Figure 10.

Proposed model for the NMDAR/PKC-dependent dorsal horn GluR2 internalization under persistent inflammatory pain conditions. NMDARs couple to AMPARs through PSD-95 (which binds to NR2A/2B) interaction with stargazin (which binds to GluR1, GluR2, and GluR4). Under normal conditions, ABP/GRIP binds to and anchors GluR2 at synapses. Under persistent inflammatory pain conditions, NMDAR activation causes Ca²⁺ influx and PKCα activation. The latter phosphorylates GluR2 at Ser⁸⁸⁰ and disrupts GluR2 binding to ABP/GRIP, which leads to GluR2 internalization. GluR2 internalization results in an increase of AMPAR Ca²⁺ permeability. The increase in [Ca²⁺]_i in dorsal horn neurons should initiate or potentiate a variety of Ca²⁺-dependent intracellular cascades that are associated with the maintenance of persistent inflammatory pain.