SPECIFICITY OF PROTEIN-KINASE INHIBITOR PEPTIDES AND INDUCTION OF LONG-TERM POTENTIATION

Previous studies have used synthetic peptide analogs, corresponding to sequences within the pseudosubstrate domain of protein kinase C (PKC) or the autoregulatory domain of Ca2+/calmodulin-dependent protein kin ase II (CaMKII), in attempts to define the contribution of each of the se protein kinases to induction of long-term potentiation (LTP). Howev er, the specificity of these inhibitor peptides is not absolute. Using intracellular delivery to rat CA1 hippocampal neurons, we have determ ined the relative potency of two protein kinase inhibitor peptides, PK C-(19-36) and [Ala(286)]CaMKII-(281-302), as inhibitors of the inducti on of LTP. Both peptides blocked the induction of LTP; however, PKC-(1 9-36) was 30-fold more potent than [Ala(286)]CaMKII-(281-302). The rel ative specificity of PKC-(19-36), [Ala(286)]CaMKII-(281-302), and seve ral other CaMKII peptide analogs for protein kinase inhibition in vitr o was also determined. A comparison of the potencies of PKC-(19-36) an d [Ala(286)]CaMKII-(281-302) in the physiological assay with their K-i values for protein kinase inhibition in vitro indicates that the bloc kade of induction of LTP observed for each peptide is attributable to inhibition of PKC.