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J. Biol. Chem., Vol. 282, Issue 9, 6548-6555, March 2, 2007

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Specific Role of the Truncated IV-Spectrin 6 in Sodium Channel Clustering at Axon Initial Segments and Nodes of Ranvier^*

Yoko Uemoto, So-ichiro Suzuki, Nobuo Terada, Nobuhiko Ohno, Shinichi Ohno, Shinya Yamanaka^¶, and Masayuki Komada¹

From the Department of Biological Sciences, Tokyo Institute of Technology, Yokohama 226-8501, the Department of Anatomy, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tyuo-shi, Yamanashi 409-3898, and the ^¶Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

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. IV-Spectrin, an essential component of the membrane skeleton at these sites, has an N-terminal-truncated isoform, 6, which is expressed at much higher levels than the full-length isoform 1. To investigate the role of IV-spectrin 6, we generated 1-deficient mice with a normal level of 6 expression (1^-/- mice), and compared their phenotypes with those of previously generated mice lacking both 1 and 6(16^-/- mice). The gross neurological defects observed in 16^-/- mice, such as hindleg contraction, were apparently ameliorated in 1^-/- mice. At cellular levels, 16^-/- and 1^-/- 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 16^-/- mice, were substantially recovered in 1^-/- mice. We conclude that the truncated IV-spectrin isoform 6 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.

Received for publication, September 28, 2006 , and in revised form, December 11, 2006.

^* This work was supported by Ministry of Education, Culture, Sports, Science, and Technology of Japan Grant-in-aid 18050011 and a research grant from the Kato Memorial Bioscience Foundation (to M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S2.

¹ To whom correspondence should be addressed: 4259-B-16 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan. Tel.: 81-45-924-5703; Fax: 81-45-924-5771; E-mail: makomada{at}bio.titech.ac.jp.

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