Specific Role of the Truncated βIV-Spectrin Σ6 in Sodium Channel Clustering at Axon Initial Segments and Nodes of Ranvier

Uemoto, Yoko; Suzuki, Sohei; Terada, Nobuo; Ohno, Nobuhiko; Ohno, Shinichi; Yamanaka, Shinya; Komada, Masayuki

doi:10.1074/jbc.m609223200

Cited by 35 publications

(50 citation statements)

References 28 publications

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“…Moreover, while it is likely that each isoform has a unique role in heart (e.g., β IVΣ6 -spectrin localizes Na v channels to AISs in neurons, ref. 28), the specific functions of β IV -spectrin splice variants in heart remain unknown. Based on conservation of the CaMKII-and ankyrin-G-binding motifs in Σ1 and Σ6 isoforms, we anticipate that both isoforms will be important for regulation of Na v channel activity and cell excitability.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, we identify β IV -spectrin, a key structural component required for ion channel clustering (including voltage-gated Na + channels) in the nervous system (27)(28)(29)(30)(31)(32)(33)(34), as a multifunctional regulatory stage for Na + channel signaling in excitable cells. β IV -spectrin targets critical structural and regulatory proteins to excitable membranes in heart and brain, and animal models harboring mutant β IV -spectrin alleles display aberrant cellular excitability and whole-animal physiology.…”

Section: Introductionmentioning

confidence: 99%

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A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Hund¹,

Koval²,

Li³

et al. 2010

J. Clin. Invest.

229

289

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Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltagegated Na + channels underlie cellular excitability and control neuronal communication, cardiac excitationcontraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na + channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β IV -spectrin as a multifunctional regulatory platform for Na + channels in mice. We found that β IV -spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β IV -spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na + channels, via direct phosphorylation by β IV -spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Hund¹,

Koval²,

Li³

et al. 2010

J. Clin. Invest.

229

289

View full text Add to dashboard Cite

show abstract

“…Mutant mouse studies showed that ␤IV⌺6 plays a specific role in nodal Nav channel clustering, whereas ␤IV⌺1 stabilizes nodal membrane integrity (3,4,7). Mutant mice lacking ␤IV⌺1 present nodal shape alterations, which are very similar to those observed in ⌬10 mice (3,4). Some degree of nodal protrusion was also observed in qv 3J mice (5).…”

Section: Discussionmentioning

confidence: 86%

“…In mammalian cells, the mechanical support of the plasma membrane, as well as the microscale organization of membrane-spanning proteins, is provided by the association of spectrins and ankyrins, which promote the formation of an actin-based network coupled to the inner surface of the plasma membrane (30). Mutant mouse studies showed that ␤IV⌺6 plays a specific role in nodal Nav channel clustering, whereas ␤IV⌺1 stabilizes nodal membrane integrity (3,4,7). Mutant mice lacking ␤IV⌺1 present nodal shape alterations, which are very similar to those observed in ⌬10 mice (3,4).…”

Section: Discussionmentioning

confidence: 99%

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Schwannomin-interacting Protein 1 Isoform IQCJ-SCHIP1 Is a Multipartner Ankyrin- and Spectrin-binding Protein Involved in the Organization of Nodes of Ranvier

Martin

Cifuentes‐Diaz

Devaux

et al. 2017

Journal of Biological Chemistry

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Edited by Velia M. FowlerThe nodes of Ranvier are essential regions for action potential conduction in myelinated fibers. They are enriched in multimolecular complexes composed of voltage-gated Nav and Kv7 channels associated with cell adhesion molecules. Cytoskeletal proteins ankyrin-G (AnkG) and ␤IV-spectrin control the organization of these complexes and provide mechanical support to the plasma membrane. IQCJ-SCHIP1 is a cytoplasmic protein present in axon initial segments and nodes of Ranvier. It interacts with AnkG and is absent from nodes and axon initial segments of ␤IV-spectrin and AnkG mutant mice. Here, we show that IQCJ-SCHIP1 also interacts with ␤IV-spectrin and Kv7.2/3 channels and self-associates, suggesting a scaffolding role in organizing nodal proteins. IQCJ-SCHIP1 binding requires a ␤IV-spectrin-specific domain and Kv7 channel 1-5-10 calmodulin-binding motifs. We then investigate the role of IQCJ-SCHIP1 in vivo by studying peripheral myelinated fibers in Schip1 knock-out mutant mice. The major nodal proteins are normally enriched at nodes in these mice, indicating that IQCJ-SCHIP1 is not required for their nodal accumulation. However, morphometric and ultrastructural analyses show an altered shape of nodes similar to that observed in ␤IV-spectrin mutant mice, revealing that IQCJ-SCHIP1 contributes to nodal membrane-associated cytoskeleton organization, likely through its interactions with the AnkG/␤IV-spectrin network. Our work reveals that IQCJ-SCHIP1 interacts with several major nodal proteins, and we suggest that it contributes to a higher organizational level of the AnkG/␤IV-spectrin network critical for node integrity.

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Reduced excitability in the dentate gyrus network of βIV‐spectrin mutant mice in vivo

et al. 2009

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The submembrane cytoskeletal meshwork of the axon contains the scaffolding protein betaIV-spectrin. It provides mechanical support for the axon and anchors membrane proteins. Quivering (qv(3j)) mice lack functional betaIV-spectrin and have reduced voltage-gated sodium channel (VGSC) immunoreactivity at the axon initial segment and nodes of Ranvier. Because VGSCs are critically involved in action potential generation and conduction, we hypothesized that qv(3j) mice should also show functional deficits at the network level. To test this hypothesis, we investigated granule cell function in the dentate gyrus of anesthetized qv(3j) mice after electrical stimulation of the perforant path in vivo. This revealed an impaired input-output relationship between stimulus intensity and granule cell population spikes and an enhanced paired-pulse inhibition of population spikes, indicating a reduced ability of granule cells to generate action potentials and decreased network excitability. In contrast, the input-output curve for evoked field excitatory postsynaptic potentials (fEPSPs) and paired-pulse facilitation of fEPSPs were unchanged, suggesting normal excitatory synaptic transmission at perforant path-granule cell synapses in qv(3j) mutants. To corroborate our findings, we analyzed the influence of VGSC density reduction on dentate network activity using an established computational model of the dentate gyrus network. This in silico approach confirmed that the loss of VGSCs is sufficient to explain the electrophysiological changes observed in qv(3j) mice. Taken together, our findings demonstrate that betaIV-spectrin is required for normal granule cell firing and for physiological levels of network excitability in the mouse dentate gyrus in vivo.

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Specific Role of the Truncated βIV-Spectrin Σ6 in Sodium Channel Clustering at Axon Initial Segments and Nodes of Ranvier

Cited by 35 publications

References 28 publications

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Schwannomin-interacting Protein 1 Isoform IQCJ-SCHIP1 Is a Multipartner Ankyrin- and Spectrin-binding Protein Involved in the Organization of Nodes of Ranvier

Reduced excitability in the dentate gyrus network of βIV‐spectrin mutant mice in vivo

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