title: PICK1 links AMPA receptor stimulation to Cdc42.
abstract: Rho-family GTPases control numerous cell biological processes via effects on actin dynamics, such as cell migration, cell adhesion, morphogenesis and vesicle traffic. In neurons, they are involved in dendritic spine morphogenesis and other aspects of neuronal morphology via regulation of the actin cytoskeleton. The Rho-family member Cdc42 regulates dendritic spine morphology via its effector N-WASP, which activates the actin-nucleating Arp2/3 complex. Excitatory synaptic transmission is known to regulate actin dynamics in dendritic spines to bring about changes in spine morphology or motility, however, the details of the signalling pathways that transduce glutamate receptor activation to Rho GTPase function are unclear. PICK1 is a PDZ and BAR domain protein that interacts with the Arp2/3 complex and the GTPase Arf1 to regulate actin polymerisation in dendritic spines. PICK1 also binds AMPA receptor subunits GluA2/3 and is involved in GluA2-dependent AMPAR trafficking. Here, we show that PICK1 binds Rac1 and Cdc42, via distinct but overlapping binding sites. Furthermore, AMPAR stimulation deactivates Cdc42 and alters its detergent solubility in neurons via a PICK1-dependent process. This work suggests a novel role for PICK1 in transducing AMPAR stimulation to Cdc42 function in neurons.
authors.affiliation: School of Biochemistry, Medical Sciences Building,University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rocca
authors.affiliation: School of Biochemistry, Medical Sciences Building,University of Bristol, University Walk, Bristol BS8 1TD, UK. Electronic address: jon.hanley@bristol.ac.uk.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hanley
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D003902:Detergents / Q000737:chemistry; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D012995:Solubility; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D003902:Detergents; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D020764:cdc42 GTP-Binding Protein
keywords: Actin cytoskeleton; BAR domain; Glutamate receptor; PDZ domain; Rho-family GTPase