Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Regulates the Stability and Function of GluA1 α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) Receptor in Neurons
Year: 2014
Type: article
Abstract: The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor abundantly expressed in neurons. Increasing evidence demonstrates that LRP1 regulates synaptic integrity and function at the post synapses, at least partially by regulating glutamate receptors. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critical ionotropic glutamate receptors consisting of homotetramer or heterotetramer of GluA1-4 subunits and play an essential role in synaptic transmission and synaptic plasticity. Our previous work has shown that neuronal deletion of the Lrp1 gene in mice leads to decreased level of GluA1 and reduced long-term potentiation. To understand the underlying mechanism, we investigated the cellular and functional consequences of LRP1 deletion in primary neurons. Here, we show that LRP1 interacts with and regulates the cellular distribution and turnover of GluA1. LRP1 knockdown in mouse primary neurons led to accelerated turnover and decreased cell surface distribution of GluA1, which correspond to decreased phosphorylation of GluA1 at S845 and S831 sites. Decreased LRP1 expression also attenuated AMPA-evoked calcium influx and reduced GluA1-regulated neurite outgrowth and filopodia density. Our results reveal a novel mechanism by which LRP1 controls synaptic integrity and function, specifically by regulating GluA1 trafficking, phosphorylation and turnover. They further demonstrate that LRP1-GluA1 pathway may hold promises as a therapeutic target for restoring synaptic functions in neurodegenerative diseases.
Source: PLoS ONE
Institutions: Mayo Clinic, Mayo Clinic in Florida, Xiamen University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: ApoE Receptor Biology and Neurodegeneration, G1925073246, ApoE pathway in cerebrovascular Aβ clearance in Alzheimer's disease, G3715146861, G5558395656, ApoE isoform-specific therapy for Alzheimer disease, ApoE isoform-specific therapy for Alzheimer disease, G8090405959, ApoE and LRP1 in brain insulin signaling and glucose metabolism (Competitive Renewal), Regional, Synaptic, Cellular Modulation of Abeta Metabolism
OpenAlex ID: W2014886405