Persistent Inflammation Induces GluR2 Internalization via NMDA Receptor-Triggered PKC Activation in Dorsal Horn Neurons
Copyright policy )Persistent Inflammation Induces GluR2 Internalization via NMDA Receptor-Triggered PKC Activation in Dorsal Horn Neurons
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 Ser880and 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 Ca2+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.
- Johns Hopkins University School of Medicine United States
- Johns Hopkins University United States
- Johns Hopkins Medicine United States
- National Institutes of Health United States
- Howard Hughes Medical Institute United States
Inflammation, Male, Time Factors, Receptors, N-Methyl-D-Aspartate, Mice, Mutant Strains, Rats, Enzyme Activation, Posterior Horn Cells, Rats, Sprague-Dawley, Mice, Animals, Female, Receptors, AMPA, Protein Kinase C
Inflammation, Male, Time Factors, Receptors, N-Methyl-D-Aspartate, Mice, Mutant Strains, Rats, Enzyme Activation, Posterior Horn Cells, Rats, Sprague-Dawley, Mice, Animals, Female, Receptors, AMPA, Protein Kinase C
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