Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting

Both acute and chronic changes in AMPA receptor (AMPAR) localization are critical for synaptic formation, maturation, and plasticity. Here I report that AMPARs are differentially sorted between recycling and degradative pathways following endocytosis. AMPAR sorting occurs in early endosomes and is r...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2000-11, Vol.28 (2), p.511-525
Main Author: Ehlers, M D
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Cell Compartmentation - physiology
Cell Membrane - metabolism
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases - metabolism
Dendrites - drug effects
Dendrites - metabolism
Endocytosis - drug effects
Endocytosis - physiology
Endosomes - metabolism
GABA Antagonists - pharmacology
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Picrotoxin - pharmacology
Protein Transport - drug effects
Protein Transport - physiology
Rats
Receptors, AMPA - metabolism
Receptors, N-Methyl-D-Aspartate - metabolism
Synapses - metabolism
Synaptic Transmission - drug effects
Synaptic Transmission - physiology
Tetrodotoxin - pharmacology
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Summary:Both acute and chronic changes in AMPA receptor (AMPAR) localization are critical for synaptic formation, maturation, and plasticity. Here I report that AMPARs are differentially sorted between recycling and degradative pathways following endocytosis. AMPAR sorting occurs in early endosomes and is regulated by synaptic activity and activation of AMPA and NMDA receptors. AMPAR intemalization triggered by NMDAR activation is Ca2+-dependent, requires protein phosphatases, and is followed by rapid membrane reinsertion. Furthermore, NMDAR-mediated AMPAR trafficking is regulated by PKA and accompanied by dephosphorylation and rephosphorylation of GluR1 subunits at a PKA site. In contrast, activation of AMPARs without NMDAR activation targets AMPARs to late endosomes and lysosomes, independent of Ca2+, protein phosphatases, or PKA. These results demonstrate that activity regulates AMPAR endocytic sorting, providing a potential mechanistic link between rapid and chronic changes in synaptic strength.
ISSN:0896-6273
DOI:10.1016/s0896-6273(00)00129-x