Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Abstract

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.

Modulation of Human Motor Cortex Excitability by Single Doses of Amantadine

“…AMA inhibits NMDA responses at clinically used concentrations (below 100 mM). The mechanism of action at the glutamatergic synapse is different from that of other NMDA antagonists characterized as 'open-channel blockers', as AMA mostly acts by stabilization of channel-closed states (Blanpied et al, 2005). However, regarding the effects on motor cortex excitability there seems to be no difference between AMA and other NMDA receptor antagonists as determined by comparable changes of both ICF and ICI.…”

“…A low-affine noncompetitive antagonism of the Nmethyl-D-aspartate (NMDA)-glutamate receptor subtype at the PCP (phencyclidine) binding site, which is localized inside the cation channel (Kornhuber et al, 1991;Parsons et al, 1996) and at the sigma 1-binding site located outside the channel (Kornhuber et al, 1993a). The antagonism of NMDA-induced neuronal currents is use-and voltage-dependent leading to a stabilization of channel closed states (Blanpied et al, 2005). Among others this leads to a reduction of acetylcholine (ACh) release from striatal interneurons in vitro Stoof et al, 1992) by blockage of nicotinergic AChreceptors (Matsubayashi et al, 1997).…”

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

“…Trapping blockers such as (ϩ)MK-801, (Ϫ)MK-801, and ketamine were rendered less effective in the presence of glutamate and glycine in the bath following MTSEA treatment, suggesting that MTSEA modified determinants of blockade beyond those involved in Mg 2ϩ block. One idea that emerges is that MK-801 may have a relatively low affinity for open channels of unmodified receptors, yet may greatly stabilize the closed state thereby promoting its own trapping (36). In this situation MTSEA modification increases the maximal open probability causing a decrease in the affinity of MK-801 for MTSEA-modified receptors.…”

“…In this situation MTSEA modification increases the maximal open probability causing a decrease in the affinity of MK-801 for MTSEA-modified receptors. This idea has previously been raised as a potential mechanism for other organic channel blockers (36).…”

“…As described above for the problem of differentiating the effects of modification on binding versus gating, the interpretation of the (ϩ)MK-801 effect is not straightforward. The decreased potency and accelerated unbinding could reflect an outright change in agonist affinity by blocker binding (possibly at a site distinct from the channel pore), or alternatively a blockerinduced promotion of channel closure with subsequent reduction in agonist affinity (because closed channels have a lower affinity for agonist than open channels (36,37)), or some combination of both (Fig. 8).…”