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Journal Article

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

MPS-Authors

Cobley,  Claire
Biophysical Chemistry, Institute of Physical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany;
Dept. New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Max Planck Society;

/persons/resource/persons76135

Spatz,  Joachim P.
Biophysical Chemistry, Institute of Physical Chemistry, University of Heidelberg, 69120 Heidelberg, Germany;
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

External Resource

https://pubs.acs.org/doi/10.1021/acsnano.0c00866
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https://doi.org/10.1021/acsnano.0c00866
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https://ndownloader.figstatic.com/files/22969427
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Citation

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, 14(6), 6866-6877. doi:10.1021/acsnano.0c00866.


Cite as: https://hdl.handle.net/21.11116/0000-0006-852A-5
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.