Abstract
Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / pharmacology
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Amino Acid Motifs / genetics
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Amino Acid Motifs / physiology
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Chlorocebus aethiops
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Cytoskeletal Proteins
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Embryo, Mammalian
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Endocytosis / drug effects
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Endocytosis / genetics
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GABA Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Green Fluorescent Proteins / genetics
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Hippocampus / cytology
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Homeostasis / genetics
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Homeostasis / physiology*
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Humans
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Immunoprecipitation / methods
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Intracellular Signaling Peptides and Proteins
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Microscopy, Confocal / methods
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N-Ethylmaleimide-Sensitive Proteins / genetics
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N-Ethylmaleimide-Sensitive Proteins / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Picrotoxin / pharmacology
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Protein Binding / drug effects
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Protein Binding / physiology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Protein Transport
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RNA Interference / physiology
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Rats
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Receptors, AMPA / metabolism*
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Synapses / drug effects
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Synapses / metabolism
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Time Factors
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Transfection / methods
Substances
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Carrier Proteins
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Cytoskeletal Proteins
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GABA Antagonists
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Grip1 protein, rat
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Intracellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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PICK1 protein, rat
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Receptors, AMPA
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Picrotoxin
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Green Fluorescent Proteins
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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Plk2 protein, rat
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N-Ethylmaleimide-Sensitive Proteins
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glutamate receptor ionotropic, AMPA 2