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

authors

• Montersino Audrey
• Brachet Anna
• Ferracci Geraldine
• Fache Marie-Pierre
• Angles d'Ortoli Stephanie
• Liu Wenjing
• Rueda-Boroni Fanny
• Castets Francis
• Dargent Bénédicte

keywords

• TTX-R voltage gated sodium channels
• Axon initial segment
• Ankyrins

abstract

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.

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