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

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 (AMP ARs) in response to NMDA receptor (NMD AR) 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 NMD AR activation to CME of AMP ARs remain elusive. PICK1 is a BAR domain protein required for NMD AR-dependent reductions in surface GluA2; however, the molecular mechanisms involved are unclear. In this study, we show that PICK1 makes direct, NMD AR-dependent interactions with the core endocytic proteins AP2 and dynamin. PICK1-AP2 interactions are required for clustering AMP ARs at endocytic zones in dendrites in response to NMD AR stimulation and for consequent AMP AR internalization. We further show that PICK1 stimulates dynamin polymerization. We propose that PICK1 is a cargospecific endocytic accessory protein required for efficient, activity-dependent AMP AR endocytosis.