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The structure and function of glutamate receptors: Mg2+ block to X-ray diffraction.

ABSTRACT: Experiments on the action of glutamate on mammalian and amphibian nervous systems started back in the 1950s but decades passed before it became widely accepted that glutamate was the major excitatory neurotransmitter in the CNS. The pace of research greatly accelerated in the 1980s when selective ligands that identified glutamate receptor subtypes became widely available, and voltage clamp techniques, coupled with rapid perfusion, began to resolve the unique functional properties of what cloning subsequently revealed to be a large family of receptors with numerous subtypes. More recently the power of X-ray crystallography and cryo-EM has been applied to the study of glutamate receptors, revealing their atomic structures, and the conformational changes that underlie their gating. In this review I summarize the history of this field, viewed through the lens of a career in which I spent 3 decades working on the structure and function of glutamate receptor ion channels. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

SUBMITTER: Mayer ML

PROVIDER: S-EPMC5075518 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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The structure and function of glutamate receptors: Mg<sup>2+</sup> block to X-ray diffraction.

Mayer Mark L ML

Neuropharmacology 20160427 Pt A

Experiments on the action of glutamate on mammalian and amphibian nervous systems started back in the 1950s but decades passed before it became widely accepted that glutamate was the major excitatory neurotransmitter in the CNS. The pace of research greatly accelerated in the 1980s when selective ligands that identified glutamate receptor subtypes became widely available, and voltage clamp techniques, coupled with rapid perfusion, began to resolve the unique functional properties of what cloning ...[more]

PMID: 27131921

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Project description:BACKGROUND: Members 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 Mg2+, and high permeability for Ca2+. Both Mg2+ sensitivity and Ca2+ 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 Mg2+ and are not permeable for Ca2+. RESULTS: Employing 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. Ca2+ permeability could be rescued by mutating the NR3 N site glycine to the NR1-like asparagine. Voltage-dependent Mg2+ block could be established by providing an Mg2+ coordination site at either the NR3 N or N+1 positions. Conversely, "conventional" receptors assembled from NR1 and NR2 could be made Mg2+ insensitive and Ca2+ impermeable by equipping either subunit with the NR3-like glycine at their N positions, with a stronger contribution of the NR1 subunit. CONCLUSIONS: This 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.

Dataset Information

The structure and function of glutamate receptors: Mg2+ block to X-ray diffraction.

Publications

The structure and function of glutamate receptors: Mg<sup>2+</sup> block to X-ray diffraction.

Similar Datasets

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