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

Shinji Matsuda (), Wataru Kakegawa, Timotheus Budisantoso, Toshihiro Nomura, Kazuhisa Kohda and Michisuke Yuzaki ()
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Shinji Matsuda: School of Medicine, Keio University
Wataru Kakegawa: School of Medicine, Keio University
Timotheus Budisantoso: School of Medicine, Keio University
Toshihiro Nomura: School of Medicine, Keio University
Kazuhisa Kohda: School of Medicine, Keio University
Michisuke Yuzaki: School of Medicine, Keio University

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3759

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