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
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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. / Nakajima, Chikako; Kulik, Akos; Frotscher, Michael; Herz, Joachim; Schäfer, Michael; Bock, Hans H; May, Petra.
in: J BIOL CHEM, Jahrgang 288, Nr. 30, 26.07.2013, S. 21909-23.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - 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
AU - Nakajima, Chikako
AU - Kulik, Akos
AU - Frotscher, Michael
AU - Herz, Joachim
AU - Schäfer, Michael
AU - Bock, Hans H
AU - May, Petra
PY - 2013/7/26
Y1 - 2013/7/26
N2 - 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.
AB - 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.
KW - Amyloid Precursor Protein Secretases
KW - Animals
KW - Blotting, Western
KW - Cell Survival
KW - Cells, Cultured
KW - Embryo, Mammalian
KW - Female
KW - Gene Expression
KW - Guanylate Kinase
KW - Male
KW - Membrane Proteins
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - N-Methylaspartate
KW - Neurons
KW - Protein Binding
KW - Protein Subunits
KW - Receptors, LDL
KW - Receptors, N-Methyl-D-Aspartate
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction
KW - Synapses
KW - Synaptosomes
KW - Tumor Suppressor Proteins
U2 - 10.1074/jbc.M112.444364
DO - 10.1074/jbc.M112.444364
M3 - SCORING: Journal article
C2 - 23760271
VL - 288
SP - 21909
EP - 21923
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 30
ER -