title: AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhou
authors.forename: S
authors.initials: S
authors.lastname: Lambert
authors.forename: P L
authors.initials: PL
authors.lastname: Malen
authors.forename: S
authors.initials: S
authors.lastname: Carpenter
authors.forename: L M
authors.initials: LM
authors.lastname: Boland
authors.forename: V
authors.initials: V
authors.lastname: Bennett
mesh_terms: D000200:Action Potentials; D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000378:metabolism*; D001259:Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism*; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009414:Nerve Growth Factors / Q000378:metabolism; D015345:Oligonucleotide Probes / Q000235:genetics; D011689:Purkinje Cells / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D017487:Ankyrins; D015815:Cell Adhesion Molecules; D009414:Nerve Growth Factors; C504593:Nfasc protein, mouse; D015345:Oligonucleotide Probes; D015222:Sodium Channels