Tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 constitutively interacts with ankyrin G

The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel Nav 1.8 is predominantly expressed in peripheral afferent neurons, but in case of neuronal injury an ectopic and detrimental expression of Nav 1.8 occurs in neurons of the CNS. In CNS neurons, Nav 1.2 and Nav 1.6 channels accumulate at the axon initial segment, the site of the generation of the action potential, through a direct interaction with the scaffolding protein ankyrin G (ankG). This interaction is regulated by protein kinase CK2 phosphorylation. In this study, we quantitatively analyzed the interaction between Nav 1.8 and ankG. GST pull-down assay and surface plasmon resonance technology revealed that Nav 1.8 strongly and constitutively interacts with ankG, in comparison to what observed for Nav 1.2. An ion channel bearing the ankyrin-binding motif of Nav 1.8 displaced the endogenous Nav 1 accumulation at the axon initial segment of hippocampal neurons. Finally, Nav 1.8 and ankG co-localized in skin nerves fibers. Altogether, these results indicate that Nav 1.8 carries all the information required for its localization at ankG micro-domains. The constitutive binding of Nav 1.8 with ankG could contribute to the pathological aspects of illnesses where Nav 1.8 is ectopically expressed in CNS neurons.