Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Na _v 1.6 in sensory neurons to promote neuropathic pain

Abstract

Palmitoylation of -catenin is critical to synapse plasticity and memory formation. We found that -catenin palmitoylation is also instrumental in the development of neuropathic pain. The abundances of palmitoylated -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 -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 -catenin, which was induced by the inflammatory cytokine TNF-, 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/-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.

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics

“…As mentioned before, zDHHC7 was reported to be activated upon insulin treatment in HEK293 cells (Du et al 2017). The abundance of zDHHC3 and S-acylation of its substrate d-catenin were increased upon exposure of cultured dorsal root ganglion neurons to the inflammatory cytokine TNF-a (Zhang et al 2018). Additionally, zDHHC3 enzymatic activity was reported to be controlled by tyrosine phosphorylation mediated by fibroblast growth factor receptor 1 (FGFR1) and Src kinases in neuroblastoma N2a cells (Lievens et al 2016).…”

Puerarin Relieves Paclitaxel-Induced Neuropathic Pain: The Role of Nav1.8 β1 Subunit of Sensory Neurons

“…Dorsal root ganglion neurons were dissociated via enzyme digestion as previously described with slight modifications (Xie et al, 2017; Zhang et al, 2018). In brief, L4-6 DRGs in control and paclitaxel rats were freed from their connective tissue sheaths and broken into pieces with a pair of sclerotic scissors in DMEM/F12 medium (Gibco, United States) under low temperature (in a mixture of ice and water).…”

Trafficking mechanisms underlying Nav channel subcellular localization in neurons

“…However, according to our experiments, an ABM Na v 1.6 mutant was still delivered (although not preferentially) to the AIS [56], suggesting that this isoform does not require AnkG as an adaptor. Interestingly, a recent report indicates that Na v 1.6 is transported to the surface of sensory neurons by a tripartite complex Na v 1.6/δ-catenin/KIF3A (as observed by SIM super-resolution three color colocalization experiments) [110], although the authors did not determine whether such interactions were direct or indirect through other proteins. Palmitoylation of δ-catenin facilitated the membrane-directed trafficking of Na v 1.6 in DRG neurons.…”