of cardiac ischemia trigger protection from subsequent prolonged ischemia (preconditioning). Protein kinase C (PKC) has been suggested to mediate preconditioning. Here, we describe an PKC-selective agonist octapeptide, receptor for activated C-kinase (RACK), derived from an PKC sequence homologous to its anchoring protein, RACK. Introduction of RACK into isolated cardiomyocytes, or its postnatal expression as a transgene in mouse hearts, increased PKC translocation and caused cardio-protection from ischemia without any deleterious effects. Our data demonstrate that PKC activation is required for protection from ischemic insult and suggest that small molecules that mimic this PKC agonist octapeptide provide a powerful therapeutic approach to protect hearts at risk for ischemia.preconditioning ͉ hypoxia ͉ transgenic pseudoreceptors for activated C-kinase ͉ ischemia

Signal transduction cascades involve multiple enzymes and are orchestrated by selective protein-protein interactions that are essential for the progression of intracellular signaling events. Modulators of these protein-protein interactions have been used to dissect the role of individual components of each signaling cascade. We describe several methods that have been developed for the identification of peptides that inhibit the interaction between signaling proteins and hence selectively modulate their functions. Such peptide modulators provide important tools for basic research and have great potential as leads for the development of new classes of therapeutic drugs.