MECHANISM OF PROTEIN-KINASE-C ACTIVATION DURING THE INDUCTION AND MAINTENANCE OF LONG-TERM POTENTIATION PROBED USING A SELECTIVE PEPTIDE SUBSTRATE

Previous reports using various protein kinase inhibitors have suggeste d that protein kinase activity is necessary for both the induction and maintenance of hippocampal long-term potentiation (LTP), a cellular p henomenon likely to contribute to mammalian memory formation. We desig ned and characterized a selective peptide substrate for protein kinase C (PKC), corresponding to amino acids 28 to 43 of the neuronal protei n neurogranin, and used the substrate to obtain direct biochemical evi dence for activation of PKC in both the induction and maintenance phas es of LTP. As the effect cannot be accounted for by either of two well -known mechanisms for persistent PKC activation, membrane insertion, o r proteolysis, the persistent activation of PKC in the maintenance pha se of LTP appears to occur via another mechanism. The maintenance phas e of LTP is associated with decreased immunoreactivity of PKC, an effe ct that can be reversed with phosphatase treatment. Thus, PKC appears to be both phosphorylated and persistently activated in the maintenanc e phase of LTP.