Specific Role of the Truncated βIV-Spectrin Σ6 in Sodium Channel Clustering at Axon Initial Segments and Nodes of Ranvier

At axon initial segments and nodes of Ranvier in neurons, the spectrin membrane skeleton plays roles in physically stabilizing the plasma membrane integrity and in clustering voltage-gated sodium channels for proper conduction of the action potential. βIV-Spectrin, an essential component of the membrane skeleton at these sites, has an N-terminal-truncated isoform, Σ6, which is expressed at much higher levels than the full-length isoform Σ1. To investigate the role of βIV-spectrin Σ6, we generated Σ1-deficient mice with a normal level of Σ6 expression (Σ1-/- mice), and compared their phenotypes with those of previously generated mice lacking both Σ1 and Σ6(Σ1Σ6-/- mice). The gross neurological defects observed in Σ1Σ6-/- mice, such as hindleg contraction, were apparently ameliorated in Σ1-/- mice. At cellular levels, Σ1Σ6-/- and Σ1-/- neurons similarly exhibited waving and swelling of the plasma membrane at axon initial segments and nodes of Ranvier. By contrast, the levels of ankyrin G and voltage-gated sodium channels at these sites, which are significantly reduced in Σ1Σ6-/- mice, were substantially recovered in Σ1-/- mice. We conclude that the truncated βIV-spectrin isoform Σ6 plays a specific role in clustering voltage-gated sodium channels, whereas it is dispensable for membrane stabilization at axon initial segments and nodes of Ranvier.