scholarly journals βIVΣ1 spectrin stabilizes the nodes of Ranvier and axon initial segments

2004 ◽  
Vol 166 (7) ◽  
pp. 983-990 ◽  
Author(s):  
Sandra Lacas-Gervais ◽  
Jun Guo ◽  
Nicola Strenzke ◽  
Eric Scarfone ◽  
Melanie Kolpe ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Actin Binding ◽  
Ultrastructural Changes ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Voltage Gated Sodium Channels ◽  
Dense Membrane ◽  
Afferent Fibers ◽  
Actin Binding Domain ◽  
Axon Initial Segments

Saltatory electric conduction requires clustered voltage-gated sodium channels (VGSCs) at axon initial segments (AIS) and nodes of Ranvier (NR). A dense membrane undercoat is present at these sites, which is thought to be key for the focal accumulation of channels. Here, we prove that βIVΣ1 spectrin, the only βIV spectrin with an actin-binding domain, is an essential component of this coat. Specifically, βIVΣ1 coexists with βIVΣ6 at both AIS and NR, being the predominant spectrin at AIS. Removal of βIVΣ1 alone causes the disappearance of the nodal coat, an increased diameter of the NR, and the presence of dilations filled with organelles. Moreover, in myelinated cochlear afferent fibers, VGSC and ankyrin G clusters appear fragmented. These ultrastructural changes can explain the motor and auditory neuropathies present in βIVΣ1 −/− mice and point to the βIVΣ1 spectrin isoform as a master-stabilizing factor of AIS/NR membranes.

scholarly journals βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier

2002 ◽  
Vol 156 (2) ◽  
pp. 337-348 ◽  
Author(s):  
Masayuki Komada ◽  
Philippe Soriano
Keyword(s):  
Sodium Channels ◽  
Embryonic Stem ◽  
Nodes Of Ranvier ◽  
Gene Trapping ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Membrane Cytoskeleton ◽  
Voltage Gated Sodium Channels ◽  
Axon Initial Segments ◽  
Sodium Channel Clustering

β-Spectrin and ankyrin are major components of the membrane cytoskeleton. We have generated mice carrying a null mutation in the βIV-spectrin gene using gene trapping in embryonic stem cells. Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. βIV-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 βIV-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, βIV-spectrin is not localized to these sites. These results indicate that βIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR.

scholarly journals Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms

2007 ◽  
Vol 177 (5) ◽  
pp. 857-870 ◽  
Author(s):  
Yulia Dzhashiashvili ◽  
Yanqing Zhang ◽  
Jolanta Galinska ◽  
Isabel Lam ◽  
Martin Grumet ◽  
...  
Keyword(s):  
Schwann Cells ◽  
Sodium Channels ◽  
Cytoskeletal Proteins ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Sites Of Action ◽  
Axon Initial Segments ◽  
Inside Out

Axon initial segments (AISs) and nodes of Ranvier are sites of action potential generation and propagation, respectively. Both domains are enriched in sodium channels complexed with adhesion molecules (neurofascin [NF] 186 and NrCAM) and cytoskeletal proteins (ankyrin G and βIV spectrin). We show that the AIS and peripheral nervous system (PNS) nodes both require ankyrin G but assemble by distinct mechanisms. The AIS is intrinsically specified; it forms independent of NF186, which is targeted to this site via intracellular interactions that require ankyrin G. In contrast, NF186 is targeted to the node, and independently cleared from the internode, by interactions of its ectodomain with myelinating Schwann cells. NF186 is critical for and initiates PNS node assembly by recruiting ankyrin G, which is required for the localization of sodium channels and the entire nodal complex. Thus, initial segments assemble from the inside out driven by the intrinsic accumulation of ankyrin G, whereas PNS nodes assemble from the outside in, specified by Schwann cells, which direct the NF186-dependent recruitment of ankyrin G.

scholarly journals βiv Spectrin, a New Spectrin Localized at Axon Initial Segments and Nodes of Ranvier in the Central and Peripheral Nervous System

2000 ◽  
Vol 151 (5) ◽  
pp. 985-1002 ◽  
Author(s):  
Stanny Berghs ◽  
Diego Aggujaro ◽  
Ronald Dirkx ◽  
Elena Maksimova ◽  
Paul Stabach ◽  
...  
Keyword(s):  
Tyrosine Phosphatase ◽  
Subcellular Fractionation ◽  
Actin Binding ◽  
Pleckstrin Homology Domain ◽  
Pleckstrin Homology ◽  
Nodes Of Ranvier ◽  
Specific Domain ◽  
Actin Binding Domain ◽  
Receptor Tyrosine Phosphatase ◽  
Axon Initial Segments

We report the identification of βIV spectrin, a novel spectrin isolated as an interactor of the receptor tyrosine phosphatase-like protein ICA512. The βIV spectrin gene is located on human and mouse chromosomes 19q13.13 and 7b2, respectively. Alternative splicing of βIV spectrin generates at least four distinct isoforms, numbered βIVΣ1–βIVΣ4 spectrin. The longest isoform (βIVΣ1 spectrin) includes an actin-binding domain, followed by 17 spectrin repeats, a specific domain in which the amino acid sequence ERQES is repeated four times, several putative SH3-binding sites and a pleckstrin homology domain. βIVΣ2 and βIVΣ3 spectrin encompass the NH2- and COOH-terminal halves of βIVΣ1 spectrin, respectively, while βIVΣ4 spectrin lacks the ERQES and the pleckstrin homology domain. Northern blots revealed an abundant expression of βIV spectrin transcripts in brain and pancreatic islets. By immunoblotting, βIVΣ1 spectrin is recognized as a protein of 250 kD. Anti–βIV spectrin antibodies also react with two additional isoforms of 160 and 140 kD. These isoforms differ from βIVΣ1 spectrin in terms of their distribution on subcellular fractionation, detergent extractability, and phosphorylation. In islets, the immunoreactivity for βIV spectrin is more prominent in α than in β cells. In brain, βIV spectrin is enriched in myelinated neurons, where it colocalizes with ankyrinG 480/270-kD at axon initial segments and nodes of Ranvier. Likewise, βIV spectrin is concentrated at the nodes of Ranvier in the rat sciatic nerve. In the rat hippocampus, βIVΣ1 spectrin is detectable from embryonic day 19, concomitantly with the appearance of immunoreactivity at the initial segments. Thus, we suggest that βIVΣ1 spectrin interacts with ankyrinG 480/270-kD and participates in the clustering of voltage-gated Na+ channels and cell-adhesion molecules at initial segments and nodes of Ranvier.

scholarly journals Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments

2001 ◽  
Vol 155 (5) ◽  
pp. 739-746 ◽  
Author(s):  
Scott M. Jenkins ◽  
Vann Bennett
Keyword(s):  
Adhesion Molecules ◽  
Sodium Channels ◽  
Action Potentials ◽  
Membrane Skeleton ◽  
Purkinje Neuron ◽  
Voltage Gated ◽  
Ankyrin G ◽  
Voltage Gated Sodium Channels ◽  
Cerebellar Purkinje Neurons ◽  
Axon Initial Segments

The axon initial segment is an excitable membrane highly enriched in voltage-gated sodium channels that integrates neuronal inputs and initiates action potentials. This study identifies Nav1.6 as the voltage-gated sodium channel isoform at mature Purkinje neuron initial segments and reports an essential role for ankyrin-G in coordinating the physiological assembly of Nav1.6, βIV spectrin, and the L1 cell adhesion molecules (L1 CAMs) neurofascin and NrCAM at initial segments of cerebellar Purkinje neurons. Ankyrin-G and βIV spectrin appear at axon initial segments by postnatal day 2, whereas L1 CAMs and Nav1.6 are not fully assembled at continuous high density along axon initial segments until postnatal day 9. L1 CAMs and Nav1.6 therefore do not initiate protein assembly at initial segments. βIV spectrin, Nav1.6, and L1 CAMs are not clustered in adult Purkinje neuron initial segments of mice lacking cerebellar ankyrin-G. These results support the conclusion that ankyrin-G coordinates the physiological assembly of a protein complex containing transmembrane adhesion molecules, voltage-gated sodium channels, and the spectrin membrane skeleton at axon initial segments.

scholarly journals Protein kinase CK2 contributes to the organization of sodium channels in axonal membranes by regulating their interactions with ankyrin G

2008 ◽  
Vol 183 (6) ◽  
pp. 1101-1114 ◽  
Author(s):  
Aline Bréchet ◽  
Marie-Pierre Fache ◽  
Anna Brachet ◽  
Géraldine Ferracci ◽  
Agnés Baude ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Protein Kinase Ck2 ◽  
Binding Motif ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
Axonal Initial Segment ◽  
Kinase Ck2

In neurons, generation and propagation of action potentials requires the precise accumulation of sodium channels at the axonal initial segment (AIS) and in the nodes of Ranvier through ankyrin G scaffolding. We found that the ankyrin-binding motif of Nav1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Nav channel interaction with ankyrins. Furthermore, we observed that CK2 is highly enriched at the AIS and the nodes of Ranvier in vivo. An ion channel chimera containing the Nav1.2 ankyrin-binding motif perturbed endogenous sodium channel accumulation at the AIS, whereas phosphorylation-deficient chimeras did not. Finally, inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.

scholarly journals Na+ channels get anchored…with a little help

2008 ◽  
Vol 183 (6) ◽  
pp. 975-977 ◽  
Author(s):  
Matthew N. Rasband
Keyword(s):  
Action Potentials ◽  
Na Channel ◽  
Na Channels ◽  
Nodes Of Ranvier ◽  
Ankyrin G ◽  
New Findings ◽  
Specific Accumulation ◽  
Channel Interactions ◽  
Kinase Ck2 ◽  
Axon Initial Segments

Neurons have high densities of voltage-gated Na+ channels that are restricted to axon initial segments and nodes of Ranvier, where they are responsible for initiating and propagating action potentials. New findings (Bréchet, A., M.-P. Fache, A. Brachet, G. Ferracci, A. Baude, M. Irondelle, S. Pereira, C. Leterrier, and B. Dargent. 2008. J. Cell Biol. 183:1101–1114) reveal that phosphorylation of several key serine residues by the protein kinase CK2 regulates Na+ channel interactions with ankyrin G. The presence of CK2 at the axon initial segment and nodes of Ranvier provides a mechanism to regulate the specific accumulation and retention of Na+ channels within these important domains.

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