Proteomic analysis of NMDA receptor–adhesion protein signaling complexes

Husi, Holger; Ward, Malcolm; Choudhary, Jyoti S.; Blackstock, Walter; Grant, Seth G. N.

doi:10.1038/76615

Cited by 1,109 publications

(996 citation statements)

References 52 publications

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“…The regulation of NMDAR is very complex and the present study did not dissect molecular pathways underlying NMDAR functional changes in mGluR5 À/À mouse. Interactions between NMDAR and mGluR5 likely occur through several mechanisms, for example, interactions with PKC (Conn and Pin, 1997), intracellular Homer/Shank proteins (Ango et al, 2001;Tu et al, 1999), other signaling molecules (Husi et al, 2000), which could mediate loss of the NMDAR function caused by lack of mGluR5 (Salter and Kalia, 2004).…”

Section: Discussionmentioning

confidence: 99%

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

Lipina

Weiss

Roder

2006

Neuropsychopharmacol

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In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5 + / + littermates, mGluR5 À/À mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5 À/À mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptorsFMK-801. PPI deficit of mGluR5 À/À mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia. Neuropsychopharmacology (2007) 32, 745-756.

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Section: Discussionmentioning

confidence: 99%

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

Lipina

Weiss

Roder

2006

Neuropsychopharmacol

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“…Although they are not exclusive locations, 9 NR2A is predominantly confined to synapses of mature neurons 5 while NR2B is distributed mainly extrasynaptically. [10][11][12] The synaptic NMDARs form large and dynamic signaling complexes in the postsynaptic membrane, 13 mainly by interaction of their intracellular NR2 C terminus with additional proteins such as postsynaptic density-95 (PSD-95), which functions as a scaffolding and organizer protein of the PSD. Synaptic NMDAR activity is extremely important for neuronal survival, 14,15 while the extrasynaptic NMDARs are coupled to cell-death pathways.…”

Section: Introductionmentioning

confidence: 99%

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

et al. 2007

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The N-methyl-D-aspartate receptor (NMDAR) is central to physiological and pathological functioning of neurons. Although promising results are beginning to be obtained in the treatment of dementias, clinical trials with NMDAR antagonists for stroke, trauma and neurodegenerative disorders, such as Hungtinton's disease, have failed before. In order to design effective therapies to prevent excitotoxic neuronal death, it is critical to characterize the consequences of excessive NMDAR activation on its expression and function. Previous data have reported partial downregulation of the NR1 and NR2B receptor subunits in response to excitotoxicity and cerebral ischemia. However, the effect of NMDAR overactivation on NR2A, a subunit fundamental to synaptic transmission and neuronal survival, is still elusive. In this study, we report the rapid and extensive proteolytic processing of NR2A, together with the scaffolding protein postsynaptic density-95 (PSD-95), induced by excitotoxic stimulation of cortical neurons in vitro and by transient focal cerebral ischemia. Processing of the C terminus of NR2A is irreversibly induced by brief agonist exposure of NR2B-containing receptors, and requires calcium influx and the activity of calpain, also responsible for PSD-95 cleavage. The outcome is a truncated NR2A subunit that is stable and capable to interact with NR1 at the surface of neurons, but lacking the structural domains required for association with scaffolding, downstream signaling and cytoskeletal proteins. Therefore, a rapid and significant uncoupling of synaptic NMDARs from downstream survival pathways is expected to occur during ischemia. This novel mechanism induced by excitotoxicity helps to explain the failure of most therapies based on NMDAR antagonists.

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“…A possible explanation might be the L-Cys excitotoxicity that suggested as coupled to NMDA receptors 29 that have a role in neuronal membrane adhesion. 50 A protective role for D-Cys has been suggested, acting via different biochemical pathway than the L-Cys. 51 Since the cysteine atop the SAMs is attached to the gold surface through a specific site, its thiol group, the neuronal membrane, interacts with the surface only via the Cys chiral sites.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Neuronal Growth on l- and d-Cysteine Self-Assembled Monolayers Reveals Neuronal Chiral Sensitivity

Baranes

Moshe

Alon

et al. 2014

ACS Chem. Neurosci.

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Studying the interaction between neuronal cells and chiral molecules is fundamental for the design of novel biomaterials and drugs. Chirality influences all biological processes that involve intermolecular interaction. One common method used to study cellular interactions with different enantiomeric targets is the use of chiral surfaces. Based on previous studies that demonstrated the importance of cysteine in the nervous system, we studied the effect of L-and D-cysteine on single neuronal growth. L-Cysteine, which normally functions as a neuromodulator or a neuroprotective antioxidant, causes damage at elevated levels, which may occur post trauma. In this study, we grew adult neurons in culture enriched with L-and D-cysteine as free compounds or as self-assembled monolayers of chiral surfaces and examined the effect on the neuronal morphology and adhesion. Notably, we have found that exposure to the L-cysteine enantiomer inhibited, and even prevented, neuronal attachment more severely than exposure to the D-cysteine enantiomer. Atop the L-cysteine surfaces, neuronal growth was reduced and degenerated. Since the cysteine molecules were attached to the surface via the thiol groups, the neuronal membrane was exposed to the molecular chiral site. Thus, our results have demonstrated high neuronal chiral sensitivity, revealing chiral surfaces as indirect regulators of neuronal cells and providing a reference for studying chiral drugs.

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Proteomic analysis of NMDA receptor–adhesion protein signaling complexes

Cited by 1,109 publications

References 52 publications

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice

Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95

Neuronal Growth on l- and d-Cysteine Self-Assembled Monolayers Reveals Neuronal Chiral Sensitivity

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