Determinants of trapping block of <i>N</i>‐methyl‐<scp>d</scp>‐aspartate receptor channels

Bolshakov, Konstantin V.; Гмиро, В. Е.; Tikhonov, Denis B.; Lg, Magazanik

doi:10.1046/j.1471-4159.2003.01956.x

Cited by 86 publications

(72 citation statements)

References 28 publications

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“…This K d is considerably larger than the amantadine IC 50 (38.9 Ϯ 4.6 M) that we measured under similar conditions in whole-cell experiments (Blanpied et al, 1997), a value in agreement with the average amantadine IC 50 (ϳ35 M) measured electrophysiologically by others (Parsons et al, 1995(Parsons et al, , 1999aSobolevsky and Yelshansky, 2000;Bolshakov et al, 2003). The observation that K d Ͼ IC 50 implies that amantadine inhibits total NMDA receptor-mediated current more effectively than it blocks open single channels.…”

Section: Divergence Of K D and Ic 50 Of Amantadinesupporting

confidence: 91%

“…Structural and functional similarities between K ϩ channels and glutamate receptors (Panchenko et al, 2001) suggest that similar ideas may apply to block of NMDA receptors. Thus, systematic molecular modification of amantadine and other blockers (Antonov and Johnson, 1996;Bolshakov et al, 2003) can be used to help define channel shape while advancing the search for more useful therapeutic drugs.…”

Section: Discussionmentioning

confidence: 99%

“…For example, blockers that act by the "sequential" (or "foot-in-the-door") mechanism, which prevent closure of the channel while blocking, inhibit whole-cell responses (or patch n ϫ P open ) much less effectively than they block single-channel currents (K d Ͻ Ͻ IC 50 ) (Neher and Steinbach, 1978;Hille, 2001;Johnson and Qian, 2002). Amantadine, in contrast, is known to be a trapping channel blocker: it permits channel closure while bound in the channel of NMDA receptors (Blanpied et al, 1997;Sobolevsky and Yelshansky, 2000;Bolshakov et al, 2003). Nevertheless, even trapping channel blockers have been found to partly inhibit channel closure during block , leading to an IC 50 that is greater than the K d .…”

Section: Divergence Of K D and Ic 50 Of Amantadinementioning

confidence: 99%

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Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Blanpied¹,

Clarke²,

Johnson³

2005

J. Neurosci.

216

136

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The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.

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Section: Divergence Of K D and Ic 50 Of Amantadinesupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Divergence Of K D and Ic 50 Of Amantadinementioning

confidence: 99%

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Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Blanpied¹,

Clarke²,

Johnson³

2005

J. Neurosci.

216

136

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“…Memantine blocks NMDARs via an uncompetitive mechanism at low micromolar concentrations, yet possesses a noncompetitive component (via partial trapping in the channel) at higher concentrations (Blanpied et al, 1997;Chen and Lipton, 1997). Lipophilic leak of memantine from its blocking site cannot explain this noncompetitive component (Mealing et al, 2001;Bolshakov et al, 2003). Instead, here we identify a second site of memantine binding of very low affinity at the channel vestibule.…”

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confidence: 53%

Pharmacological Implications of Two Distinct Mechanisms of Interaction of Memantine withN-Methyl-d-aspartate-Gated Channels

Chen

Lipton²

2005

J Pharmacol Exp Ther

102

112

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Unlike other N-methyl-D-aspartate receptor (NMDAR) antagonists, clinical trials have shown that memantine is clinically tolerated and effective in the treatment of Alzheimer's disease. The mechanism for memantine tolerability, however, remains contentious but may be partly explained by its uncompetitive antagonism. The specific site of memantine block in the NMDAR channel interacts with magnesium and is assumed to be at or near a narrow constriction representing the channel selectivity filter. A second, very low-affinity site of memantine action has also been reported. Here, using mutational analysis and substituted cysteine accessibility methods on recombinant NR1/NR2A NMDARs expressed in Xenopus oocytes, we precisely localize both the specific and second memantine-blocking sites. Intriguingly, memantine interacts with its specific blocking site in the same fashion as intracellular rather than extracellular Mg 2ϩ . Thus, the N-site asparagine (N) in the M2 region of the NR1 subunit represents the dominant site for uncompetitive antagonism by memantine. The N and N ϩ 1 site asparagines in NR2A produce strong electrostatic interactions with memantine. In contrast, the second (superficial) memantine-blocking site, located at the extracellular vestibule of the channel, appears to be nonspecific and overlaps the site occupied by the nonspecific pore blocker hexamethonium. Residues in the post-M3 segment of the NR1 subunit are not directly involved in memantine binding. The distinct patterns of interaction and the relative degree of affinity of memantine for these two binding sites contribute to the drug's excellent pharmacological profile of clinical tolerability. In the future, these parameters should be considered in searching for improved neuroprotective agents in this class.

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“…Dextrorphan, a channel blocker with structural determinants for binding that are unique from those of MK-801 (30), showed reduced channel block after MTSEA modification that was insensitive to the presence of agonist. Similarly, memantine and amantadine, which appear to be partial trapping blockers at hyperpolarized potentials with perhaps two intra-pore binding sites (31)(32)(33), also showed reduced channel block after MTSEA modification that was identical in the absence and presence of agonists following MTSEA modification (Table II). Thus, receptor block by dextrorphan, amantadine, and memantine following MTSEA modification of NR1-A7C/NR2A mutant receptors was significantly reduced compared with unmodified receptors (p Ͻ 0.001), yet insensitive to the absence or presence of agonist.…”

Section: Fig 5 Competitive Antagonists and Allosteric Modulators Ofmentioning

confidence: 93%

Conserved Structural and Functional Control of N-Methyl-d-aspartate Receptor Gating by Transmembrane Domain M3

Yuan

Erreger

Dravid

et al. 2005

Journal of Biological Chemistry

100

129

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The N-methyl-D-aspartate (NMDA) 1 subtype of ionotropic glutamate receptor plays a major role in physiological (longterm synaptic plasticity) and pathological (epilepsy, excitotoxicity in stroke) processes in the brain (1). NMDA receptors function as heteromeric assemblies composed of glycine-binding NR1 subunits in combination with at least one type of glutamate-binding NR2 subunit (2-4). NMDA receptors have three transmembrane domains (M1, M3, and M4) plus a cytoplasmic re-entrant membrane loop (M2) (5). Contained within the M3 transmembrane domain is the motif with the strictest amino acid conservation (SYTANLAAF, Fig. 1) among all the members of the ionotropic glutamate receptor family, indicating an important role in channel function (6 -8). In the naturally occurring lurcher mutant mice, GluR␦2 receptors contain an alanine to threonine mutation in this motif (9). The lurcher mice suffer cerebellar degeneration resulting in ataxia and impaired motor learning. Introducing the analogous lurcher mutation into NR1, GluR1, or GluR6 receptors decreases agonist EC 50 values and/or decreases the rate of receptor deactivation (10 -12). This suggests that transmembrane domain M3 may play a critical role in the channel gating of ionotropic glutamate receptors. Jones et al. (13) reported that replacement of the alanine at position 7 of the SYTANLAAF motif of NR1 or NR2A with cysteine (hereafter A7C) produced agonistinduced accessibility changes for sulfhydryl-modifying reagents. This residue was susceptible to covalent modification by extracellular MTSEA only when it was co-applied during channel activation by glutamate and glycine, suggesting that a change in solvent accessibility of this residue is associated with channel activation. MTSEA modification dramatically slowed the deactivation of the mutated NMDA receptors, indicating that M3 functions as a transduction element whose conformational change couples ligand binding with channel opening. Here we demonstrate that this role for M3 is conserved not only between NR1 and NR2A, but also for NR2B, NR2C, and NR2D. The MTSEA modification of the mutation A7C on NR1, NR2A, NR2B, NR2C, or NR2D potentiates currents to a varying degree depending on the identity of the NR2 subunit, and the MTSEA-modified channels remain open even following removal of glutamate and glycine from the external solution. These modified channels are insensitive to competitive NMDA antagonists (APV and 7-Cl-kynurenic acid) and allosteric modulators of gating (low pH and Zn 2ϩ ). MTSEA-modified channels are inhibited by channel blockers (Mg 2ϩ , (ϩ)MK-801, (Ϫ)MK-801, ketamine, memantine, amantadine, dextrorphan), although divergent effects for some of these blockers were observed in the absence or presence of the agonists. We interpret these results as evidence that the M3 transmembrane domain plays a conserved role in channel function for all NMDA subunits.

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Determinants of trapping block of N‐methyl‐d‐aspartate receptor channels

Cited by 86 publications

References 28 publications

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Pharmacological Implications of Two Distinct Mechanisms of Interaction of Memantine withN-Methyl-d-aspartate-Gated Channels

Conserved Structural and Functional Control of N-Methyl-d-aspartate Receptor Gating by Transmembrane Domain M3

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