Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (AMPA) receptor in neurons

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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 -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.

Original languageEnglish (US)
Article numbere113237
JournalPLoS One
Volume9
Issue number12
DOIs
StatePublished - Dec 12 2014

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Low Density Lipoprotein Receptor-Related Protein-1
Lipoprotein Receptors
Isoxazoles
AMPA Receptors
low density lipoprotein
Neurons
neurons
lipoproteins
receptors
Proteins
proteins
Phosphorylation
Neurodegenerative diseases
Ionotropic Glutamate Receptors
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Pseudopodia
Neuronal Plasticity
phosphorylation
Long-Term Potentiation
Gene Deletion

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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title = "Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (AMPA) receptor in neurons",
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 -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.",
author = "Ming Gan and Peizhou Jiang and McLean, {Pamela J} and Takahisa Kanekiyo and Bu, {Guojun D}",
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T1 - Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (AMPA) receptor in neurons

AU - Gan, Ming

AU - Jiang, Peizhou

AU - McLean, Pamela J

AU - Kanekiyo, Takahisa

AU - Bu, Guojun D

PY - 2014/12/12

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