title: The PICK1 Ca2+sensor modulatesN-methyl-d-aspartate (NMDA) receptor-dependent microRNA-mediated translational repression in neurons.
abstract: MicroRNAs (miRNAs) are important regulators of localized mRNA translation in neuronal dendrites. The presence of RNA-induced silencing complex proteins in these compartments and the dynamic miRNA expression changes that occur in response to neuronal stimulation highlight their importance in synaptic plasticity. Previously, we demonstrated a novel interaction between the major RNA-induced silencing complex component Argounaute-2 (Ago2) and the BAR (bin/amphiphysin/rvs) domain protein PICK1. PICK1 recruits Ago2 to recycling endosomes in dendrites, where it inhibits miRNA-mediated translational repression. Chemical induction of long-term depression via NMDA receptor activation causes the dissociation of Ago2 from PICK1 and a consequent increase in dendritic miRNA-mediated gene silencing. The mechanism that underlies the regulation of PICK1-Ago2 binding is unknown. In this study, we demonstrate that the PICK1-Ago2 interaction is directly sensitive to Ca2+ions so that high [Ca2+]freereduces PICK1 binding to Ago2. Mutating a stretch of C-terminal Ca2+-binding residues in PICK1 results in a complete block of NMDA-induced PICK1-Ago2 disassociation in cortical neurons. Furthermore, the same mutant also blocks NMDA-stimulated miRNA-mediated gene silencing. This study defines a novel mechanism whereby elevated [Ca2+] induced by NMDA receptor activation modulates Ago2 and miRNA activity via PICK1. Our work suggests a Ca2+-dependent process to regulate miRNA activity in neurons in response to the induction of long-term depression.
authors.affiliation: From the School of Biochemistry and the Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Dipen
authors.initials: D
authors.lastname: Rajgor
authors.affiliation: From the School of Biochemistry and the Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Fiuza
authors.affiliation: From the School of Biochemistry and the Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Gabrielle T
authors.initials: GT
authors.lastname: Parkinson
authors.affiliation: From the School of Biochemistry and the Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom jon.hanley@bristol.ac.uk.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Hanley
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003598:Cytoskeletal Proteins; D003712:Dendrites / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
chemical_list: C466422:AGO2 protein, human; C582332:Ago2 protein, rat; D060565:Argonaute Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; C498297:PICk1 protein, human; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium
keywords: AMPA receptor (AMPAR); Argonaute; calcium; dendrite; synaptic plasticity