title: Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression.
abstract: NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the hippocampus is mediated primarily by the calcium-dependent removal of AMPA receptors (AMPARs) from the postsynaptic density. The AMPAR-binding, PDZ (PSD-95/Dlg/ZO1) and BAR (Bin/amphiphysin/Rvs) domain-containing protein PICK1 has been implicated in the regulation of AMPAR trafficking underlying several forms of synaptic plasticity. Using a strategy involving small hairpin RNA-mediated knockdown of PICK1 and its replacement with recombinant PICK1, we performed a detailed structure-function analysis of the role of PICK1 in hippocampal synaptic plasticity and the underlying NMDAR-induced AMPAR trafficking. We found that PICK1 is not necessary for maintenance of the basal synaptic complement of AMPARs or expression of either metabotropic glutamate receptor-dependent LTD or NMDAR-dependent LTP. Rather, PICK1 function is specific to NMDAR-dependent LTD and the underlying AMPAR trafficking. Furthermore, although PICK1 does not regulate the initial phase of NMDAR-induced AMPAR endocytosis, it is required for intracellular retention of internalized AMPARs. Detailed biophysical analysis of an N-terminal acidic motif indicated that it is involved in intramolecular electrostatic interactions that are disrupted by calcium. Mutations that interfered with the calcium-induced structural changes in PICK1 precluded LTD and the underlying NMDAR-induced intracellular retention of AMPARs. These findings support a model whereby calcium-induced modification of PICK1 structure is critical for its function in the retention of internalized AMPARs that underlies the expression of hippocampal NMDAR-dependent LTD.
authors.affiliation: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304, USA.
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.forename: Samarjit
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Wade
authors.initials: W
authors.lastname: Morishita
authors.forename: Scarlett
authors.initials: S
authors.lastname: Fang
authors.forename: Josep
authors.initials: J
authors.lastname: Rizo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018683:Excitatory Amino Acid Agents; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D049452:Green Fluorescent Proteins; D008734:Methoxyhydroxyphenylglycol; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol