title: PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression.
abstract: The dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses is crucial for synaptic transmission, plasticity, learning, and memory. The protein interacting with C-kinase 1 (PICK1) directly interacts with GluA2/3 subunits of the AMPARs. Although the role of PICK1 in regulating AMPAR trafficking and multiple forms of synaptic plasticity is known, the exact molecular mechanisms underlying this process remain unclear. Here, we report a unique interaction between PICK1 and all three members of the protein kinase C and casein kinase II substrate in neurons (PACSIN) family and show that they form a complex with AMPARs. Our results reveal that knockdown of the neuronal-specific protein, PACSIN1, leads to a significant reduction in AMPAR internalization following the activation of NMDA receptors in hippocampal neurons. The interaction between PICK1 and PACSIN1 is regulated by PACSIN1 phosphorylation within the variable region and is required for AMPAR endocytosis. Similarly, the binding of PICK1 to the ubiquitously expressed PACSIN2 is also regulated by the homologous phosphorylation sites within the PACSIN2-variable region. Genetic deletion of PACSIN2, which is highly expressed in Purkinje cells, eliminates cerebellar long-term depression. This deficit can be fully rescued by overexpressing wild-type PACSIN2, but not by a PACSIN2 phosphomimetic mutant, which does not bind PICK1 efficiently. Taken together, our data demonstrate that the interaction of PICK1 and PACSIN is required for the activity-dependent internalization of AMPARs and for the expression of long-term depression in the cerebellum.
authors.affiliation: The Solomon H Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Anggono
authors.forename: Yeliz
authors.initials: Y
authors.lastname: Koç-Schmitz
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Widagdo
authors.forename: Jan
authors.initials: J
authors.lastname: Kormann
authors.forename: Annie
authors.initials: A
authors.lastname: Quan
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.forename: Markus
authors.initials: M
authors.lastname: Plomann
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004926:Escherichia coli; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; C117738:Pacsin1 protein, rat; D034741:RNA, Small Interfering; D018091:Receptors, AMPA
keywords: receptor trafficking; syndapin
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