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J. Cell Biol.,
Volume 143, Number 5, November 30, 1998 1295-1304
* Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina
27710; 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.
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01545; and § Department of Physiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455
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