Stargazin regulates AMPA receptor trafficking through adaptor protein complexes during long-term depression.
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.
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.
Shinji
S
Matsuda
Wataru
W
Kakegawa
Timotheus
T
Budisantoso
Toshihiro
T
Nomura
Kazuhisa
K
Kohda
Michisuke
M
Yuzaki
D033963:Adaptor Protein Complex 3; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D016202:N-Methylaspartate / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D050656:Transcription Factor AP-2
D033963:Adaptor Protein Complex 3; D048868:Adaptor Proteins, Signal Transducing; C491912:CACNG2 protein, human; D015220:Calcium Channels; D018091:Receptors, AMPA; D050656:Transcription Factor AP-2; D016202:N-Methylaspartate