LDL receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes
11.06.2013
Nakajima C, Kulik A, Frotscher M, Herz J, Schäfer M, Bock HH, May P.
J Biol Chem. 2013;288(30):21909-23
The LRP1 is located postsynaptically. Basal and NMDA-induced phosphorylation of CREB as well as NMDA target gene transcription are reduced in LRP1-deficient neurons. In control neurons NMDA promotes gamma-secretase-dependent
release of the LRP1 intracellular domain. However, pulldown and chromatin immunoprecipitation assays showed no direct interaction between the LRP1-ICD and either CREB or target gene promoters. On the other hand, NMDA-induced degradation of PSD-95 was impaired in the absence of LRP1 while 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.
