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

Palmitoylation of delta-catenin is critical to synapse plasticity and memory formation. We found that delta-catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated delta-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 delta-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 delta-catenin, which was induced by the inflammatory cytokine TNF-alpha, facilitated its interaction with the voltage-gated sodium channel Na(v)1.6 and the kinesin motor protein KIF3A, which promoted the trafficking of Na(v)1.6 to the plasma membrane in DRG neurons and contributed to mechanical hypersensitivity and allodynia in rats. These findings suggest that a palmitoylation-mediated KIF3A/delta-catenin/Na(v)1.6 complex enhances the transmission of mechanical and nociceptive signals; thus, blocking this mechanism may be therapeutic in patients with neuropathic pain.