Evidence for functional native NMDA receptors activated by glycine or <scp>d</scp>‐serine alone in the absence of glutamatergic coagonist

Paudice, Paolo; Gemignani, Anita; Raiteri, Maurizio

doi:10.1046/j.1460-9568.1998.00302.x

Cited by 41 publications

(36 citation statements)

References 58 publications

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“…Many studies have reported trace glycine contamination of buffer solutions, ranging from 10 to 50 nM (Johnson and Ascher, 1987;Lerma et al, 1990;Zhang et al, 1997;Paudice et al, 1998). In our glycine concentration-response experiments, WT receptors exhibited no response to 10 nM glycine in the presence of 100 M glutamate (0.00 Ϯ 0.00; Fig.…”

Section: Resultsmentioning

confidence: 62%

The NR1 M3 Domain Mediates Allosteric Coupling in theN-Methyl-D-aspartate Receptor

Blanke

VanDongen²

2008

Mol Pharmacol

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N-Methyl-D-aspartate (NMDA) receptors play a critical role in both development of the central nervous system and adult neuroplasticity. However, although the NMDA receptor presents a valuable therapeutic target, the relationship between its structure and functional properties has yet to be fully elucidated. To further explore the mechanism of receptor activation, we characterized two gain-of-function mutations within the NR1 M3 segment, a transmembrane domain proposed to couple ligand binding and channel opening. Both mutants (A7Q and A7Y) displayed significant glycine-independent currents, indicating that their M3 domains may preferentially adopt a more activated conformation. Substituted cysteine modification experiments revealed that the glycine binding clefts of both A7Q and A7Y are inaccessible to modifying reagents and resistant to competitive antagonism. These data suggest that perturbation of M3 can stabilize the ligand binding domain in a closed cleft conformation, even in the absence of agonist. Both mutants also displayed significant glutamate-independent current and insensitivity to glutamate-site antagonism, indicating partial activation by either glycine or glutamate alone. Furthermore, A7Q and A7Y increased accessibility of the NR2 M3 domain, providing evidence for intersubunit coupling at the transmembrane level and suggesting that these NR1 mutations dominate the properties of the intact heteromeric receptor. The equivalent mutations in NR2 did not exhibit comparable phenotypes, indicating that the NR1 and NR2 M3 domains may play different functional roles. In summary, our data demonstrate that the NR1 M3 segment is functionally coupled to key structural domains in both the NR1 and NR2 subunits.

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Section: Resultsmentioning

confidence: 62%

The NR1 M3 Domain Mediates Allosteric Coupling in theN-Methyl-D-aspartate Receptor

Blanke

VanDongen²

2008

Mol Pharmacol

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“…More likely, synaptosomal NMDARs in Mg 2ϩ -free medium were already activated. Activation of NMDARs on noradrenergic terminals occurs by simply removing Mg 2ϩ from the medium (Paudice et al, 1998). Moreover, the preparation of synaptosomes itself leads to their partial depolarization (Saller and Salama, 1984), and activity of NR2B- Up to now, histamine was considered to interact with the polyamine site of the NMDAR (Brown et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Histamine Potentiates N-Methyl-d-aspartate Receptors by Interacting with an Allosteric Site Distinct from the Polyamine Binding Site

Burban¹,

Faucard²,

Armand³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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Histamine potentiates activation of native and recombinant Nmethyl-D-aspartate receptors (NMDARs), but its mechanisms of action and physiological functions in the brain remain controversial. Using four different models, we have further investigated the histamine-induced potentiation of various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also potentiated the NMDA-induced increase in intracellular calcium in the absence, as well as with saturating concentrations, of exogenous D-serine, indicating both glycine-dependent and glycine-independent components of its effect. In rat hippocampal synaptosomes, histamine strongly potentiated NMDA-induced [ 3 H]noradrenaline release. The profile of this response contained several signatures of the histaminemediated effect at neuronal or recombinant NMDARs. It was NR2B-selective, being sensitive to micromolar concentrations of ifenprodil. It was reproduced by tele-methylhistamine, the metabolite of histamine in brain, and it was antagonized by impromidine, an antagonist/inverse agonist of histamine on NMDA currents. Up to now, histamine was generally considered to interact with the polyamine site of the NMDAR. However, spermine did not enhance NMDA-induced [ H]ifenprodil binding, whereas histamine and tele-methylhistamine had no effect. In conclusion, the histamine-induced potentiation of NMDARs occurs in the brain under normal conditions. Histamine does not bind to the polyamine site, but to a distinct entity, the so-called histamine site of the NMDAR.Histamine neurons constitute a long and highly divergent system arising from the tuberomammillary nucleus in the posterior hypothalamus and projecting in a diffuse manner to many cerebral areas. The function of these neurons in the modulation of physiological processes such as arousal or cognitive functions is well documented, but their involvement in brain disorders remains poorly understood. In the brain, the effects of histamine are mediated by three histamine receptor subtypes (H 1 , H 2 , and H 3 ), which are all G protein-coupled receptors. Brain histamine is metabolized via transmethylation into tele-methylhistamine (MeHA) catalyzed by histamine N-methyltransferase, and this metabolite is devoid of any activity at histamine receptors (Brown et al., 2001).More than 15 years ago, histamine has been reported to act as a positive allosteric modulator of the N-methyl-Daspartate receptor (NMDAR). Histamine potentiated NMDA currents in isolated (Vorobjev et al., 1993) and cultured (Bekkers, 1993) hippocampal neurons. Its effect resulted from a direct interaction with the NMDAR, the potentiation being observed on recombinant NMDARs. Moreover, it was selective for receptors containing NR1

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“…Because exogenous D-serine potentiates NMDA receptormediated neurotransmission (8)(9)(10)(11)) and D-[ 3 H]serine selectively binds to the glycine site (6), D-serine has been proposed as an endogenous ligand for the strychnine-insensitive glycine site of the NMDA receptor (6). Activation of NMDA receptors requires the presence of a coagonist, initially thought to be glycine (8,(12)(13)(14), and a glycine-selective recognition domain has been localized on NMDA receptors (15)(16)(17).…”

mentioning

confidence: 99%

d -Serine is an endogenous ligand for the glycine site of the N -methyl- d -aspartate receptor

Mothet

Parent

Wolosker

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

1,050

719

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Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of D-serine with D-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied D-serine, which by itself did not potentiate NMDA receptormediated synaptic responses. Thus, D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses. D-Amino acids play prominent roles in bacteria but have not been thought to occur in substantial quantity or to have any important function in vertebrates. Recently, techniques to distinguish isomers of amino acids in routine assays have led to the identification in some mammalian tissues of substantial amounts of at least two D-amino acids, D-serine and D-aspartate (1). Although D-aspartate is present in selected neuronal populations in the brain, it is concentrated mainly in glands, especially the epinephrine-containing cells of the adrenal medulla, the posterior pituitary, and the pineal gland (2-4).In contrast, D-serine occurs primarily in the brain, with highest concentrations in regions enriched in N-methyl-D-aspartate (NMDA) receptors (5-7). In these areas immunohistochemical studies have localized D-serine to protoplasmic astrocytes, which ensheathe nerve terminals especially in areas of the brain enriched in NMDA receptors (7). Stimulation of the kainate subtype of glutamate receptor releases D-serine from protoplasmic astrocytes (7).Because exogenous D-serine potentiates NMDA receptormediated neurotransmission (8-11) and D-[ 3 H]serine selectively binds to the glycine site (6), D-serine has been proposed as an endogenous ligand for the strychnine-insensitive glycine site of the NMDA receptor (6). Activation of NMDA receptors requires the presence of a coagonist, initially thought to be glycine (8,(12)(13)(14), and a glycine-selective recognition domain has been localized on NMDA receptors (15-17). However, D-serine is at least as potent as glycine as a coagonist at this site (8,10,14). In addition, immunohistochemical studies have revealed an overlapping distribution of D-serine and NMDA receptor immunoreactivity in forebrain (7). In the developing cerebellum, D-serine is localized to Bergmann glia that regulate granule cell migration during development via NMDA receptors (7). In contrast, glycine immunoreactivity is localized differently from that of NMDA receptors except in the brainstem, where it closely parallels the distribution of NMDA receptors (7). Extracell...

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Evidence for functional native NMDA receptors activated by glycine or d‐serine alone in the absence of glutamatergic coagonist

Cited by 41 publications

References 58 publications

The NR1 M3 Domain Mediates Allosteric Coupling in theN-Methyl-D-aspartate Receptor

The NR1 M3 Domain Mediates Allosteric Coupling in theN-Methyl-D-aspartate Receptor

Histamine Potentiates N-Methyl-d-aspartate Receptors by Interacting with an Allosteric Site Distinct from the Polyamine Binding Site

d -Serine is an endogenous ligand for the glycine site of the N -methyl- d -aspartate receptor

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