Phosphorylation and regulation of glutamate receptors by calcium/calmodulin-dependent protein kinase II

THE major postsynaptic density (PSD) protein 1,2 at glutaminergic synapses is calcium/calmodulin-dependent protein kinase II (CaM-K II), but its function in the PSD is not known. We have examined glutamate receptors (GluRs) as substrates for CaM-K II because (1) they are colocalized in the PSD 3 , (2) cloned GluRs 4–7 contain consensus phosphorylation sites for protein kinases including CaM-K II, and (3) several GluRs are regulated by other protein kinases 8–12 . Regulation of GluRs, which are involved in excitatory synaptic transmission and in mechanisms of learning and memory 13 , by CaM-K II is of interest because of the postulated role of CaM-K II in synaptic plasticity 14,15 and its known involvement in induction of long-term potentiation 16 . Furthermore, mice lacking the major neural isoform of CaM-K II exhibit deficits in models of learning and memory that require hippocampal input 17,18 . We report here that CaM-K II phosphorylates GluR in several in vitro systems, including the PSD, and that activated CaM-K II enhances kainate-induced ion current three- to fourfold in cultured hippocampal neurons. These results are consistent with a role for PSD CaM-K II in strengthening postsynaptic GluR responses in synaptic plasticity.