Tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 constitutively interacts with ankyrin G

The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel Na(v)1.8 is predominantly expressed in peripheral afferent neurons, but in case of neuronal injury an ectopic and detrimental expression of Na(v)1.8 occurs in neurons of the CNS. In CNS neurons, Na(v)1.2 and Na(v)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 Na(v)1.8 and ankG. GST pull-down assay and surface plasmon resonance technology revealed that Na(v)1.8 strongly and constitutively interacts with ankG, in comparison to what observed for Na(v)1.2. An ion channel bearing the ankyrin-binding motif of Na(v)1.8 displaced the endogenous Na(v)1 accumulation at the axon initial segment of hippocampal neurons. Finally, Na(v)1.8 and ankG co-localized in skin nerves fibers. Altogether, these results indicate that Na(v)1.8 carries all the information required for its localization at ankG micro-domains. The constitutive binding of Na(v)1.8 with ankG could contribute to the pathological aspects of illnesses where Na(v)1.8 is ectopically expressed in CNS neurons.