Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons

Jang Su Park, Nana Voitenko, Ronald S. Petralia, Xiaowei Guan, Ji Tian Xu, Jordan P. Steinberg, Kogo Takamiya, Andrij Sotnik, Olga Kopach, Richard L. Huganir, Yuan Xiang Tao

Research output: Contribution to journalArticlepeer-review

Abstract

Spinal cord GluR2-lacking AMPA receptors (AMPARs) contribute to nociceptive hypersensitivity in persistent pain, but the molecular mechanisms underlying this event are not completely understood. We report that complete Freund's adjuvant (CFA)-induced peripheral inflammation induces synaptic GluR2 internalization in dorsal horn neurons during the maintenance of CFA-evoked nociceptive hypersensitivity. This internalization is initiated by GluR2 phosphorylation at Ser 880 and subsequent disruption of GluR2 binding to its synaptic anchoring protein (GRIP), resulting in a switch of GluR2-containing AMPARs to GluR2-lacking AMPARs and an increase of AMPAR Ca 2+ permeability at the synapses in dorsal horn neurons. Spinal cord NMDA receptor-mediated triggering of protein kinase C (PKC) activation is required for the induction and maintenance of CFA-induced dorsal horn GluR2 internalization. Moreover, preventing CFA-induced spinal GluR2 internalization through targeted mutation of the GluR2 PKC phosphorylation site impairs CFA-evoked nociceptive hypersensitivity during the maintenance period. These results suggest that dorsal horn GluR2 internalization might participate in the maintenance of NMDA receptor/PKC-dependent nociceptive hypersensitivity in persistent inflammatory pain.

Original languageEnglish (US)
Pages (from-to)3206-3219
Number of pages14
JournalJournal of Neuroscience
Volume29
Issue number10
DOIs
StatePublished - Mar 11 2009

ASJC Scopus subject areas

  • Neuroscience(all)

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