Gutenberg Open Science: LRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7817

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DC Field	Value	Language
dc.contributor.author	Maier, Wladislaw	-
dc.contributor.author	Bednorz, Mariola	-
dc.contributor.author	Meister, Sabrina	-
dc.contributor.author	Roebroek, Anton	-
dc.contributor.author	Weggen, Sascha	-
dc.contributor.author	Schmitt, Ulrich	-
dc.contributor.author	Pietrzik, Claus	-
dc.date.accessioned	2022-10-04T10:18:52Z	-
dc.date.available	2022-10-04T10:18:52Z	-
dc.date.issued	2013	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/7832	-
dc.description.abstract	BACKGROUND: The N-methyl-D-aspartate receptors are key mediators of excitatory transmission and are implicated in many forms of synaptic plasticity. These receptors are heterotetrameres consisting of two obligatory NR1 and two regulatory subunits, usually NR2A or NR2B. The NR2B subunits are abundant in the early postnatal brain, while the NR2A/NR2B ratio increases during early postnatal development. This shift is driven by NMDA receptor activity. A functional interplay of the Low Density Lipoprotein Receptor Related Protein 1 (LRP1) NMDA receptor has already been reported. Such abilities as interaction of LRP1 with NMDA receptor subunits or its important role in tPa-mediated NMDA receptor signaling were already demonstrated. Moreover, mice harboring a conditional neuronal knock-out mutation of the entire Lrp1 gene display NMDA-associated behavioral changes. However, the exact role of LRP1 on NMDA receptor function remains still elusive. RESULTS: To provide a mechanistic explanation for such effects we investigated whether an inactivating knock-in mutation into the NPxY2 motif of LRP1 might influence the cell surface expression of LRP1 and NMDA receptors in primary cortical neurons. Here we demonstrate that a knock-in into the NPxY2 motif of LRP1 results in an increased surface expression of LRP1 and NR2B NMDA receptor subunit due to reduced endocytosis rates of LRP1 and the NR2B subunit in primary neurons derived from LRP1DeltaNPxY2 animals. Furthermore, we demonstrate an altered phosphorylation pattern of S1480 and Y1472 in the NR2B subunit at the surface of LRP1DeltaNPxY2 neurons, while the respective kinases Fyn and casein kinase II are not differently regulated compared with wild type controls. Performing co-immunoprecipitation experiments we demonstrate that binding of LRP1 to NR2B might be linked by PSD95, is phosphorylation dependent and this regulation mechanism is impaired in LRP1DeltaNPxY2 neurons. Finally, we demonstrate hyperactivity and changes in spatial and reversal learning in LRP1DeltaNPxY2 mice, confirming the mechanistic interaction in a physiological readout. CONCLUSIONS: In summary, our data demonstrate that LRP1 plays a critical role in the regulation of NR2B expression at the cell surface and may provide a mechanistic explanation for the behavioral abnormalities detected in neuronal LRP1 knock-out animals reported earlier.	en_GB
dc.description.sponsorship	DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin	de
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/2.0/	*
dc.subject.ddc	610 Medizin	de_DE
dc.subject.ddc	610 Medical sciences	en_GB
dc.title	LRP1 is critical for the surface distribution and internalization of the NR2B NMDA receptor subtype	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-7817	-
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 04 Medizin	de
jgu.organisation.number	2700	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Molecular neurodegeneration	de
jgu.journal.volume	8	de
jgu.pages.alternative	Art. 25	de
jgu.publisher.year	2013	-
jgu.publisher.name	BioMed central	de
jgu.publisher.place	London u.a.	de
jgu.publisher.uri	http://dx.doi.org/10.1186/1750-1326-8-25	de
jgu.publisher.issn	1750-1326	de
jgu.organisation.place	Mainz	-
jgu.identifier.pmid	23866919	-
jgu.subject.ddccode	610	de
opus.date.modified	2018-08-01T09:57:36Z	-
opus.subject.dfgcode	00-000	-
opus.organisation.string	FB 04: Medizin: Institut für Pathologie	de_DE
opus.identifier.opusid	25279	-
opus.importsource	pubmed	-
opus.institute.number	0423	-
opus.metadataonly	false	-
opus.type.contenttype	Keine	de_DE
opus.type.contenttype	None	en_EN
opus.affiliated	Meister, Sabrina	-
opus.affiliated	Pietrzik, Claus	-
jgu.publisher.doi	10.1186/1750-1326-8-25	de
jgu.organisation.ror	https://ror.org/023b0x485	-
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)

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