The Journal of Neurophysiology Vol. 77 No. 1 January 1997, pp. 309-323
Copyright ©1997 The American Physiological Society

Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine

Thomas A. Blanpied¹, Faye A. Boeckman², Elias Aizenman², and Jon W. Johnson¹

¹ Department of Neuroscience, University of Pittsburgh, 15260 and ² Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Blanpied, Thomas A., Faye Boeckman, Elias Aizenman, and Jon W. Johnson. Trapping channel block of NMDA-activated responses by amantadine and memantine. J. Neurophysiol. 77: 309-323, 1997. We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl-D-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated channels by binding to a site at which they could be trapped after channel closure and agonist unbinding. For neuronal receptors, the IC₅₀s of amantadine and memantine at 67 mV were 39 and 1.4 µM, respectively. When memantine and agonists were washed off after steady-state block, one-sixth of the blocked channels released rather than trapped the blocker; memantine exhibited "partial trapping." Thus memantine appears to have a lesser tendency to be trapped than do phencyclidine or (5R,10S)-(+)-5m e t h y l - 1 0 , 1 1 - d i h y d r o - 5 H - d i b e n z o [ 1 , d ] c y c l i h e p t e n - 5 , 1 0 - i m i n e(MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits. In these receptors, as in the native receptors, the drug was released from one-sixth of blocked channels rather than being trapped in all of them. The partial trapping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultured cortical neurons. Amantadine and memantine each noncompetitively inhibited NMDA-activated responses by binding at a second site with roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A simple kinetic model of blocker action was used to demonstrate that partial trapping can result if the presence of memantine in the channel affects the gating transitions or agonist affinity of the NMDA receptor. Partial trapping guarantees that during synaptic communication in the presence of blocker, some channels will release the blocker between synaptic responses. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their modulation of NMDA-receptor-mediated excitatory postsynaptic potentials.

This article has been cited by other articles:

				D. C. Wrighton, E. J. Baker, P. E. Chen, and D. J. A. Wyllie Mg2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes J. Physiol., January 1, 2008; 586(1): 211 - 225. [Abstract] [Full Text] [PDF]

				S. M. Dravid, K. Erreger, H. Yuan, K. Nicholson, P. Le, P. Lyuboslavsky, A. Almonte, E. Murray, C. Mosley, J. Barber, et al. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block J. Physiol., May 15, 2007; 581(1): 107 - 128. [Abstract] [Full Text] [PDF]

				C. Cui, M. Xu, and M. Atzori Voltage-Dependent Block of N-Methyl-D-aspartate Receptors by Dopamine D1 Receptor Ligands Mol. Pharmacol., November 1, 2006; 70(5): 1761 - 1770. [Abstract] [Full Text] [PDF]

				H.-S. V. Chen and S. A. Lipton Pharmacological Implications of Two Distinct Mechanisms of Interaction of Memantine with N-Methyl-D-aspartate-Gated Channels J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 961 - 971. [Abstract] [Full Text] [PDF]

				H. Yuan, K. Erreger, S. M. Dravid, and S. F. Traynelis Conserved Structural and Functional Control of N-Methyl-D-aspartate Receptor Gating by Transmembrane Domain M3 J. Biol. Chem., August 19, 2005; 280(33): 29708 - 29716. [Abstract] [Full Text] [PDF]

				T. A. Blanpied, R. J. Clarke, and J. W. Johnson Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block J. Neurosci., March 30, 2005; 25(13): 3312 - 3322. [Abstract] [Full Text] [PDF]

				R. Planells-Cases, C. Montoliu, M. Humet, A. M. Fernandez, C. Garcia-Martinez, E. Valera, J. M. Merino, E. Perez-Paya, A. Messeguer, V. Felipo, et al. A Novel N-Methyl-D-aspartate Receptor Open Channel Blocker with in Vivo Neuroprotectant Activity J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 163 - 173. [Abstract] [Full Text] [PDF]

				K. Kashiwagi, T. Masuko, C. D. Nguyen, T. Kuno, I. Tanaka, K. Igarashi, and K. Williams Channel Blockers Acting at N-Methyl-D-aspartate Receptors: Differential Effects of Mutations in the Vestibule and Ion Channel Pore Mol. Pharmacol., March 1, 2002; 61(3): 533 - 545. [Abstract] [Full Text] [PDF]

				G. A. R. Mealing, T. H. Lanthorn, D. L. Small, R. J. Murray, K. C. Mattes, T. M. Comas, and P. Morley Structural Modifications to an N-Methyl-D-aspartate Receptor Antagonist Result in Large Differences in Trapping Block J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 906 - 914. [Abstract] [Full Text]

				R. A. Giniatullin, E. M. Sokolova, S. Di Angelantonio, A. Skorinkin, M. V. Talantova, and A. Nistri Rapid Relief of Block by Mecamylamine of Neuronal Nicotinic Acetylcholine Receptors of Rat Chromaffin Cells In Vitro: An Electrophysiological and Modeling Study Mol. Pharmacol., October 1, 2000; 58(4): 778 - 787. [Abstract] [Full Text]

				Y. Li-Smerin, E. Aizenman, and J. W. Johnson Inhibition by Intracellular Mg2+ of Recombinant N-Methyl-D-aspartate Receptors Expressed in Chinese Hamster Ovary Cells J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 1104 - 1110. [Abstract] [Full Text]

				A. I. Sobolevsky, S. G. Koshelev, and B. I. Khodorov Probing of NMDA Channels with Fast Blockers J. Neurosci., December 15, 1999; 19(24): 10611 - 10626. [Abstract] [Full Text] [PDF]

				R. Dingledine, K. Borges, D. Bowie, and S. F. Traynelis The Glutamate Receptor Ion Channels Pharmacol. Rev., March 1, 1999; 51(1): 7 - 62. [Abstract] [Full Text] [PDF]

				G. A. R. Mealing, T. H. Lanthorn, C. L. Murray, D. L. Small, and P. Morley Differences in Degree of Trapping of Low-Affinity Uncompetitive N-Methyl-D-aspartic Acid Receptor Antagonists with Similar Kinetics of Block J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 204 - 210. [Abstract] [Full Text]

				D. Bowie, G. D. Lange, and M. L. Mayer Activity-Dependent Modulation of Glutamate Receptors by Polyamines J. Neurosci., October 15, 1998; 18(20): 8175 - 8185. [Abstract] [Full Text] [PDF]