PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 α-appendage and dynamin

Maria Fiuza, Christine Rostosky, Gabrielle Parkinson, Alexei Bygrave, Nagaraj Halemani, Marcio Baptista, Ira Milosevic, Jonathan Hanley

Research output: Contribution to journalArticle (Academic Journal)peer-review

29 Citations (Scopus)
208 Downloads (Pure)

Abstract

Clathrin-mediated endocytosis (CME) is used to internalize a diverse range of cargo proteins from the cell surface, often in response to specific signals. In neurons, the rapid endocytosis of GluA2-containing AMPA receptors (AMPARs) in response to NMDA receptor (NMDAR) stimulation causes a reduction in synaptic strength and is the central mechanism for long-term depression, which underlies certain forms of learning. The mechanisms that link NMDAR activation to CME of AMPARs remain elusive. PICK1 is a BAR domain protein required for NMDAR-dependent reductions in surface GluA2; however, the molecular mechanisms involved are unclear. In this study, we show that PICK1 makes direct, NMDAR-dependent interactions with the core endocytic proteins AP2 and dynamin. PICK1-AP2 interactions are required for clustering AMPARs at endocytic zones in dendrites in response to NMDAR stimulation and for consequent AMPAR internalization. We further show that PICK1 stimulates dynamin polymerization. We propose that PICK1 is a cargo-specific endocytic accessory protein required for efficient, activity-dependent AMPAR endocytosis.
Original languageEnglish
Pages (from-to)3323-3338
Number of pages16
JournalJournal of Cell Biology
Volume216
Issue number10
Early online date30 Aug 2017
DOIs
Publication statusPublished - 2 Oct 2017

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