Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Nav1.6 in sensory neurons to promote neuropathic pain

Palmitoylation and painChronic pain is associated with inflammation and increased synaptic activity in sensory neurons. Zhang et al. found that induction of the inflammatory cytokine TNF-α after chemotherapy or nerve injury in rats promoted the formation of a complex between the cell adhesion protein δ-catenin, the voltage-gated sodium channel Nav1.6, and the kinesin motor protein KIF3A, which increased the trafficking of the sodium channel to the cell membrane. Formation of this complex was dependent on the palmitoylation of δ-catenin, and inhibiting the activity of palmitoyl acyltransferases prevented the increase in both Nav1.6 surface abundance in sensory neurons and pain sensitivity in rats. These findings reveal potential therapeutic targets for treating chronic, neuropathic pain in patients.Palmitoylation of δ-catenin is critical to synapse plasticity and memory formation. We found that δ-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated δ-catenin and the palmitoyl acyltransferase DHHC3 were increased in dorsal root ganglion (DRG) sensory neurons in rat models of neuropathic pain. Inhibiting palmitoyl acyltransferases or decreasing δ-catenin abundance in the DRG by intrathecal injection of 2-bromopalmitate or shRNA, respectively, alleviated oxaliplatin or nerve injury–induced neuropathic pain in the rats. The palmitoylation of δ-catenin, which was induced by the inflammatory cytokine TNF-α, facilitated its interaction with the voltage-gated sodium channel Nav1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Nav1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/δ-catenin/Nav1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.