TY - JOUR T1 - Evidence for Direct Protein Kinase-C Mediated Modulation of<em>N</em>-Methyl-<span class="sc">d</span>-aspartate Receptor Current JF - Molecular Pharmacology JO - Mol Pharmacol SP - 960 LP - 964 DO - 10.1124/mol.59.5.960 VL - 59 IS - 5 AU - Guey-Ying Liao AU - David A. Wagner AU - Michael H. Hsu AU - John P. Leonard Y1 - 2001/05/01 UR - http://molpharm.aspetjournals.org/content/59/5/960.abstract N2 - Protein kinase-C (PKC) activation differentially affects currents fromN-methyl-d-aspartate (NMDA) type glutamate receptors depending upon their subunit composition. Experiments using chimeras initially indicated that the cytoplasmic C-terminal tails of NR2B (responsive to PKC) and NR2C (unresponsive to PKC) subunits contain the amino acid residues responsible for the observed disparity of PKC effects. However, truncation and point mutation experiments have suggested that PKC action on NMDA receptors may be entirely indirect, working via the phosphorylation of associated proteins. Here we suggest that PKC does, in fact, affect NR2B/NR1–011 NMDA currents by direct phosphorylation of the NR2B tail at residues S1303 and S1323. Replacement of either of these residues with Ala severely reduces PKC potentiation. To verify that S1303 and S1323 are sites of direct phosphorylation by PKC, synthetic peptides from the regions surrounding these sites were used as substrates for in vitro assays with purified rat brain PKC. These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. The direct action of PKC on certain NMDA receptor subtypes may be important in any physiological or pathological process where PKC and NR2B/NR1 receptors interact. ER -