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

6533b830fe1ef96bd129717c

RESEARCH PRODUCT

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

Michael Frotscher Michael Frotscher Michael K. E. Schäfer Michael K. E. Schäfer Hans H. Bock Chikako Nakajima Chikako Nakajima Joachim Herz Joachim Herz Petra May Petra May Akos Kulik

subject

Male N-Methylaspartate Cell Survival Blotting Western Gene Expression Mice Transgenic macromolecular substances AMPA receptor Biology CREB Receptors N-Methyl-D-Aspartate Biochemistry Mice Neurobiology Postsynaptic potential Animals Molecular Biology Cells Cultured Mice Knockout Neurons Reverse Transcriptase Polymerase Chain Reaction musculoskeletal neural and ocular physiology Tumor Suppressor Proteins Membrane Proteins Cell Biology Embryo Mammalian LRP1 Cell biology Protein Subunits Receptors LDL nervous system Synapses LDL receptor biology.protein NMDA receptor Female Amyloid Precursor Protein Secretases Signal transduction Disks Large Homolog 4 Protein Guanylate Kinases Postsynaptic density Low Density Lipoprotein Receptor-Related Protein-1 Protein Binding Signal Transduction Synaptosomes

description

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.

year	journal	country	edition	language
2013-06-14	Journal of Biological Chemistry

https://doi.org/10.1074/jbc.m112.444364