Regulatory Phosphorylation of AMPA-Type Glutamate Receptors by CaM-KII During Long-Term PotentiationLong-term potentiation (LTP), a cellular model of learning and memory, requires calcium-dependent protein kinases. Induction of LTP increased the phosphorus-32 labeling of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA-Rs), which mediate rapid excitatory synaptic transmission. This AMPA-R phosphorylation appeared to be catalyzed by Ca2+- and calmodulin-dependent protein kinase II (CaM-KII): (i) it correlated with the activation and autophosphorylation of CaM-KII, (ii) it was blocked by the CaM-KII inhibitor KN-62, and (iii) its phosphorus-32 peptide map was the same as that of GluR1 coexpressed with activated CaM-KII in HEK-293 cells. This covalent modulation of AMPA-Rs in LTP provides a postsynaptic molecular mechanism for synaptic plasticity.
Contributions of Quisqualate and NMDA Receptors to the Induction and Expression of LTPThe contributions of two subclasses of excitatory amino acid transmitter receptors to the induction and expression of long-term potentiation (LTP) were analyzed in hippocampal slices. The quisqualate/kainate receptor antagonist DNQX (6,7-dinitro-quinoxaline-2,3-dione) blocked 85% of the evoked field potential, leaving a small response that was sensitive to D-AP5 (D-2-amino-5-phosphonopentanoate), an N-methyl-D-aspartate (NMDA) receptor blocker. This residual D-AP5-sensitive response was of comparable size in control and previously potentiated inputs. High-frequency stimulation in the presence of DNQX did not result in the development of robust LTP. Washout of the drug, however, revealed the potentiation effect. Thus NMDA-mediated responses can induce, but are not greatly affected by, LTP; non-NMDA receptors, conversely, mediate responses that are not needed to elicit LTP but that are required for its expression.