Molecular cloning, distribution and functional analysis of the NAV1.6. Voltage-gated sodium channel from human brain

Burbidge, Stephen A.; Dale, Timothy; Powell, Andrew J.; Whitaker, William R. J.; Xie, Xinmin; Romanos, Michael A.; Clare, Jeffrey J.

doi:10.1016/s0169-328x(02)00188-2

Cited by 83 publications

(97 citation statements)

References 30 publications

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“…In contrast, dysmyelinating CNS axons, which express Na v 1.2 rather than Na v 1.6, (3,23), are substantially less sensitive than myelinated axons to this type of injury (53). Na v 1.6 channels produce a persistent current in addition to a transient current (33,37), and the persistent current produced by Na v 1.6 is much larger than the persistent current produced by Na v 1.2 (33). Herzog et al (38) performed patchclamp analysis on dorsal root ganglion neurons expressing recombinant Na v 1.6 channels and detected persistent Na v 1.6 currents in all cells that were studied.…”

Section: Discussionmentioning

confidence: 99%

“…Na v 1.2 channels produce rapidly activating and inactivating currents (32)(33)(34) and appear to support actionpotential conduction, which occurs before myelination (35,36), suggesting that newly produced Na v 1.2 channels can support conduction in demyelinated axons. Na v 1.6 channels, on the other hand, produce a persistent current in addition to rapidly activating and inactivating currents (33,37,38), and Na v 1.6 is coexpressed together with the Na ϩ ͞Ca 2ϩ exchanger (NCX) along degenerating axons in EAE (31).…”

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confidence: 99%

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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

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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Section: Discussionmentioning

confidence: 99%

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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“…Cell Culture and Transfection-HEK293 cells stably expressing Nav1.6 were obtained from Dr. J. J. Clare (28) and grown in DMEM supplemented with 10% (v/v) FBS and 400 g/ml G418 (Invitrogen). HEK293 Nav1.6 cells were transfected with various plasmids using Effectene transfection reagent (Qiagen) or with siRNA using Lipofectamine RNAiMAX transfection reagent (Invitrogen) according to the instructions of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Liu

Tan

Xiao

et al. 2015

Journal of Biological Chemistry

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Background: Loss-of-function amyloid precursor protein (APP) and Nav1.6 transgenic mice share similar phenotypes. Results: APP interacts with Nav1.6 and enhances its cell surface expression through a G o -coupled JNK pathway. Conclusion: APP regulates Nav1.6 function, likely through a G o -coupled JNK pathway. Significance: This finding advances the current understanding of APP functions and has implications for novel therapies for neurodegenerative disorders.

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“…This was then inserted upstream of the internal ribosome entry site (IRES) element in the mammalian expression vector pCIN5 (Rees et al, 1996). Cell lines stably expressing hNa v 1.1 were isolated after transfection of human embryonic kidney (HEK) 293 cells with 2 g of pCIN5-hNa v 1.1 and selection for 3-4 weeks in 800 g/ml Geneticin-G418 (Burbidge et al, 2002). Clonal cell lines CL1 and CL2 were isolated after two rounds of single-cell dilution cloning.…”

Section: Methodsmentioning

confidence: 99%

Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

Mantegazza¹,

Yu²,

Powell³

et al. 2005

J. Neurosci.

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Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current, I NaP , has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein ␤␥ subunits increase I NaP , but the sodium channel subtypes that conduct I NaP and the target site(s) on the sodium channel molecule required for modulation by G␤␥ are poorly defined. Here, we show that I NaP conducted by Na v 1.1 and Na v 1.2 channels (Na v 1.1 Ͼ Na v 1.2) is modulated by G␤␥; Na v 1.4 and Na v 1.5 channels produce smaller I NaP that is not regulated by G␤␥. These qualitative differences in modulation by G␤␥ are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by G␤␥. However, the C-terminal domains determine the quantitative extent of modulation of Na v 1.2 channels by G␤␥. Studies of chimeric and truncated Na v 1.2 channels identify molecular determinants that affect modulation of I NaP located between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by G␤␥ when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I NaP and identify crucial molecular determinants in the C-terminal domain required for modulation by G␤␥ when attached to the transmembrane body of a responsive sodium channel.

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Molecular cloning, distribution and functional analysis of the NAV1.6. Voltage-gated sodium channel from human brain

Cited by 83 publications

References 30 publications

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

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

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

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Molecular cloning, distribution and functional analysis of the NAV1.6. Voltage-gated sodium channel from human brain

Cited by 83 publications

References 30 publications

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

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

Amyloid Precursor Protein Enhances Nav1.6 Sodium Channel Cell Surface Expression

Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits

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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

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