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

Shinji Matsuda, Wataru Kakegawa, Timotheus Budisantoso, Toshihiro Nomura, Kazuhisa Kohda, Michisuke Yuzaki

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)


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.

Original languageEnglish
Article number2759
JournalNature communications
Publication statusPublished - 2013

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


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