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PICK1 interacts with PACSIN to regulate AMPA receptor internalization and cerebellar long-term depression.

Authors: Anggono, Victor  Koรง-Schmitz, Yeliz  Widagdo, Jocelyn  Kormann, Jan  Quan, Annie  Chen, Chih-Ming  Robinson, Phillip J  Choi, Se-Young  Linden, David J  Plomann, Markus  Huganir, Richard L 
Citation: Anggono V, etal., Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13976-81. doi: 10.1073/pnas.1312467110. Epub 2013 Aug 5.
Pubmed: (View Article at PubMed) PMID:23918399
DOI: Full-text: DOI:10.1073/pnas.1312467110

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.

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CRRD Object Information
CRRD ID: 13702399
Created: 2018-07-18
Species: All species
Last Modified: 2018-07-18
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.