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

Chikako Nakajima,Akos Kulik,Michael Frotscher,Joachim Herz,Michael Schäfer,Hans H Bock,Petra May

doi:10.1074/jbc.m112.444364

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.

Highlights

LDL receptor-related protein 1 (LRP1)-deficient mice show severe neurological signs and symptoms
LRP1 Is Completely Absent from NestinCreLRP1lox/lox Neurons—The LDL receptor-related protein 1 (LRP1) is critically important for the normal functioning of the central nervous system, as shown by the analysis of different conditionally LRP1-deficient mouse models [2, 3]
Because the LRP1-ICD binds PSD-95 [24] and because PSD-95 is degraded in response to NMDA treatment [25], we examined whether NMDA-induced loss of PSD-95 was LRP1-dependent and LRP1 could regulate the composition of postsynaptic protein complexes

Summary

Background

LRP1-deficient mice show severe neurological signs and symptoms. Results: Neuronal LRP1 is cleaved by ␥-secretase and regulates NMDA-dependent signaling and protein turnover. Tion 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. LRP1 Modulates Postsynaptic Signaling action with the adaptor protein PSD-95 [6] and to mediate the transactivation of Trk receptors by an Src family kinase-dependent pathway [7] These distinct functions seem to play a role in securing neuronal viability and differentiation as well as preventing neural inflammation [3]. In the absence of direct transcriptional regulation by the LRP1-ICD, its role could be to regulate postsynaptic protein complexes, because in the absence of LRP1, NMDA-induced degradation of PSD-95 is reduced, its ubiquitination is increased, and internalization of the AMPA receptor subunit GluA1 is impaired

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION