AMPA receptor trafficking and synaptic plasticity require SQSTM1/p62.
SQSTM1/p62 is a multidomain/scaffold for the atypical protein kinase Cs (aPKC). Phosphorylation of AMPA receptors by PKC has been shown to regulate their insertion in the postsynaptic membrane. Here, we directly tested whether p62 could interact with AMPA receptor subunits and influence their trafficking and phosphorylation. GluR1 receptor intracellular loop L2-3 and the ZZ-type zinc finger domain of p62 are essential for the interaction between these two proteins. In this context, both p62 and aPKC-mediated phosphorylation were necessary for surface delivery of the receptor. Our findings reveal that p62 is the first protein identified that interacts with a region of the GluR receptor other than the C-terminal tail. Furthermore, mice deficient in p62 displayed impaired hippocampal CA1 long-term potentiation (LTP), along with diminished surface expression of GluR1 and phosphorylation of S818. Lastly, we identify a conserved sequence (ISExSL) shared by all p62 interacting-aPKC substrates. These findings support a model where p62 interaction and aPKC phosphorylation act together to mediate AMPA receptor trafficking and long-term synaptic plasticity in the hippocampus.
Jiang
Jianxiong
J
Department of Biological Sciences and Program in Cellular and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, USA.
Parameshwaran
Kodeeswaran
K
Seibenhener
M Lamar
ML
Kang
Myoung-Goo
MG
Suppiramaniam
Vishnu
V
Huganir
Richard L
RL
Diaz-Meco
Maria T
MT
Wooten
Marie W
MW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology*; D010766:Phosphorylation; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D000071456:Sequestosome-1 Protein; D009435:Synaptic Transmission
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D011493:Protein Kinase C; D018091:Receptors, AMPA; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C115015:PKC-3 protein