CaM kinase II in long-term potentiation

The observation that autophosphorylation converts CaM kinase II from the Ca²⁺-dependent form to the Ca²⁺-independent form has led to speculation that the formation of the Ca²⁺-independent form of the enzyme could encode frequency of synaptic usage and serve as a molecular explanation of 'memory'. In cultured rat hippocampal neurons, glutamate elevated the Ca²⁺-independent activity of CaM kinase II through autophosphorylation, and this response was blocked by an NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate (AP5). In addition, we confirmed that high, but not low frequency stimulation, applied to two groups of CA1 afferents in the rat hippocampus, resulted in LTP induction with concomitant long-lasting increases in Ca²⁺-independent and total activities of CaM kinase II. In experiments with ³²P-labeled hippocampal slices, the LTP induction in the CA1 region was associated with increases in autophosphorylation of both α and β subunits of CaM kinase II 1 h after LTP induction. Significant increases in phosphorylation of endogenous CaM kinase II substrates, synapsin I and microtubule-associated protein 2 (MAP2), which are originally located in presynaptic and postsynaptic regions, respectively, were also observed in the same slice. All these changes were prevented when high frequency stimulation was applied in the presence of AP5 or a calmodulin antagonist, calmidazolium. Furthermore, in vitro phosphorylation of the AMPA receptor by CaM kinase II was reported in the postsynaptic density and infusion of the constitutively active CaM kinase II into the hippocampal neurons enhanced kainate-induced response. These results support the idea that CaM kinase II contributes to the induction of hippocampal LTP in both postsynaptic and presynaptic regions through phosphorylation of target proteins such as the AMPA receptor, MAP2 and synapsin I.