This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.106.103176v1 93/6/1981    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chang, H.-R. Articles by Kuo, C.-C. Search for Related Content PubMed PubMed Citation Articles by Chang, H.-R. Articles by Kuo, C.-C.

Extracellular Proton-Modulated Pore-Blocking Effect of the Anticonvulsant Felbamate on NMDA Channels

Huai-Ren Chang ^* and Chung-Chin Kuo ^* 

^* Department of Physiology, National Taiwan University College of Medicine; and Department of Neurology, National Taiwan University Hospital

Correspondence: Address reprint requests to Chung-Chin Kuo, Tel.: 886-2-2312-3456, ext. 8236; E-mail: chungchinkuo{at}ntu.edu.tw.

Felbamate (FBM) is a potent nonsedative anticonvulsant whose clinical effect is chiefly related to gating modification (and thus use-dependent inhibition) rather than pore block of N-methyl-D-aspartate (NMDA) channels at pH 7.4. Using whole-cell recording in rat hippocampal neurons, we examined the effect of extracellular pH on FBM action. In sharp contrast to the findings at pH 7.4, the inhibitory effect of FBM on NMDA currents shows much weakened use-dependence at pH 8.4. Moreover, FBM neither accelerates the activation kinetics of the NMDA channel, nor enhances the currents elicited by very low concentrations of NMDA at pH 8.4. These differential effects of FBM between pH 7.4 and 8.4 are abolished in the mutant NMDA channels which lack proton sensitivity. Most interestingly, the inhibitory effect of FBM becomes flow-dependent and is evidently stronger in inward than in outward NMDA currents at pH 8.4. These findings indicate that FBM has a significantly more manifest pore-blocking effect on the NMDA channel at pH 8.4 than at pH 7.4. FBM therefore acts as an opportunistic pore blocker modulated by extracellular proton, suggesting that the FBM binding site is located at the junction of a widened and a narrow part of the ion conduction pathway. Also, we find that the inhibitory effect of FBM on NMDA currents is antagonized by external but not internal Na⁺, and that increase of external Na⁺ decreases the binding rate without altering the unbinding rate of FBM. These findings indicate that the FBM binding site faces the extracellular rather than the intracellular solution, and coincides with the outmost ionic (e.g., Na⁺) site in the NMDA channel pore. We conclude that the FBM binding site very likely is located in the external pore mouth, where extracellular proton, Na⁺, FBM, and NMDA channel gating have an orchestrating effect.

This article has been cited by other articles:

				H.-R. Chang and C.-C. Kuo The Activation Gate and Gating Mechanism of the NMDA Receptor J. Neurosci., February 13, 2008; 28(7): 1546 - 1556. [Abstract] [Full Text] [PDF]