IDENTIFICATION OF THE CA2+ CALMODULIN-DEPENDENT PROTEIN-KINASE-II REGULATORY PHOSPHORYLATION SITE IN THE NO-3-HYDROXYL-5-METHYL-4-ISOXAZOLE-PROPIONATE-TYPE GLUTAMATE-RECEPTOR/

Ca2+/CaM-dependent protein kinase II (CaM-KII) can phosphorylate and p otentiate responses of no-3-hydroxyl-5-methyl-4-isoxazole-propionate-t ype glutamate receptors in a number of systems, and recent studies imp licate this mechanism in long term potentiation, a cellular model of l earning and memory. In this study we have identified this CaM-KII regu latory site using deletion and site-specific mutants of glutamate rece ptor 1 (GluR1). Only mutations affecting Ser(831) altered the P-32 pep tide maps of GluR1 from HEK-298 cells coexpressing an activated CaM-KI I. Likewise, when CaM-KII was infused into cells expressing GluR1, the Ser(831) to Ala mutant failed to show potentiation of the GluR1 curre nt. The Ser(831) site is specific to GluR1, and CaM-KII did not phosph orylate or potentiate current in cells expressing GluR2, emphasizing t he importance of the GluR1 subunit in this regulatory mechanism. Becau se Ser(831) has previously been identified as a protein kinase C phosp horylation site (Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhard t, J., and Huganir, R. L. (1996) Neuron 16, 1179-1188), this raises th e possibility of synergistic interactions between CaM-RII and protein kinase C in regulating synaptic plasticity.