Staggering of subunits in NMDAR channels

Published on 12.01.2002 in Biophysical Journal

Authors:

Alexander I. Sobolevsky, LeeAnn Rooney, Lonnie P. Wollmuth

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Abstract

Functional N-methyl-D-aspartate receptors (NMDARs) are heteromultimers formed by NR1 and NR2 subunits. The M3 segment, as contributed by NR1, forms the core of the extracellular vestibule, including binding sites for channel blockers, and represents a critical molecular link between ligand binding and channel opening. Taking advantage of the substituted cysteine accessibility method along with channel block and multivalent coordination, we studied the contribution of the M3 segment in NR2C to the extracellular vestibule. We find that the M3 segment in NR2C, like that in NR1, contributes to the core of the extracellular vestibule. However, the M3 segments from the two subunits are staggered relative to each other in the vertical axis of the channel. Compared to NR1, homologous positions in NR2C, including those in the highly conserved SYTANLAAF motif, are located about four amino acids more externally. The staggering of subunits may represent a key structural feature underlying the distinct functional properties of NMDARs.

**Figure 1.** Schematic representation of staggering of the NMDAR subunits. Amino acid residues in NR1 or NR2C are aligned along the central axis of the channel pore. Parts of the NR1 and NR2C M3 segment and adjacent region forming the core of the extracellular vestibule are shown. Filled ellipses indicate positions exposed to the lumen of the channel. The SYTANLAAF motif is shown in gray. Thin horizontal lines indicate the apparent fraction of the membrane voltage (zδ) experienced by MTSEA reaching the substituted cysteine at the corresponding depth in the channel. The black circle in the center illustrates coordination of Cu²⁺ by cysteines substituted at positions NR1(T+2) and NR2C(L-2). Extreme left and right panels show the ratio k/k_9-AA, which summarizes the effect of 9-AA on chemical modification of substituted cysteines. (See paper for details).

This work was done in Lonnie P. Wollmuth lab.

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