N-Terminal Domains in the NR2 Subunit Control Desensitization of NMDA Receptors

Krupp, Johannes; Vissel, Bryce; Heinemann, Stephen F.; Westbrook, Gary L.

doi:10.1016/s0896-6273(00)80459-6

Cited by 150 publications

(131 citation statements)

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“…Glycine-independent desensitization of NMDA receptors was assigned to two regions in the NR2A subunit, the X domain and an area within the S1 segment (13,17). Moreover, participation of the N-terminal domain in the regulation of NMDA receptor channel function by allosteric modulators, including Zn 2ϩ ions (14,16), ifenprodil (8,15,16), spermine (8), protons (25), and redox agents (26), has been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…First, this domain is implicated as a determinant in the assembly of oligomeric channels (10 -12). Second, the X domain may mediate the allosteric transitions involved in the channel activation, desensitization, or modulation by ions and drugs as has been observed for NMDA receptors (8,(13)(14)(15)(16)(17). Third, the X domain may provide docking sites for extracellular proteins, which serve to cluster the receptors or stabilize their localization.…”

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confidence: 99%

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α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

Pasternack¹,

Coleman²,

Jouppila³

et al. 2002

Journal of Biological Chemistry

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Ionotropic glutamate receptor (iGluR) subunits contain a ϳ400-residue extracellular N-terminal domain ("X domain"), which is sequence-related to bacterial amino acid-binding proteins and to class C G-protein-coupled receptors. The X domain has been implicated in the assembly, transport to the cell surface, allosteric ligand binding, and desensitization in various members of the iGluR family, but its actual role in these events is poorly characterized. We have studied the properties of homomeric ␣-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA)-selective GluR-D glutamate receptors carrying N-terminal deletions. Our analysis indicates that, surprisingly, transport to the cell surface, ligand binding properties, agonist-triggered channel activation, rapid desensitization, and allosteric potentiation by cyclothiazide can occur normally in the complete absence of the X domain (residues 22-402). The relatively intact ligand-gated channel function of a homomeric AMPA receptor in the absence of the X domain indirectly suggests more subtle roles for this domain in AMPA receptors, e.g. in the assembly of heteromeric receptors and in synaptic protein interactions.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

Pasternack¹,

Coleman²,

Jouppila³

et al. 2002

Journal of Biological Chemistry

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“…23 The GluR7 contains an exonic thymine/guanine nucleotide variation that determines a serine or alanine at position 310 in the N-terminal extracellular domain of the receptor. 24 This domain has been reported to affect receptor desensitization 25 and to participate in ligand binding. 26,27 Prior electrophysiological investigations of both alleles in HEK 293 cells did not indicate that the replacement of serine 310 by alanine affects receptor responses to glutamate.…”

Section: Introductionmentioning

confidence: 99%

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

et al. 2005

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“…Magnitude of glycine-independent desensitization and calcium dependent inactivation are controlled by the key residues in the NR2 subunit [11]. The degree of desensitization is inversely dependent on the saturation degree of the glycine binding site and results from a weakening of glycine affinity upon channel activation [6,12].…”

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confidence: 99%

Zinc reverses glycine-dependent inactivation of NMDARs in cultured rat hippocampal neurons

Chen

Jiang

et al. 2012

Sci. China Life Sci.

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In the presence of glutamate and co-agonists, e.g., glycine, the N-methyl-D-aspartate receptor (NMDAR) plays an important role in physiological and pathophysiological brain processes. Previous studies indicate glycine could inhibit NMDAR responses induced by high concentration of NMDA in hippocampal neurons. The mechanism underlying this inhibitory impact, however, has been unclear. In this study, the whole-cell patch-clamp recording and Ca 2+ imaging with Fluo-3/AM under laser scanning confocal microscope were used to analyze the possible involvement of NMDAR subunits in this effect. We found that the peak current of NMDARs and Ca 2+ influx induced by high concentration of NMDA were reduced by treatment of glycine (0.03-10 mol L 1 ) in a dose-dependent manner, and that the glycine-dependent inhibition of NMDAR responses, which were induced at 300 mol L 1 NMDA, was reversed by ZnCl 2 through the blocking of the NR2A subunit of NMDARs, but was less influenced by ifenprodil, a NR2B inhibitor. Our results suggest that the glycine-dependent inactivation of NMDARs is potentially modulated by the regulatory subunit NR2A. N-methyl-D-aspartate (NMDA), NMDARs (NMDARs), glycine, zinc, inactivation, hippocampal neurons Citation:Li X, Chen Z Q, Jiang Z L, et al. Zinc reverses glycine-dependent inactivation of NMDARs in cultured rat hippocampal neurons. Sci China Life Sci, 2012Sci, , 55: 1075Sci, -1081Sci, , doi: 10.1007 N-methyl-D-aspartate receptor (NMDAR) ion channels are generally considered as postsynaptic targets of glutamate-mediated synaptic transmission in the central nervous system. NMDARs play critical roles in physiological processes such as synaptic plasticity and memory by allowing glutamate-gated calcium influx into neuronal cells [1]. A property of the NMDARs is its voltage-dependent activation, a result of ion channel block by extracellular Mg 2+ ions, which allows the flow of Na + and small amounts of Ca 2+ ions into the cell and K + out of the cell [2]. Besides, the NMDAR requires co-activation of the glycine site located on its NR1 subunit by D-serine or glycine in addition to the synaptically released neurotransmitter glutamate [3,4].However, the mechanistic connection between glutamate and glycine binding in the modulation of NMDAR activation and inactivation is unclear. Many mechanisms have been proposed to account for the mediation of the inactivation of NMDARs, including glycine-dependent desensitization, glycine-independent desensitization [5,6], Ca 2+ -dependent inactivation [7][8][9] and surface membrane receptors internalization [10]. Activation of NMDARs that have been pre-equilibrated with glycine produces a peak current, which decays or desensitizes to a steady-state level at high concentrations of NMDA. According to the desensitization of currents in the presence of saturation concentrations of glutamate and glycine agonists, two types of desensitization, glycine-independent or glycine-dependent, have been characterized for NMDARs.

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N-Terminal Domains in the NR2 Subunit Control Desensitization of NMDA Receptors

Cited by 150 publications

References 50 publications

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics

Zinc reverses glycine-dependent inactivation of NMDARs in cultured rat hippocampal neurons

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