[Beta]IV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier.
beta-Spectrin and ankyrin are major components of the membrane cytoskeleton. We have generated mice carrying a null mutation in the betaIV-spectrin gene using gene trapping in embryonic stem cells. Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. betaIV-spectrin expression is mostly restricted to neurons, where it colocalizes with and binds to ankyrin-G at axon initial segments (AISs) and nodes of Ranvier (NR). In betaIV-spectrin-null neurons, neither ankyrin-G nor voltage-gated sodium channels (VGSC) are correctly clustered at these sites, suggesting that impaired action potential caused by mislocalization of VGSC leads to the phenotype. Conversely, in ankyrin-G-null neurons, betaIV-spectrin is not localized to these sites. These results indicate that betaIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR.
Komada
Masayuki
M
Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. makomada@bio.titech.ac.jp
Soriano
Philippe
P
D000818:Animals; D017487:Ankyrins / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006614:Hindlimb / Q000002:abnormalities; D015640:Ion Channel Gating; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011901:Ranvier's Nodes / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015222:Sodium Channels / Q000378:metabolism*; D013049:Spectrin / Q000235:genetics / Q000378:metabolism*; D014202:Tremor / Q000235:genetics
C094681:Ank3 protein, mouse; D017487:Ankyrins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D015222:Sodium Channels; C417303:betaIV spectrin; D013049:Spectrin