A kinetic analysis of the modulation of N‐methyl‐D‐aspartic acid receptors by glycine in mouse cultured hippocampal neurones.

Benveniste, Morris; Clements, John D.; Vyklický, Ladislav; Mayer, Mark L.

doi:10.1113/jphysiol.1990.sp018215

Cited by 210 publications

(185 citation statements)

References 32 publications

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“…Glycine has been shown to reduce the inactivation of NMDA responses (Mayer et al, 1989;Benveniste et al, 1990;Vyklicky et al, 1990). In 0.2 PM glycine, the I,,,, showed a noticeable glycine-dependent inactivation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Modulation of glycine affinity for NMDA receptors by extracellular Ca2+ in trigeminal neurons

Huang

1994

J. Neurosci.

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Glycine and the divalent cation Ca2+ play key roles in regulating the activity of excitatory amino acid NMDA receptor channels. There is accumulating evidence that the concentration of glycine at the synaptic cleft is below a saturated level. We examined the effect of external Ca2+ on NMDA responses in various concentrations of glycine in isolated trigeminal neurons. We found that external Ca2+ potentiated NMDA responses and this potentiation occurred only when glycine sites were unsaturated. Since single-channel conductance decreases in the high external Ca2+ solution, the observation cannot be explained by an increase in Ca2+ influx through the channels. Studying the dose- response curves for glycine in different Ca2+ solutions, we found that the apparent dissociation constant (EC50) for glycine decreases with increasing external Ca2+ concentrations. Kinetics studies of glycine binding to NMDA receptors indicated that external Ca2+ causes a decrease in the off rate of the glycine binding, while having no effect on the on rate. Our analyses suggest that the apparent glycine affinity increases by about 3.7 times in Ca-containing solution. Thus, external Ca2+ contributes to the unusually high glycine affinity for NMDA receptors and may have a role in regulating the NMDA receptor channel activities during intensive or sustained neuronal stimulation.

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Section: Resultsmentioning

confidence: 99%

Modulation of glycine affinity for NMDA receptors by extracellular Ca2+ in trigeminal neurons

Huang

1994

J. Neurosci.

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“…However, provided two glycine molecules must be bound for receptor activation to occur (Clements and Westbrook, 1991), then the results in this study suggest that the effect of calmodulin would be the same at other glycine concentrations. These considerations are also relevant to the fact that patch excision is known to prolong channel open times compared with the open times of cell-attached patches and removes glycinesensitive desensitization (Sather et al, 1992) caused by the negative allosteric effect of agonist binding at the glutamate site on the glycine affinity at the glycine site (Benveniste et al, 1990). Although the rates of channel closing and desensitization are therefore likely to be different for receptors on an intact cell, the effect of calmodulin will remain.…”

Section: Inhibition Of Nmda Receptor Single-channel Activity By Calmomentioning

confidence: 99%

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

Rycroft

Gibb

2002

J. Neurosci.

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NMDA receptors are glutamate-sensitive ion channel receptors that mediate excitatory synaptic transmission and are widely implicated in synaptic plasticity and integration of synaptic activity in the CNS. This is in part attributable to the high calcium permeability of the ion channel, which allows receptor activation to influence the intracellular calcium concentration and also the slow time course of NMDA receptor-mediated synaptic currents. NMDA receptor activity is also regulated by the intracellular calcium concentration through activation of various calcium-dependent proteins, including calmodulin, calcineurin, protein kinase C, and ␣-actinin-2. Here, we have shown that calmodulin reduces the duration of native NMDA receptor single-channel openings from 3.5 Ϯ 0.6 msec to 1.71 Ϯ 0.2 msec in agreement with previous studies on recombinant NMDA receptors (Ehlers et al., 1996). NMDA receptor single-channel amplitudes and shut times were not affected.However, calmodulin reduced the duration of groups of channel openings called superclusters, which determine the slow time course of synaptic currents, from 121 Ϯ 25.4 msec to 60.4 Ϯ 11.6 msec. In addition, total open time, number of channel openings, and charge transfer per supercluster were all reduced by calmodulin. A 68% decrease in charge transfer per supercluster suggests that calmodulin activation will significantly reduce calcium influx during synaptic transmission. These results suggest that calmodulin-dependent inhibition of NMDA receptors will reduce the amplitude and time course of excitatory synaptic currents and thus affect synaptic plasticity and integration of synaptic activity in the CNS.

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“…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]. The mechanisms underlying desensitization or inactivation of NMDAR are complicated.…”

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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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A kinetic analysis of the modulation of N‐methyl‐D‐aspartic acid receptors by glycine in mouse cultured hippocampal neurones.

Cited by 210 publications

References 32 publications

Modulation of glycine affinity for NMDA receptors by extracellular Ca2+ in trigeminal neurons

Modulation of glycine affinity for NMDA receptors by extracellular Ca2+ in trigeminal neurons

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

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

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