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Nat Commun. 2013;4:2759. doi: 10.1038/ncomms3759.

Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression.

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1] Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan [2] Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.


Long-term depression (LTD) underlies learning and memory in various brain regions. Although postsynaptic AMPA receptor trafficking mediates LTD, its underlying molecular mechanisms remain largely unclear. Here we show that stargazin, a transmembrane AMPA receptor regulatory protein, forms a ternary complex with adaptor proteins AP-2 and AP-3A in hippocampal neurons, depending on its phosphorylation state. Inhibiting the stargazin-AP-2 interaction disrupts NMDA-induced AMPA receptor endocytosis, and inhibiting that of stargazin-AP-3A abrogates the late endosomal/lysosomal trafficking of AMPA receptors, thereby upregulating receptor recycling to the cell surface. Similarly, stargazin's interaction with AP-2 or AP-3A is necessary for low-frequency stimulus-evoked LTD in CA1 hippocampal neurons. Thus, stargazin has a crucial role in NMDA-dependent LTD by regulating two trafficking pathways of AMPA receptors--transport from the cell surface to early endosomes and from early endosomes to late endosomes/lysosomes--through its sequential binding to AP-2 and AP-3A.

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