Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression

Ami Citri, Samarjit Bhattacharyya, Cong Ma, Wade Morishita, Scarlett Fang, Jose Rizo-Rey, Robert C. Malenka

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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.

Original languageEnglish (US)
Pages (from-to)16437-16452
Number of pages16
JournalJournal of Neuroscience
Volume30
Issue number49
DOIs
StatePublished - Dec 8 2010

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AMPA Receptors
N-Methyl-D-Aspartate Receptors
Calcium
Neuronal Plasticity
Post-Synaptic Density
Complement Receptors
Metabotropic Glutamate Receptors
Endocytosis
Static Electricity
Small Interfering RNA
Hippocampus
Maintenance
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)

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Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression. / Citri, Ami; Bhattacharyya, Samarjit; Ma, Cong; Morishita, Wade; Fang, Scarlett; Rizo-Rey, Jose; Malenka, Robert C.

In: Journal of Neuroscience, Vol. 30, No. 49, 08.12.2010, p. 16437-16452.

Research output: Contribution to journalArticle

Citri, Ami ; Bhattacharyya, Samarjit ; Ma, Cong ; Morishita, Wade ; Fang, Scarlett ; Rizo-Rey, Jose ; Malenka, Robert C. / Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 49. pp. 16437-16452.
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