TY - JOUR T1 - Use-Dependent Inhibition of the <em>N</em>-Methyl-D-aspartate Currents by Felbamate: a Gating Modifier with Selective Binding to the Desensitized Channels JF - Molecular Pharmacology JO - Mol Pharmacol SP - 370 LP - 380 DO - 10.1124/mol.65.2.370 VL - 65 IS - 2 AU - Chung-Chin Kuo AU - Bei-Jung Lin AU - Huai-Ren Chang AU - Chi-Pan Hsieh Y1 - 2004/02/01 UR - http://molpharm.aspetjournals.org/content/65/2/370.abstract N2 - Felbamate (FBM) is a potent nonsedative anticonvulsant whose clinical effect may be related to the inhibition of N-methyl-d-aspartate (NMDA) currents, but the exact molecular action remains unclear. Using whole-cell patch-clamp recording in rat hippocampal neurons, we found that submillimolar FBM effectively modifies the gating process of NMDA channels. During a single high-concentration (1 mM) NMDA pulse, FBM significantly inhibits the late sustained current but not the early peak current. However, if the 1 mM NMDA pulse is preceded by a low-concentration (10 μM) NMDA prepulse, then FBM significantly inhibits both the peak and the sustained currents in the 1 mM pulse. In sharp contrast, the NMDA currents elicited by micromolar NMDA are only negligibly inhibited or even enhanced by FBM. These findings indicate that the inhibitory effect of FBM on NMDA currents is stronger with both higher NMDA concentration and longer NMDA exposure, and is thus “use-dependent”. FBM also slows recovery of the desensitized NMDA channel, and quantitative analyses of FBM effects on the activation kinetics and the desensitization curve of the NMDA currents further disclose dissociation constants of ∼200, ∼110, and ∼55 μM for FBM binding to the resting, activated, and desensitized NMDA channels, respectively. We conclude that therapeutic concentrations (50–300 μM) of FBM could bind to and modify a significant proportion of the resting NMDA channel even when NMDA or other glutamatergic ligand is not present and then decrease the NMDA currents at subsequent NMDA pulses by stabilization of the desensitized channels. Because the inhibitory effect is apparent only when there is excessive NMDA exposure, FBM may effectively inhibit many seizure discharges but preserve most normal neuronal firings. ER -