Spatially restricted CK2 activity increases the affinity of Nav channels for ankG. (A) AISs have high densities of Nav channels (red) and ankG (green). (A, inset) Nodes of Ranvier have complementary distributions of ankyrins, with ankB at paranodes (red) and ankG at nodes (green). Bars, 5 μm. (B) CK2 is restricted to the AIS and nodes of Ranvier, where it promotes the interaction between Nav channels and ankG. AnkG also interacts with neurofascin-186 (NF-186) in a phosphorylation-dependent manner, and is linked to the cytoskeleton through βIV spectrin. In contrast, distal axons and paranodes contain ankB that is linked to the cytoskeleton through βII spectrin. CK2 is not present in these regions, resulting in a much lower affinity between Nav channels and ankB. (C) CK2 phosphorylates four serine residues in the AIS-targeting motif. This increases the affinity of the AIS-targeting motif for the ankyrin MBD by 1,000-fold. It is possible that the density of channels in the axon and at the AIS could be dynamically regulated through increasing or decreasing levels of CK2, or through the activity of yet-to-be identified phosphatases.
