Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK.
Jun N-terminal kinases (JNKs) are implicated in various neuropathological conditions. However, physiological roles for JNKs in neurons remain largely unknown, despite the high expression level of JNKs in brain. Here, using bioinformatic and biochemical approaches, we identify the AMPA receptor GluR2L and GluR4 subunits as novel physiological JNK substrates in vitro, in heterologous cells and in neurons. Consistent with this finding, GluR2L and GluR4 associate with specific JNK signaling components in the brain. Moreover, the modulation of the novel JNK sites in GluR2L and GluR4 is dynamic and bi-directional, such that phosphorylation and de-phosphorylation are triggered within minutes following decreases and increases in neuronal activity, respectively. Using live-imaging techniques to address the functional consequence of these activity-dependent changes we demonstrate that the novel JNK site in GluR2L controls reinsertion of internalized GluR2L back to the cell surface following NMDA treatment, without affecting basal GluR2L trafficking. Taken together, our results demonstrate that JNK directly regulates AMPA-R trafficking following changes in neuronal activity in a rapid and bi-directional manner.
Thomas
Gareth M
GM
Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Lin
Da-Ting
DT
Nuriya
Mutsuo
M
Huganir
Richard L
RL
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000873:Anthracenes; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; C104724:glutamate receptor ionotropic, AMPA 4; D049452:Green Fluorescent Proteins; C432165:pyrazolanthrone; D016202:N-Methylaspartate; D048031:JNK Mitogen-Activated Protein Kinases; C104722:glutamate receptor ionotropic, AMPA 2