Nature Neuroscience
3, 1282 - 1290 (2000)
doi:10.1038/81814
Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalizationJerry W. Lin1, 2, William Ju3, 4, Kelly Foster1, 2, Sang Hyoung Lee1, 2, Gholamreza Ahmadian3, 4, Michael Wyszynski1, 2, Yu Tian Wang3, 4
& Morgan Sheng1, 21
Howard Hughes Medical Institute, Massachusetts General Hospital (Wellman 423), 50 Blossom Street, Boston, Massachusetts 02114, USA
2
Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, Massachusetts 02115, USA
3
Programme in Brain and Behavior and Division of Pathology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada
4
Department of Laboratory Medicine and Pathobiology, University of Toronto, 100 College St., Toronto, Ontario M5G 1X8, Canada
Internalization of postsynaptic AMPA receptors depresses excitatory transmission, but the underlying dynamics and mechanisms of this process are unclear. Using immunofluorescence and surface biotinylation, we characterized and quantified basal and regulated AMPA receptor endocytosis in cultured hippocampal neurons, in response to synaptic activity, AMPA and insulin. AMPA-induced AMPA receptor internalization is mediated in part by secondary activation of voltage-dependent calcium channels, and in part by ligand binding independent of receptor activation. Although both require dynamin, insulin- and AMPA-induced AMPA receptor internalization are differentially dependent on protein phosphatases and sequence determinants within the cytoplasmic tails of GluR1 and GluR2 subunits. AMPA receptors internalized in response to AMPA stimulation enter a recycling endosome system, whereas those internalized in response to insulin diverge into a distinct compartment. Thus, the molecular mechanisms and intracellular sorting of AMPA receptors are diverse, and depend on the internalizing stimulus.
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