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  Conopeptide-functionalized nanoparticles selectively antagonize extrasynaptic n-methyl-d-aspartate receptors and protect hippocampal neurons from excitotoxicity in vitro

Valente, P., Kiryushko, D., Sacchetti, S., Machado, P., Cobley, C., Mangini, V., et al. (2020). Conopeptide-functionalized nanoparticles selectively antagonize extrasynaptic n-methyl-d-aspartate receptors and protect hippocampal neurons from excitotoxicity in vitro. ACS Nano, e-pup(866), A-L. doi:10.1021/acsnano.0c00866.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-852A-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-8B5E-5
Genre: Journal Article

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 Creators:
Valente, Pierluigi, Author
Kiryushko, Darya, Author
Sacchetti, Silvio, Author
Machado, Pedro, Author
Cobley, Claire1, 2, Author
Mangini, Vicenzo, Author
Porter, Alexandra, Author
Spatz, Joachim P.1, 3, Author              
Fleck, Roland, Author
Benfenati, Fabio, Author
Fiammengo, Roberto, Author
Affiliations:
1Biophysical Chemistry, Institute of Physical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany, ou_persistent22              
2Dept. New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Max Planck Society, ou_1497649              
3Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society, ou_2364731              

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Free keywords: Metal nanoparticles,Antagonists,Peptides and proteins,Nanoparticles,Inhibition
 Abstract: N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors controlling fundamental physiological processes in the central nervous system, such as learning and memory. Excessive activation of NMDARs causes excitotoxicity and results in neurodegeneration, which is observed in a number of pathological conditions. Because of their dichotomous role, therapeutic targeting of NMDAR is difficult. However, several lines of evidence suggest that excitotoxicity is predominantly linked to extrasynaptically located NMDARs. Here, we report on a nanoparticle-based strategy to inhibit extrasynaptic NMDARs exclusively and subtype selectively, while allowing synaptic NMDARs activity. We designed gold nanoparticles (AuNPs) carrying conopeptide derivatives conjugated on their poly(ethylene glycol) coating as allosteric NMDAR inhibitors and show that these nanoparticles antagonize exclusively extrasynaptic NMDAR-mediated currents in cultured hippocampal neurons. Additionally, we show that conopeptide-functionalized AuNPs are neuroprotective in an in vitro model of excitotoxicity. By using AuNPs carrying different allosteric inhibitors with distinct NMDAR subtype selectivity such as peptide conantokin-G or peptide conantokin-R, we suggest activation of extrasynaptic GluN2B-containing diheteromeric NMDARs as the main cause of excitotoxicity.

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Language(s): eng - English
 Dates: 2020-01-312020-06-012020-06-082020
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1021/acsnano.0c00866
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Title: ACS Nano
  Other : ACS Nano
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: e-pup (866) Sequence Number: - Start / End Page: A - L Identifier: ISSN: 1936-0851
CoNE: https://pure.mpg.de/cone/journals/resource/1936-0851