title: Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes.
abstract: The lipoprotein receptor LRP1 is essential in neurons of the central nervous system, as was revealed by the analysis of conditional Lrp1-deficient mouse models. The molecular basis of its neuronal functions, however, is still incompletely understood. Here we show by immunocytochemistry, electron microscopy, and postsynaptic density preparation that LRP1 is located postsynaptically. Basal and NMDA-induced phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) as well as NMDA target gene transcription are reduced in LRP1-deficient neurons. In control neurons, NMDA promotes γ-secretase-dependent release of the LRP1 intracellular domain (LRP1-ICD). However, pull-down and chromatin immunoprecipitation (ChIP) assays showed no direct interaction between the LRP1-ICD and either CREB or target gene promoters. On the other hand, NMDA-induced degradation of the postsynaptic scaffold protein PSD-95 was impaired in the absence of LRP1, whereas its ubiquitination was increased, indicating that LRP1 influences the composition of postsynaptic protein complexes. Accordingly, NMDA-induced internalization of the AMPA receptor subunit GluA1 was impaired in LRP1-deficient neurons. These results show a role of LRP1 in the regulation and turnover of synaptic proteins, which may contribute to the reduced dendritic branching and to the neurological phenotype observed in the absence of LRP1.
authors.affiliation: Department of Medicine II, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Chikako
authors.initials: C
authors.lastname: Nakajima
authors.forename: Akos
authors.initials: A
authors.lastname: Kulik
authors.forename: Michael
authors.initials: M
authors.lastname: Frotscher
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.forename: Hans H
authors.initials: HH
authors.lastname: Bock
authors.forename: Petra
authors.initials: P
authors.lastname: May
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051528:Guanylate Kinases / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D013574:Synaptosomes / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D008565:Membrane Proteins; D021122:Protein Subunits; D011973:Receptors, LDL; D016194:Receptors, N-Methyl-D-Aspartate; D025521:Tumor Suppressor Proteins; D016202:N-Methylaspartate; D051528:Guanylate Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Glutamate Receptors; Lipoprotein Receptor; Secretases; Signaling; Synapses