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Abstract

The structure of the NMDA receptor channel M2 segment was investigated by probing the extracellular and cytoplasmic faces of cysteine−substituted NR1?NR2C channels with charged sulfhydryl−specific reagents. The pattern of accessible positions suggests that the M2 segment forms a channel−lining loop originating and ending on the cytoplasmic side of the channel, with the ascending limb in an ?−helical structure and the descending limb in an extended structure. A functionally critical asparagine (N−site) is positioned at the tip of the loop, and a cluster of hydrophilic residues of the descending limb, adjacent to the tip, forms the narrow constriction of the channel. An apparent asymmetric positioning of the NR1− and NR2−subunit N−site asparagines may account for their unequal role in Ca²⁺ permeability and Mg²⁺ block