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© The Rockefeller University Press, 0021-9525/1998//1295 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1295-1304

Article

AnkyrinG Is Required for Clustering of Voltage-gated Na Channels at Axon Initial Segments and for Normal Action Potential Firing



Daixing Zhou*, Stephen Lambert{ddagger}, Peter L. Malen§, Scott Carpenter*, Linda M. Boland§, and Vann Bennett*

* Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710; {ddagger} Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01545; and § Department of Physiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-specific knockout of ankyrinG in the mouse cerebellum. Mutant mice exhibited a progressive ataxia beginning around postnatal day P16 and subsequent loss of Purkinje neurons. In mutant mouse cerebella, NaCh were absent from axon initial segments of granule cell neurons, and Purkinje cells showed deficiencies in their ability to initiate action potentials and support rapid, repetitive firing. Neurofascin, a member of the L1CAM family of ankyrin-binding cell adhesion molecules, also exhibited impaired localization to initial segments of Purkinje cell neurons. These results demonstrate that ankyrinG is essential for clustering NaCh and neurofascin at axon initial segments and is required for physiological levels of sodium channel activity.

Key Words: ankyrinG • sodium channel • neurofascin • clustering • action potential

Abbreviations used in this paper: NaCh, voltage-gated sodium channel(s); O2-ACSF, oxygenated artificial cerebrospinal fluid; P, postnatal day.

Cheryl Bock is gratefully acknowledged for culture and transfection of ES cells, as well as blastocyst injections. Paula Scotland is gratefully acknowledged for culture and identification of ES cells with homologous recombination.

This research was supported in part by a grant from the National Institutes of Health (V. Bennett), the McKnight Foundation (L.M. Boland) and the Edward J. Mallinckrodt, Jr. Foundation (S. Lambert).

Address all correspondence to Vann Bennett, Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710. Tel.: (919) 684-3105. Fax: (919) 684-3590. E-mail: vbennett{at}acpub.duke.edu


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