Modeling of the Pore Domain of the GLUR1 Channel: Homology with K + Channel and Binding of Channel Blockers

Abstract

Molecular models of the M2 segments of the GluR1 channel have been elaborated using a molecular mechanics approach. The models are based on the homology between pore-lining segments of AMPA receptor channels and the KcsA K + channel and on cyclic H bonds at the Q/R site of the AMPA receptor channel. The N-terminal region of an M2 segment of the channel is assumed, like that of the K + channel, to adopt a helical conformation. Due to a deletion, the C-terminal end of the M2 segment of the AMPA receptor is more stretched than that of the K + channel. As a result, only a single oxygen ring may be exposed to the AMPA receptor channel pore. Data on the block of AMPA receptor channels by dicationic adamantane derivatives have been used to select the most relevant model. The model with the oxygen of a Gly residue (position +2 from the Q/R site) exposed to the pore best fits the experimental data. This model also fits experimental data for another class of AMPA receptor antagonists, the polyamine amides. According to the model, the side-chains of the C-terminal residues are involved in intra-receptor interactions that stabilize the structure of the channel rather than in interactions with ions in the pore.