KIF5B is critical for the forward transport and axonal function of Na_v1.8

Na_v1.8 is a tetrodotoxin-resistant voltage-gated sodium channel selectively expressed in primary sensory neurons. Peripheral inflammation and nerve injury induce Na_v1.8 accumulation in peripheral nerves. However, the mechanisms and related significance of channel accumulation in nerves are not clearly clarified. Now, researchers from Chinese Academy of Sciences (CAS) reveal that KIF5B is critical for the forward transport and axonal function of Na_v1.8.

PhD student SU Yuanyuan and her colleagues, under the supervision of Dr. BAO Lan at Shanghai Institute of Biochemistry and Cell Biology, CAS, used a series of in vivo and in vitro experiments to show that KIF5B promotes the forward transport of Na_v1.8 to the plasma membrane and axons in dorsal root ganglion (DRG) neurons of the rat. In peripheral inflammation induced through the intraplantar injection of complete Freund’s adjuvant, increased KIF5 expression and Na_v1.8 accumulation were observed in the sciatic nerve. The knockdown of KIF5B, a highly expressed member of the KIF5 protein family in DRGs, reduced the current density of Nav1.8 in both cultured DRG neurons and ND7-23 cells. KIF5B overexpression in ND7-23 cells increased the surface expression and current density of Na_v1.8, which were abolished through brefeldin A treatment, while these effects were lost in the KIF5B mutants defective in ATP hydrolysis or cargo binding. KIF5B overexpression also decreased the proteasome-associated degradation of Na_v1.8. Meanwhile, co-immunoprecipitation experiments showed interactions between the N-terminus of Na_v1.8 and the 511-620 amino acid sequence in the stalk domain of KIF5B.

Furthermore, KIF5B increased Na_v1.8 accumulation, Na_v1.8 current and neuronal excitability detected in the axons of cultured DRG neurons, which was completely abolished by the disruption of the interactions between KIF5B and the N-terminus of Na_v1.8. Thus, these results reveal that KIF5B is required for the forward transport and axonal function of Na_v1.8, suggesting a mechanism for the axonal accumulation of Na_v1.8 in inflammatory pain.

This work entitled “KIF5B promotes the forward transport and axonal function of the voltage-gated sodium channel Na_v1.8” was published in The Journal of Neuroscience on Nov 6, 2013. It was supported by the grants from the Chinese Academy of Sciences, National Natural Science Foundation of China, the Ministry of Science and Technology.