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Abstract
Ca2+/CaM-dependent protein kinase II (CaM-KII) can phosphorylate and potentiate responses of alpha-amino3-hydroxyl-5-methyl-4-isoxazole-propionate-type glutamate receptors in a number of systems, and recent studies implicate this mechanism in long term potentiation, a cellular model of learning and memory. In this study we have identified this CaM-KII regulatory site using deletion and site-specific mutants of glutamate receptor 1 (GluR1). Only mutations affecting Ser831 altered the 32P peptide maps of GluR1 from HEK-293 cells co-expressing an activated CaM-KII. Likewise, when CaM-KII was infused into cells expressing GluR1, the Ser831 to Ala mutant failed to show potentiation of the GluR1 current. The Ser831 site is specific to GluR1, and CaM-KII did not phosphorylate or potentiate current in cells expressing GluR2, emphasizing the importance of the GluR1 subunit in this regulatory mechanism. Because Ser831 has previously been identified as a protein kinase C phosphorylation site (Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J., and Huganir, R. L. (1996) Neuron 16, 1179-1188), this raises the possibility of synergistic interactions between CaM-KII and protein kinase C in regulating synaptic plasticity.
Highlights
Brief trains of high frequency stimulation to monosynaptic excitatory pathways in the hippocampus and several other brain regions cause an abrupt and sustained increase in the efficiency of synaptic transmission
PKA and PKC can phosphorylate amino3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors (AMPA-Rs) in cortical neurons and glutamate receptor 1 (GluR1) expressed in 293 cells [19], and recently the PKA (Ser845) and PKC (Ser831) phosphorylation sites in GluR1 were identified in the intracellular COOH terminus [20]
We have reported that mutagenesis of Ser627 eliminates the effect of CaM-dependent protein kinase II (CaM-KII) on AMPA currents in Xenopus oocytes expressing GluR1 [7]
Summary
Brief trains of high frequency stimulation to monosynaptic excitatory pathways in the hippocampus and several other brain regions cause an abrupt and sustained increase in the efficiency of synaptic transmission. PKA and PKC can phosphorylate AMPA-Rs in cortical neurons and GluR1 expressed in 293 cells [19], and recently the PKA (Ser845) and PKC (Ser831) phosphorylation sites in GluR1 were identified in the intracellular COOH terminus [20].
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