Structural basis for explaining open-channel blockade of the NMDA receptor

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Conflicting interpretations exist regarding ionic interactions within the N-methyl-D-aspartate (NMDA) receptor pore.
• Understanding the NMDA receptor's pore structure is crucial for elucidating its function in neuronal signaling.

Purpose of the Study:

• To investigate the open-channel structure of the NMDA receptor.
• To resolve discrepancies in understanding ionic interactions within the NMDA receptor pore.
• To characterize the pore's dimensions and binding sites using various ammonium derivatives.

Main Methods:

• Utilized patch-clamp techniques on tissue-cultured rat hippocampal neurons (CA1 region).
• Studied permeability and open-channel blocking characteristics of diverse ammonium derivatives.

Main Results:

• The NMDA receptor pore is asymmetric with a larger external entrance and high-affinity binding for external organic cations.
• A minimum rectangular cross-section (0.45 x 0.57 nm) acts as a single-occupancy binding site for small permeant cations.
• The pore's narrow region's shape explains voltage-dependent blockades, with blockers potentially interacting with permeant ions.

Conclusions:

• A structurally based hypothesis explains voltage-dependent blockades through electrostatic interactions between blocking and permeant ion sites.
• The asymmetric pore structure and specific binding sites dictate ion permeation and blockade mechanisms in NMDA receptors.