title: The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity.
abstract: Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
authors.affiliation: School of Biochemistry, Centre for Synaptic Plasticity, Medical Sciences Building and Dorothy Hodgkin Building, University of Bristol, University Walk, Bristol BS8 1TD, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rocca
authors.forename: Mascia
authors.initials: M
authors.lastname: Amici
authors.forename: Anna
authors.initials: A
authors.lastname: Antoniou
authors.forename: Elena
authors.initials: E
authors.lastname: Blanco Suarez
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Halemani
authors.forename: Kai
authors.initials: K
authors.lastname: Murk
authors.forename: Jennifer
authors.initials: J
authors.lastname: McGarvey
authors.forename: Nadia
authors.initials: N
authors.lastname: Jaafari
authors.forename: Jack R
authors.initials: JR
authors.lastname: Mellor
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hanley
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D051376:Actin-Related Protein 2-3 Complex / Q000037:antagonists & inhibitors / Q000502:physiology*; D000199:Actins / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D057809:HEK293 Cells; D006801:Humans; D009473:Neuronal Plasticity / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D009924:Organ Culture Techniques; D058105:Polymerization; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / 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; D020823:ADP-Ribosylation Factor 1
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