TY - JOUR
T1 - Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression
AU - Matsuda, Shinji
AU - Kakegawa, Wataru
AU - Budisantoso, Timotheus
AU - Nomura, Toshihiro
AU - Kohda, Kazuhisa
AU - Yuzaki, Michisuke
N1 - Funding Information:
We express great gratitude to J. Miyazaki (Osaka University) for providing the pCAGGS expression vector. We thank J. Motohashi, S. Narumi, E. Miura and A. Takahashi for their technical assistance. This work was supported by JST PRESTO to S.M., JST CREST to M.Y., JSPS KAKENHI to W.K. (23689012) and M.Y. (23240053, 23110009), the Keio Gijuku Academic Development Funds (S.M. and W.K.) and the Takeda Science Foundation (W.K. and M.Y.).
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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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U2 - 10.1038/ncomms3759
DO - 10.1038/ncomms3759
M3 - Article
C2 - 24217640
AN - SCOPUS:84887712658
SN - 2041-1723
VL - 4
JO - Nature Communications
JF - Nature Communications
M1 - 2759
ER -