Phosphorylation-dependent regulation of N-methyl-D-aspartate receptors by calmodulin.
The N-methyl-D-aspartate (NMDA) receptor plays important roles in synaptic plasticity and brain development. The NMDA receptor subunits have large intracellular domains in the COOH-terminal region that may interact with signal-transducing proteins. By using the yeast two-hybrid system, we found that calmodulin interacts with the COOH terminus of the 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 suggests that PKC-mediated phosphorylation of NR1 prevents calmodulin from 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 1alpha, which potentiates NMDA channels through PKC, decreases the ability of NR1 to bind to calmodulin. Thus, our data provide clues to understanding the basis of cross-talk between two types of receptors, metabotropic glutamate receptors and the NR1 subunit, in NMDA channel potentiation.
Hisatsune
C
C
Department of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan.
Umemori
H
H
Inoue
T
T
Michikawa
T
T
Kohda
K
K
Mikoshiba
K
K
Yamamoto
T
T
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002147:Calmodulin; D016194:Receptors, N-Methyl-D-Aspartate; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium