title: Inhibition of Arp2/3-mediated actin polymerization by PICK1 regulates neuronal morphology and AMPA receptor endocytosis.
abstract: The dynamic regulation of actin polymerization plays crucial roles in cell morphology and endocytosis. The mechanistic details of these processes and the proteins involved are not fully understood, especially in neurons. PICK1 is a PDZ-BAR-domain protein involved in regulated AMPA receptor (AMPAR) endocytosis in neurons. Here, we demonstrate that PICK1 binds filamentous (F)-actin and the actin-nucleating Arp2/3 complex, and potently inhibits Arp2/3-mediated actin polymerization. RNA interference (RNAi) knockdown of PICK1 in neurons induces a reorganization of the actin cytoskeleton resulting in aberrant cell morphology. Wild-type PICK1 rescues this phenotype, but a mutant PICK1, PICK1(W413A), that does not bind or inhibit Arp2/3 has no effect. Furthermore, this mutant also blocks NMDA-induced AMPAR internalization. This study identifies PICK1 as a negative regulator of Arp2/3-mediated actin polymerization that is critical for a specific form of vesicle trafficking, and also for the development of neuronal architecture.
authors.affiliation: MRC Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rocca
authors.forename: Stéphane
authors.initials: S
authors.lastname: Martin
authors.forename: Emma L
authors.initials: EL
authors.lastname: Jenkins
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hanley
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000502:physiology*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002465:Cell Movement; D003598:Cytoskeletal Proteins; D003599:Cytoskeleton / Q000378:metabolism; D004705:Endocytosis; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D018091:Receptors, AMPA