Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca2 permeability and Mg2 blockReport as inadecuate

Residues at the tip of the pore loop of NR3B-containing NMDA receptors determine Ca2 permeability and Mg2 block - Download this document for free, or read online. Document in PDF available to download.

BMC Neuroscience

, 11:133

First Online: 19 October 2010Received: 26 October 2009Accepted: 19 October 2010


BackgroundMembers of the complex N-methyl-D-aspartate receptor NMDAR subfamily of ionotropic glutamate receptors iGluRs conventionally assemble from NR1 and NR2 subunits, the composition of which determines receptor properties. Hallmark features of conventional NMDARs include the requirement for a coagonist, voltage-dependent block by Mg, and high permeability for Ca. Both Mg sensitivity and Ca permeability are critically dependent on the amino acids at the N and N+1 positions of NR1 and NR2. The recently discovered NR3 subunits feature an unprecedented glycine-arginine combination at those critical sites within the pore. Diheteromers assembled from NR1 and NR3 are not blocked by Mg and are not permeable for Ca.

ResultsEmploying site-directed mutagenesis of receptor subunits, electrophysiological characterization of mutants in a heterologous expression system, and molecular modeling of the NMDAR pore region, we have investigated the contribution of the unusual NR3 N and N+1 site residues to the unique functional characteristics of receptors containing these subunits. Contrary to previous studies, we provide evidence that both the NR3 N and N+1 site amino acids are critically involved in mediating the unique pore properties. Ca permeability could be rescued by mutating the NR3 N site glycine to the NR1-like asparagine. Voltage-dependent Mg block could be established by providing an Mg coordination site at either the NR3 N or N+1 positions. Conversely -conventional- receptors assembled from NR1 and NR2 could be made Mg insensitive and Ca impermeable by equipping either subunit with the NR3-like glycine at their N positions, with a stronger contribution of the NR1 subunit.

ConclusionsThis study sheds light on the structure-function relationship of the least characterized member of the NMDAR subfamily. Contrary to previous reports, we provide evidence for a critical functional involvement of the NR3 N and N+1 site amino acids, and propose them to be the essential determinants for the unique pore properties mediated by this subunit.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2202-11-133 contains supplementary material, which is available to authorized users.

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Author: Nora A Cavara - Angela Orth - Gordon Hicking - Guiscard Seebohm - Michael Hollmann


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