PHOSPHORYLATION-DEPENDENT REGULATION OF N-METHYL-D-ASPARTATE RECEPTORS BY CALMODULIN

The N-methyl-D-aspartate (NMDA) receptor plays important roles in syna ptic plasticity and brain development. The NMDA receptor subunits have large intracellular domains in the COOH-terminal region that may inte ract with signal-transducing proteins. By using the yeast two-hybrid s ystem, we found that calmodulin interacts with the COOH terminus of th e NR1 subunit and inactivates the channels in a Ca2+-dependent manner, Here we show that protein kinase C (PKC)-mediated phosphorylation on serine residues of NR1 decreases its affinity for calmodulin. This sug gests that PKC-mediated phosphorylation of NR1 prevents calmodulin fro m binding to the NR1 subunit and thereby inhibits the inactivation of NMDA receptors by calmodulin, In addition, we show that stimulation of metabotropic glutamate receptor 1 alpha, which potentiates NMDA chann els through PKC, decreases the ability of NR1 to bind to calmodulin, T hus, our data provide clues to understanding the basis of cross-talk b etween two types of receptors, metabotropic glutamate receptors and th e NR1 subunit, in NMDA channel potentiation.