Retromer Sends mGluRs to Synapses, Promoting Pain

Retromer Sends mGluRs to Synapses, Promoting Pain

Proper trafficking of membrane proteins in exocytic and endocytic pathways is essential for normal neuronal function. After endocytosis, receptors can be transported to lysosomes, to the trans-Golgi network, or back to the plasma membrane. The route taken is determined by interactions with endosomal protein complexes, such as retromer.

The retromer complex includes a module for recognizing cargoes and a module that targets cargo toward the appropriate destination. The recognition module includes proteins of the vacuolar protein sorting-associated (VPS) protein family, such as VPS26A, whereas the targeting module contains proteins of the sorting nexin (SNX) family. SNX27 is unusual in that it both recognizes endocytosed cargoes that have PDZ domains (including many synaptic proteins), and directs these cargoes to be recycled to the plasma membrane. One such cargo is the AMPA receptor subunit GluA1, which SNX27 delivers to postsynaptic sites to mediate long-term potentiation (LTP).

Neuropathic pain results from plasticity in pain-sensing pathways, and like LTP, it is mediated at least partially by increased delivery of glutamate receptors—in this case, metabotropic glutamate receptors (mGluRs)—to the plasma membrane. Because mGluRs have a PDZ domain, Lin et al. asked whether SNX27, in association with retromer, directs mGluR insertion after spinal nerve ligation, a model of neuropathic pain. Consistent with this hypothesis, ligation-induced mechanical hypersensitivity was accompanied by increased expression of SNX27, VPS26A, and mGluR5 in rat dorsal horn neurons. The interaction between these proteins was also increased by nerve ligation. Moreover, knocking down SNX27 or VPS26A attenuated the increase in synaptic mGluR5 expression induced by nerve ligation and reduced ligation-induced mechanical hypersensitivity.

These results suggest that SNX27, as part of the retromer complex, promotes delivery of mGluR5 to synaptic membranes in dorsal horn neurons after spinal nerve ligation. This delivery appears to enhance synaptic responses to mechanical stimulation, thus resulting in hypersensitivity. Interfering with this targeting might therefore help to alleviate neuropathic pain.