Source: https://www.nature.com/articles/nn.3859?error=cookies_not_supported&code=27ac902f-c277-436f-a420-27c38bec3543
Timestamp: 2019-04-26 06:29:10+00:00

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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 βI spectrin substitute for and rescue nodal Na+ channel clustering. In addition, channel clustering is also rescued after loss of nodal βIV spectrin by βI spectrin and ankyrin-R. In mice lacking both ankyrin-G and ankyrin-R, Na+ channels fail to cluster at nodes. Thus, ankyrin R–βI 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.
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We thank K. Susuki for discussions. This research was supported by US National Institutes of Health grants NS044916 (MNR), NS069688 (MNR), NS49119 (ECC), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and CURE (Citizens United for Research on Epilepsy). V.B. is an investigator of the Howard Hughes Medical Institute.
Department of Pathology, Yale University, New Haven, Connecticut, USA.
M.N.R. and T.S.-Y.H. conceived the project, designed the experiments and wrote the manuscript. D.R.Z. performed the electrophysiology experiments and analyzed the data. M.N.R. performed intravitreal injections of AAV. T.S.-Y.H. performed all other experiments and analyzed the data. K.-J.C. supervised the RT-qPCR experiments. K.-J.C., M.X., E.C.C., M.C.S. and V.B. provided crucial reagents, mice and support.
Correspondence to Matthew N Rasband.
Na+ channel clustering is delayed in AnkG-deficient axons.
AnkG-deficient nodes of Ranvier remain intact in aged mice.
AnkG-deficient nodes of Ranvier have Na+ channels that co-localize with AnkR and βI spectrin.
βIV spectrin is lost from many AnkG-deficient nodes.
AnkR is not detected at developing optic nerve nodes of Ranvier.
Schematic representation of the mechanisms of sodium channel clustering at nodes of Ranvier.
Na+ channels are clustered at nodes of Ranvier in exon 1b AnkG knockout (KO) mice.
Axon initial segments fail to form in AnkG-deficient retinal and dorsal root ganglion cells.
18 month-old old Six3-Cre;Ank3F/F mice.
18 month-old old Ank3F/F mice.

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