Activation of CA(2+)/calmodulin-dependent protein kinase IV in cultured rat hippocampal neurons

Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) is a multifunctional enzyme that is abundantly present in the nuclei of neurons. We report the properties of phosphorylation and activation of CaM kinase IV in comparison to CaM kinase II in cultured rat hippocampal neurons. Phosphorylation and activity of CaM kinase IV as well as CaM kinase II were increased by treatment of neurons either with glutamate or high K(+). Glutamate-induced phosphorylation and activity of CaM kinase IV were blocked by N-methyl-D-asparate (NMDA) antagonists, and NMDA application instead of glutamate did increase CaM kinase IV phosphorylation. CaM kinase IV phosphorylation was also increased by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and was blocked by an inhibitor of NMDA receptor. The AMPA-induced phosphorylation was blocked by tetrodotoxin, a Na(+) channel blocker, that was expected to block endogenous glutamate transmission indirectly. On the other hand, high K(+)-induced phosphorylation and activation were not blocked by inhibitors of glutamate receptors, and effectively blocked by nifedipine, an L-type Ca(2+) channel blocker. These properties were similar between CaM kinase IV and CaM kinase II.