Abstract
Removal of synaptic AMPA receptors is important for synaptic depression. Here, we characterize the roles of individual subunits in the inducible redistribution of AMPA receptors from the cell surface to intracellular compartments in cultured hippocampal neurons. The intracellular accumulation of GluR2 and GluR3 but not GluR1 is enhanced by AMPA, NMDA, or synaptic activity. After AMPA-induced internalization, homomeric GluR2 enters the recycling pathway, but following NMDA, GluR2 is diverted to late endosomes/lysosomes. In contrast, GluR1 remains in the recycling pathway, and GluR3 is targeted to lysosomes regardless of NMDA receptor activation. Interaction with NSF plays a role in regulated lysosomal targeting of GluR2. GluR1/GluR2 heteromeric receptors behave like GluR2 homomers, and endogenous AMPA receptors show differential activity-dependent sorting similar to homomeric GluR2. Thus, GluR2 is a key subunit that controls recycling and degradation of AMPA receptors after internalization.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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COS Cells
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Cell Membrane / metabolism
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Cells, Cultured
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Chlorocebus aethiops
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Cytoplasm / metabolism
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Endocytosis*
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Excitatory Amino Acid Agonists / pharmacology
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Hippocampus / cytology
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Hippocampus / metabolism*
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Intracellular Membranes / metabolism
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Lysosomes / metabolism
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N-Methylaspartate / pharmacology
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Neurons / metabolism*
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Protein Isoforms / metabolism
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Protein Structure, Tertiary / physiology
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RNA, Small Interfering / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, AMPA / chemistry
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Receptors, AMPA / deficiency
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism*
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Synapses / physiology
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Tissue Distribution
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Excitatory Amino Acid Agonists
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Protein Isoforms
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RNA, Small Interfering
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Receptors, AMPA
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glutamate receptor ionotropic, AMPA 3
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N-Methylaspartate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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glutamate receptor ionotropic, AMPA 2
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glutamate receptor ionotropic, AMPA 1