Differential Control of Clustering of the Sodium Channels Nav1.2 and Nav1.6 at Developing CNS Nodes of Ranvier

Kaplan, Miriam R.; Cho, Min Hee; Ullian, Erik M.; Isom, Lori L.; Levinson, S. Rock; Barres, Ben A.

doi:10.1016/s0896-6273(01)00266-5

Cited by 271 publications

(254 citation statements)

References 70 publications

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“…We proposed that axonal ␤1 subunits located at the nodal-paranodal border may interact in cis with axonal contactin molecules in the paranode or in trans with glial Nf155 molecules at the nodal-paranodal border region. Alternatively, because we have also shown ␤1 expression in oligodendrocytes (53), it is possible that glial ␤1 subunits may interact in trans with axonal ␤1 subunits, in cis with glial Nf155, or in trans with axonal contactin molecules. In the present study, we tested the hypothesis that ␤1 interacts with Nf155 and showed that these molecules interact in our assay.…”

Section: Discussionmentioning

confidence: 84%

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

McEwen

Isom

2004

Journal of Biological Chemistry

103

101

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Voltage-gated sodium channels localize at high density in axon initial segments and nodes of Ranvier in myelinated axons. Sodium channels consist of a poreforming ␣ subunit and at least one ␤ subunit. ␤1 is a member of the immunoglobulin superfamily of cell adhesion molecules and interacts homophilically and heterophilically with contactin and Nf186. In this study, we characterized ␤1 interactions with contactin and Nf186 in greater detail and investigated interactions of ␤1 with NrCAM, Nf155, and sodium channel ␤2 and ␤3 subunits. Using Fc fusion proteins and immunocytochemical techniques, we show that ␤1 interacts with the fibronectin-like domains of contactin. ␤1 also interacts with NrCAM, Nf155, sodium channel ␤2, and Nf186 but not with sodium channel ␤3. The interaction of the extracellular domains of ␤1 and ␤2 requires the region 169 TEEEGKTDGEGNA 181 located in the intracellular domain of ␤2. Interaction of ␤1 with Nf186 results in increased Na v 1.2 cell surface density over ␣ alone, similar to that shown previously for contactin and ␤2. We propose that ␤1 is the critical communication link between sodium channels, nodal cell adhesion molecules, and ankyrin G .

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Section: Discussionmentioning

confidence: 84%

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

McEwen

Isom

2004

Journal of Biological Chemistry

103

101

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“…Based on their physiological properties, it would be expected that Na v 1.2 and Na v 1.6, which both produce rapidly activating and inactivating currents (32)(33)(34), would both support actionpotential generation. Consistent with this, Na v 1.6 is the predominant sodium channel at nodes of Ranvier (2), whereas Na v 1.2 is expressed along premyelinated CNS axons (3,22), which are known to conduct action potentials (35,36). There is evidence suggesting that some sodium channels, when colocalized with the NCX, can contribute to axonal degeneration.…”

Section: Discussionmentioning

confidence: 86%

“…During the development of myelinated CNS tracts, Na v 1.2 channels [which are also present along unmyelinated axons (3,20,21)] are initially expressed along premyelinated axons, with a transition to clusters of Na v 1.6 at mature nodes of Ranvier (3,22). In dysmyelinated axons from Shiverer mice, Na v 1.2 channels are retained, and Na v 1.6 is not expressed (3,23), and in axons from Plp͞Ϫ mice, which myelinate normally and then lose their myelin, there is a loss of Na v 1.6 clustering and increased expression of Na v 1.2 (24).…”

mentioning

confidence: 99%

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger

Craner

Newcombe

Black

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

423

305

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Although voltage-gated sodium channels are known to be deployed along experimentally demyelinated axons, the molecular identities of the sodium channels expressed along axons in human demyelinating diseases such as multiple sclerosis (MS) have not been determined. Here we demonstrate changes in the expression of sodium channels in demyelinated axons in MS, with Nav1.6 confined to nodes of Ranvier in controls but with diffuse distribution of Nav1.2 and Nav1.6 along extensive regions of demyelinated axons within acute MS plaques. Using triple-labeled fluorescent immunocytochemistry, we also show that Nav1.6, which is known to produce a persistent sodium current, and the Na ؉ ͞Ca 2؉ exchanger, which can be driven by persistent sodium current to import damaging levels of calcium into axons, are colocalized with ␤-amyloid precursor protein, a marker of axonal injury, in acute MS lesions. Our results demonstrate the molecular identities of the sodium channels expressed along demyelinated and degenerating axons in MS and suggest that coexpression of Nav1.6 and Na ؉ ͞Ca 2؉ exchanger is associated with axonal degeneration in MS.demyelinating diseases ͉ action potential conduction ͉ axonal degeneration

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“…In the CNS, oligodendroglia are known to similarly direct nodal Na ϩ channel clustering but are devoid of ERM proteins (26). We hypothesize that JN serves a CNS function similar to that of the ERM proteins in the PNS, based on its putative ERM-like actin-binding domain, its influence on oligodendroglial-process outgrowth͞branching to approach the putative target axons, and its selective positioning to the juxtanodal terminal loops next to the node.…”

Section: Jn: An Oligodendroglia Marker Of a Previously Unidentified Pmentioning

confidence: 97%

Juxtanodin: An oligodendroglial protein that promotes cellular arborization and 2′,3′-cyclic nucleotide-3′-phosphodiesterase trafficking

Zhang

Cao²,

Guo³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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In the process of screening cell-type-specific genes, we identified juxtanodin (JN), an oligodendroglial protein featuring a putative C-terminal actin-binding domain. At the cellular level, JN in the rat CNS colocalized with 2 ,3 -cyclic nucleotide-3 -phosphodiesterase (CNPase), a cytoskeleton-related oligodendroglial protein. In the myelin sheath, JN was found mainly in the abaxon and the lateral few terminal loops. Its apposition to the myelinated axon, through the latter, defined an axonal subregion, herewith termed juxtanode, at the Ranvier node-paranode junction. During forebrain ontogenesis, JN expression paralleled that of MBPs but lagged behind CNPase. Juxtanodin transfection promoted arborization of cultured OLN-93 cells and augmented endogenous CNPase expression and transport to the process arbors of cultured primary oligodendrocyte precursors. These results reveal JN as a cytoskeleton-related oligodendroglial protein that delineates the juxtanode and might serve oligodendrocyte motility, differentiation, or myelin-axon signaling. Functionally, JN may be involved in CNS myelination and͞or specialization of the node of Ranvier.myelin-axon interaction ͉ oligodendrocyte ͉ node of Ranvier ͉ cytoskeleton O ligodendroglia are highly specialized myelin-forming cells of the CNS. Adequate myelination serves to insulate and accelerate the propagation of action potentials. Abnormalities in myelin formation͞maintenance may underlie diverse neurological disorders, ranging from multiple sclerosis to schizophrenia (1, 2). Matched with highly specialized functions and unique architecture, various oligodendrocyte͞myelin-selective molecules, such as myelin basic protein (MBP), myelin-associated glycoprotein, and 2Ј,3Ј-cyclic nucleotide-3Ј-phosphodiesterase (CNPase), have been isolated and characterized (1, 3). It is likely that many more are yet to be revealed. The identification and characterization of such molecules will probably help elucidate molecular mechanisms of myelination and dys-or demyelinating diseases.The unique architecture of the myelin sheath entails specialized, yet elusive, cytoskeletal mechanisms of myelin-forming cells. Here, we report the molecular features, cellular expression, and functional roles of juxtanodin (JN), a previously unidentified cytoskeleton-related oligodendrocyte-specific protein. Materials and MethodsIdentification and Characterization of the mRNA. Cell-type-specific CNS genes were sought out by in situ hybridization histochemistry (ISH). Briefly, cDNA clones (n ϭ 1,500) from a rat brain cDNA library (Invitrogen) were sequenced and compared by BLAST searches against National Center for Biotechnology Information nucleotide and protein nonredundant databases (4). For the unannotated cDNA sequences (n ϭ 274), expression of the mRNAs in the CNS was mapped by ISH using digoxigeninlabeled riboprobes. A 3.6-kb cDNA clone with a predicted ORF encoding 282 amino acid residues was thereby identified, and the gene was subsequently named juxtanodin (JN). A search of EST databases revealed an...

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Differential Control of Clustering of the Sodium Channels Nav1.2 and Nav1.6 at Developing CNS Nodes of Ranvier

Cited by 271 publications

References 70 publications

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger

Juxtanodin: An oligodendroglial protein that promotes cellular arborization and 2′,3′-cyclic nucleotide-3′-phosphodiesterase trafficking

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Differential Control of Clustering of the Sodium Channels Nav1.2 and Nav1.6 at Developing CNS Nodes of Ranvier

Cited by 271 publications

References 70 publications

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

Heterophilic Interactions of Sodium Channel β1 Subunits with Axonal and Glial Cell Adhesion Molecules

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na v 1.2 and Na v 1.6 sodium channels and Na + /Ca 2 + exchanger

Juxtanodin: An oligodendroglial protein that promotes cellular arborization and 2′,3′-cyclic nucleotide-3′-phosphodiesterase trafficking

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Product

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Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger