A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier

The scaffolding protein ankyrin-G is required for Na+ channel clustering at axon initial segments. It is also considered essential for Na+ channel clustering at nodes of Ranvier to facilitate fast and efficient action potential propagation. However, notwithstanding these widely accepted roles, we show here that ankyrin-G is dispensable for nodal Na+ channel clustering in vivo. Unexpectedly, in the absence of ankyrin-G, erythrocyte ankyrin (ankyrin-R) and its binding partner bI spectrin substitute for and rescue nodal Na+ channel clustering. In addition, channel clustering is also rescued after loss of nodal bIV spectrin by bI spectrin and ankyrin-R. In mice lacking both ankyrin-G and ankyrin-R, Na+ channels fail to cluster at nodes. Thus, ankyrin R-bI spectrin protein complexes function as secondary reserve Na+ channel clustering machinery, and two independent ankyrin-spectrin protein complexes exist in myelinated axons to cluster Na+ channels at nodes of Ranvier.