CALCIUM CALMODULIN-DEPENDENT PROTEIN KINASE-II REGULATES HIPPOCAMPAL SYNAPTIC TRANSMISSION

Extracellular application of protein kinase inhibitors was used to exa mine the role of calcium/calmodulin-dependent protein kinase II (CaM-K II) in synaptic transmission in the CA1 region of rat hippocampus. Bat h application of the broad spectrum, membrane permeable kinase inhibit or H7 (250 muM) decreased excitatory synaptic responses elicited in hi ppocampal slices. Whereas H7 inhibits several protein kinases and has non-specific effects, several synthetic peptides have been developed a s specific inhibitors of CaM-KII. Using in situ phosphorylation in hip pocampal slices, we demonstrate that extracellular application of synt hetic peptide inhibitors of CaM-KII preferentially suppresses the phos phorylation of synapsin I at the CaM-KII specific site. This suppressi on was not reversed by the application of a calcium ionophore indicati ng the decrease in phosphorylation does not result only from blockade of presynaptic calcium influx. Thus, it appears the peptides gain acce ss to intracellular compartments and retain their inhibitory propertie s. Further, we found that extracellular application of these peptide i nhibitors decreased excitatory synaptic responses elicited in the CA1 region of hippocampal slices with relative potencies consistent with t heir ability to block CaM-KII activity in vitro. Peptide application d id not alter the input resistance of postsynaptic cells nor responses elicited by glutamate iontophoresis. These results suggest that CaM-KI I activity, possibly through phosphorylation of presynaptic synapsin I , is required for sustained synaptic transmission at mammalian synapse s.