Figure 5. Competitive binding hypothesis of partial trapping.

We hypothesized that partial trapping of memantine by NMDA receptors is the result of competitive binding while the channel is open at two inhibitory binding sites that cannot be occupied simultaneously (upper panels). Blocker (represented by an open circle with +) can only be trapped by channel closure (bottom left) when occupying the deep trapping site. Blocker binding and unbinding at the deep site requires that the channel be open, and is strongly voltage dependent. Memantine or ketamine can bind at the deep site (left panels). Binding and unbinding of blocker at the superficial non-trapping site (right panels) may occur whether or not channels are open. Memantine, but not ketamine, can bind at the superficial site (right panels), which is located external to the trapping gate (horizontal line at channel entrance in lower panels). Memantine unbinding from the superficial site after channel closure (bottom right) is hypothesized to result in partial trapping.