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ßIV1 spectrin stabilizes the nodes of Ranvier and axon initial segments

¹ Experimental Diabetology and ² Department of Psychiatry, University of Technology Dresden, 01307 Dresden, Germany
³ Department of Cell Biology and Howard Hughes Medical Institute, Yale University, New Haven, CT 06510
⁴ Department of Otolaryngology, University of Goettingen, 37075 Goettingen, Germany
⁵ Centre de Recherches de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, 34293 Montpellier, France
⁶ Department of Neurosciences, University of Connecticut, Farmington, CT 06030

Address correspondence to M. Solimena, Medical School, University of Technology Dresden, Fetscherstrasse, 74, 01307 Dresden, Germany. Tel.: 49-351-4586611. Fax: 49-351-4586330. email: michele.solimena{at}mailbox.tu-dresden.de

Abstract

Saltatory electric conduction requires clustered voltage-gated sodium channels (VGSCs) at axon initial segments (AIS) and nodes of Ranvier (NR). A dense membrane undercoat is present at these sites, which is thought to be key for the focal accumulation of channels. Here, we prove that ßIV1 spectrin, the only ßIV spectrin with an actin-binding domain, is an essential component of this coat. Specifically, ßIV1 coexists with ßIV6 at both AIS and NR, being the predominant spectrin at AIS. Removal of ßIV1 alone causes the disappearance of the nodal coat, an increased diameter of the NR, and the presence of dilations filled with organelles. Moreover, in myelinated cochlear afferent fibers, VGSC and ankyrin G clusters appear fragmented. These ultrastructural changes can explain the motor and auditory neuropathies present in ßIV1 –/– mice and point to the ßIV1 spectrin isoform as a master-stabilizing factor of AIS/NR membranes.

Key Words: cytoskeleton; deafness; sciatic nerve; cochlea; cerebellum

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