The PICK1 Ca2+ sensor modulates N-methyl-D-aspartate (NMDA) receptor-dependent microRNA-mediated translational repression in neurons

Dipen Rajgor, Maria Fiuza, Gabrielle Parkinson, Jonathan Hanley

Research output: Contribution to journalArticle (Academic Journal)peer-review

8 Citations (Scopus)
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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+]free reduces 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.
Original languageEnglish
Pages (from-to)9774-9786
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number23
Early online date12 Apr 2017
DOIs
Publication statusPublished - 9 Jun 2017

Keywords

  • AMPA receptor (AMPAR)
  • Argonaute
  • calcium
  • dendrite
  • synaptic plasticity

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