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

12 September 2017

Congratulations to the laboratory of Dr Jon Hanley for their recent paper 'PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 α-appendage and dynamin', published in the Journal of Cell Biology.

AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Changes in synaptic strength (synaptic plasticity) underlie the development of neural circuits and their modification during learning, and are brought about by altering the number of synaptic AMPARs by tight regulation of endocytosis and endosomal recycling. Furthermore, AMPAR trafficking is affected in various neurological disorders, including Alzheimer’s, Huntington’s, brain ischaemia (stroke), etc.

For the down-regulation of synaptic strength, AMPARs must be rapidly and efficiently recruited to endocytic sites in response to NMDA receptor-mediated Ca2+ signals. A mechanism that provides the necessary Ca2+-regulated link between AMPARs and the core endocytic machinery for cargo selection has remained elusive.

We show that the Ca2+-sensing, AMPAR-binding protein PICK1 makes direct, functional interactions with dynamin and the endocytic adaptor complex AP2, which are regulated by NMDA receptor stimulation. PICK1 enhances dynamin polymerisation, and the PICK1-AP2 interaction is required for NMDA-stimulated clustering AMPA receptors at endocytic sites and for consequent AMPA receptor endocytosis, defining PICK1 as a cargo-specific endocytic accessory protein.

Further information

Paper:

'PICK1 regulates AMPA receptor endocytosis via direct interactions with AP2 α-appendage and dynamin' by Maria Fiuza, Christine M. Rostosky, Gabrielle T. Parkinson, Alexei M. Bygrave, Nagaraj Halemani, Marcio Baptista, Ira Milosevic, and Jonathan G. Hanley in the Journal of Cell Biology

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