We will study the roles of PICK1 (Protein Interacting with C Kinase-1) and its regulator, NSF (N-ethylmaleimide Sensitive Factor) in AMPA receptor (AMPAR) trafficking. AMPAR are the major source of excitatory currents in the CNS and changes in AMPAR synaptic abundance regulate synaptic strength. PICK1 and NSF bind to the C-terminal, cytoplasmic domain of the AMPAR GluR2 subunit, and have opposing roles in controlling AMPAR synaptic levels. PICK1 binds to GluR2 via a PDZ domain and colocalizes with AMPAR in endosome-like vesicles in hippocampal pyramidal neurons. PICK1 expression reduces AMPAR synaptic membrane abundance and PICK is implicated in the mechanism of long term depression (LTD), all indicating a role for PICK1 in AMPAR endocytosis. NSF, together with the SNAP proteins, is known for dissociating SNARE complexes. In the case of AMPAR, the interaction of NSF with GluR2 is necessary for maintaining AMPAR currents and synaptic abundance. Our recent work has revealed a novel function for NSF. NSF binds together with the SNAPs to the PICK1-GluR2 complex and displaces PICK1 from GluR2. By displacing an endocytosis factor, NSF maintains AMPAR in the synapse.
The Aims of this project are: 1) To determine the structural basis for assembly of the GluR2-PICK1-NSF-SNAP complex and its disassembly by NSF. We will define protein-protein contacts that stabilize the complex and determine whether the SNAPs transmit rotational torque from NSF to PICK1 during disassembly. We will determine the basis for the differential ability of alpha- and beta-SNAPs to disrupt PICK1-GluR2 complexes. 2) To determine the role of PICK1 in AMPAR trafficking. We will identify the starting and destination membranes and the roles of G proteins in the transport mechanism. 3) To determine regulation in vivo by physiologic stimuli, including the role of PICK1 in GluR2/GluR3 constitutive recycling. These studies will reveal basic mechanisms relevant to synapse regulation and memory formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067229-05
Application #
7163462
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Asanuma, Chiiko
Project Start
2003-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$491,418
Indirect Cost
Name
New York University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Pick, Joseph E; Ziff, Edward B (2018) Regulation of AMPA receptor trafficking and exit from the endoplasmic reticulum. Mol Cell Neurosci 91:3-9
Pick, Joseph E; Khatri, Latika; Sathler, Matheus F et al. (2017) mGluR long-term depression regulates GluA2 association with COPII vesicles and exit from the endoplasmic reticulum. EMBO J 36:232-244
Kim, Seonil; Pick, Joseph E; Abera, Sinedu et al. (2016) Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior. Learn Mem 23:435-41
Kim, Seonil; Titcombe, Roseann F; Zhang, Hong et al. (2015) Network compensation of cyclic GMP-dependent protein kinase II knockout in the hippocampus by Ca2+-permeable AMPA receptors. Proc Natl Acad Sci U S A 112:3122-7
Wincott, Charlotte M; Abera, Sinedu; Vunck, Sarah A et al. (2014) cGMP-dependent protein kinase type II knockout mice exhibit working memory impairments, decreased repetitive behavior, and increased anxiety-like traits. Neurobiol Learn Mem 114:32-9
Tukey, David S; Ziff, Edward B (2013) Ca2+-permeable AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and dopamine D1 receptors regulate GluA1 trafficking in striatal neurons. J Biol Chem 288:35297-306
Wincott, Charlotte M; Kim, Seonil; Titcombe, Roseann F et al. (2013) Spatial memory deficits and motor coordination facilitation in cGMP-dependent protein kinase type II-deficient mice. Neurobiol Learn Mem 99:32-7
Incontro, Salvatore; Ciruela, Francisco; Ziff, Edward et al. (2013) The type II cGMP dependent protein kinase regulates GluA1 levels at the plasma membrane of developing cerebellar granule cells. Biochim Biophys Acta 1833:1820-31
Peng, Xing-Xiang; Ziff, Edward B; Carr, Kenneth D (2011) Effects of food restriction and sucrose intake on synaptic delivery of AMPA receptors in nucleus accumbens. Synapse 65:1024-31
Wang, Jing; Goffer, Yossef; Xu, Duo et al. (2011) A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 115:812-21

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