GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions

Mao Lifang, Kogo Takamiya, Gareth Thomas, Da Ting Lin, Richard L. Huganir

Research output: Contribution to journalArticle

Abstract

PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein-protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the Ctermini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steadystate trafficking and endocytosis, but strikingly impaired activitydependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity-dependent AMPA-R trafficking.

Original languageEnglish (US)
Pages (from-to)19038-19043
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number44
DOIs
StatePublished - Nov 2 2010

Keywords

  • Endocytosis
  • KO
  • Long-term depression
  • NMDA
  • PSD-95/SAP90/DLG/ZO-1

ASJC Scopus subject areas

  • General

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