Modulation of Triheteromeric NMDA Receptors by N-Terminal Domain Ligands

Hatton, C. J.; Paoletti, Pierre

doi:10.1016/j.neuron.2005.03.005

Cited by 213 publications

(252 citation statements)

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“…If the NMDA-EPSC were mediated by receptors composed of two distinct diheteromeric populations, then removal of the slower NR1/NR2B NMDAR current, using either Ro 25-6981 or ifenprodil, would result in an alteration of kinetics, as seen in the hippocampus from 2-week-old rat hippocampus (Bartlett et al, 2006). In support of this, recent experiments demonstrated that ifenprodil has a much reduced efficacy, but similar potency, of inhibition of triheteromeric vs diheteromeric NMDARs, consistent with our observed incomplete inhibition of the NMDA-EPSC by Ro 25-6981 and ifenprodil (Hatton and Paoletti, 2005). When extrapolated to a synaptic response, if the receptors were primarily triheteromeric, the application of an NR2B-selective antagonist would inhibit all receptors and thus would not selectively remove any one component, resulting in no change in kinetics (illustrated in Figure 6B).…”

Section: Nmdar Composition In the Vbnstsupporting

confidence: 89%

“…(Bb) A schematic representation of the effects of an NR2B antagonist on triheteromeric receptors. Recent evidence (Hatton and Paoletti, 2005) demonstrated that NR2B antagonists can inhibit triheteromeric receptors, albeit with reduced efficacy, as demonstrated with the reduced amplitude of the traces as compared to those in b1. However, it is important to note the lack of alteration in the decay kinetics, reflecting the results obtained in the vBNST.…”

Section: Nmdar Composition In the Vbnstmentioning

confidence: 99%

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Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

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Components of the mesolimbic dopamine system, in particular dopaminergic cells in the ventral tegmental area (VTA), have been implicated in the acute reinforcing actions of ethanol. The ventral bed nucleus of the stria terminalis (vBNST) potently regulates dopaminergic cell firing in the VTA, and has been implicated in the behavioral actions of ethanol. The N-methyl-D-asparate receptor (NMDAR) is a major molecular target of ethanol, however, current evidence suggests that ethanol regulation of NMDAR function is widely variable and likely depends on a number of factors. Thus, it is critical to investigate ethanol regulation of NMDAR function at synapses relevant to ethanol-regulated behaviors, such as in the vBNST. Here we show, using multiple techniques, that ethanol inhibits NMDAR function in vBNST neurons in a postsynaptic fashion. Further, we demonstrate the functional presence of both NR2A and NR2B-containing NMDARs in the vBNST. While genetic removal of NR2A did not alter the magnitude of ethanol inhibition, pharmacological blockade of NR2B rendered synaptically activated NMDARs insensitive to ethanol inhibition. Finally, we demonstrate that ethanol inhibits NMDARs in cells in the vBNST that project to the VTA, providing a direct means by which ethanol in the vBNST can modulate the dopaminergic system.

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Section: Nmdar Composition In the Vbnstsupporting

confidence: 89%

Section: Nmdar Composition In the Vbnstmentioning

confidence: 99%

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Kash

Matthews

Winder

2007

Neuropsychopharmacol

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“…Because of the lack of a selective antagonist for these receptors, their contributions to cell survival and/or death remain to be determined. Given that Ro 25-6981 has a much higher potency toward the NR1/NR2B diheteromeric receptors than NR1/NR2A/NR2B triheteromeric receptors (Hatton and Paoletti, 2005), it is reasonable to speculate that most of the NMDA-induced cell death actions observed in the present study are primarily a result of activation of NR1/NR2B receptors. In contrast, although the sensitivity of NVP-AAM077 toward the NR1/NR2A/NR2B triheteromeric receptors has not been investigated previously, because NVP-AAM077 is a competitive antagonist at the agonist binding sites of NR2A subunits and because both binding sites need to be occupied to open the channel, we speculate that NVP-AAM077 may inhibit all NR2A-containing receptors.…”

Section: Discussionmentioning

confidence: 70%

“…However, several recent studies have demonstrated that such a marginal effect may not significantly alter the utility of NVP-AAM077 as an NR2A-subunit preferential antagonist under experimental conditions such as in the present study Massey et al, 2004;Tigaret et al, 2006). Previous studies have indicated that Ro 25-6981 specifically blocks NR1/NR2B diheteromeric NMDA receptors with little effect on NR1/ NR2A/NR2B triheteromeric NMDA receptors (Hatton and Paoletti, 2005). The relative potency of NVP-AAM077 for NR1/ NR2A/NR2B versus NR1/NR2A receptors remains to be determined; however, considering that NVP-AAM077 is a competitive antagonist at glutamate binding sites, and that both glutamate binding sites must be occupied to open the channel Westbrook, 1991, 1994), it is likely able to block all NR2A-containing NMDA receptors.…”

Section: Resultsmentioning

confidence: 98%

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

Liu¹,

Wong²,

Aarts³

et al. 2007

J. Neurosci.

702

608

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Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

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“…NMDARs containing the NR2A subunit exhibit high affinity voltage-independent inhibition by Zn 2+ [23]. The molecular determinants of high affinity zinc binding have been demonstrated to lie in the amino terminal domain of the NR2A subunit [24]. Studies of Gielen et al [25] and Erreger et al [26] suggest an allosteric interaction between Zn 2+ and glutamate binding domains on NR2A.…”

Section: Discussionmentioning

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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Modulation of Triheteromeric NMDA Receptors by N-Terminal Domain Ligands

Cited by 213 publications

References 50 publications

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

Alcohol Inhibits NR2B-Containing NMDA Receptors in the Ventral Bed Nucleus of the Stria Terminalis

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

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

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