Fig. 7. The two paths by which memantine can access the deep channel blocking site in NMDARs.

a Traditional channel block path. Top, charged memantine in the extracellular solution cannot access the deep site when the channel is closed. Bottom, charged memantine in the extracellular solution can transit to the deep site through the channel after agonists (A) bind and the channel gate opens. b MCI path. Top, uncharged memantine in the membrane cannot access the deep site when the membrane to channel fenestration is closed. Bottom, uncharged memantine in the membrane (shown here shortly after extracellular memantine has been washed away) can transit to the deep site through the gated fenestration after agonists bind and the fenestration opens.