STRUCTURAL BASIS FOR EXPLAINING OPEN-CHANNEL BLOCKADE OF THE NMDA RECEPTOR

The open-channel structure of the N-methyl-D-aspartate (NMDA) receptor was investigated to explain apparently conflicting interpretations ab out ionic interactions within the pore. Patch-clamp techniques were ap plied to tissue-cultured rat hippocampal neurons from the CA1 region. A wide range of ammonium derivatives was studied to learn about the st ructure of the pore from permeability and open-channel blocking charac teristics. We conclude that the pore is asymmetric, having higher-affi nity binding for organic cations from the outside and having a larger external entrance. The minimum cross-sectional area of the pore is rec tangular (approximate to 0.45 x 0.57 nm) and is the! single-occupancy binding site(s) for small permeant cations. The narrow region extendin g from this minimum cross section is short, and its shape underlies th e voltage dependencies of blocking cations. While occupying the blocki ng site, some open-channel blockers can interact with permeant cations at their binding site in the minimum cross section. A structurally ba sed hypothesis is presented, explaining that the electrostatic interac tions between the blocking site and permeant-ion site produce a high v olta!ae dependence for blockade by some cations.