Cloning and Characterization of a Mouse Sensory Neuron Tetrodotoxin-Resistant Voltage-Gated Sodium Channel Gene, Scn10a

Souslova, Veronika; Fox, Margaret; Wood, John N.; Akopian, Armen N.

doi:10.1006/geno.1997.4669

Cited by 59 publications

(71 citation statements)

References 69 publications

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“…1. Cre recombinase with the 3Ј-UTR of Na v 1.8 was knocked into the Na v 1.8 initiator methionine so that the translational start-site of Na v 1.8 was substituted by Cre recombinase (21). After screening for homologous recombination in 129͞Sv embryonic stem cells selected for the presence of the neo r cassette, a single positive cell line was used to generate transgenic mice, which were analyzed for germ-line transmission by Southern blotting with probes shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Nassar

Stirling

Forlani

et al. 2004

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

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622

514

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Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Nav1.7, Nav1.8, and Na v1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Nav1.7 (PN1) in pain pathways. A global Nav1.7-null mutant was found to die shortly after birth. We therefore used the Cre؊loxP system to generate nociceptor-specific knockouts. Na v1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na v1.8 locus to generate heterozygous mice expressing Cre recombinase in Nav1.8-positive sensory neurons. Crossing these animals with mice where Na v1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na v1.7 gene, SCN9A. Dominant Na v1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na v1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.

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Section: Resultsmentioning

confidence: 99%

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Nassar

Stirling

Forlani

et al. 2004

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

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622

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“…Future studies should endeavor to identify p38 phosphorylation sites in sodium channel subunits to test whether the modulation of TTX-R is mediated by direct phosphorylation of the channel. For example, the published mouse Nav1.8 sequence contains 15 consensus sites for phosphorylation by MAPKs, including p38 (Souslova et al, 1997;Sharrocks et al, 2000). Twelve of these consensus sites are located on predicted intracellular domains, making them possible targets for p38-mediated phosphorylation and modulation of Nav1.8.…”

Section: Discussionmentioning

confidence: 99%

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Jin¹,

Gereau²

2006

J. Neurosci.

443

373

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Tumor necrosis factor-␣ (TNF␣) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNF␣ can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNF␣ itself. However, the speed with which TNF␣ induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNF␣ may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNF␣ induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1 Ϫ/Ϫ mice. In contrast, TNF␣ produced equivalent mechanical hypersensitivity in TRPV1 Ϫ/Ϫ mice and wild-type littermates, suggesting a role for TRPV1 in TNF␣-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na ϩ channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNF␣ on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNF␣ rapidly enhances TTX-resistant Na ϩ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNF␣ is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNF␣ is also significantly reduced by SB202190. These results suggest that TNF␣ may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na ϩ channels.

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“…First, we focused on the inter-domain loop region between transmembrane domains I and II (loop I-II). In mammals, SCN4A has two exons coding for loop I-II while genes in the three other SCNA groups have four (Dib-Hajj et al 1999b;George et al 1993;Plummer et al 1998;Souslova et al 1997;Wang et al 1996). Similar to mammals, one zebrafish gene, scn4aa, has two exons, E9 and E10 (Table 3).…”

Section: Exon Organization Of Scna Genesmentioning

confidence: 99%

“…We also examined the regions coding for loop II-III, because it also has variable exon organization in mammals (Dib-Hajj et al 1999b;George et al 1993;Plummer et al 1998;Souslova et al 1997;Wang et al 1996). For loop II-III, SCN5A, SCN10A and SCN11A have three exons (E14, E15A, E15B), while other SCNA genes typically have only two (E14 and E15 only; (Dib-Hajj et al 1999b;George et al 1993;Plummer et al 1998;Souslova et al 1997;Wang et al 1996;Plummer and Meisler 1999).…”

Section: Exon Organization Of Scna Genesmentioning

confidence: 99%

“…For loop II-III, SCN5A, SCN10A and SCN11A have three exons (E14, E15A, E15B), while other SCNA genes typically have only two (E14 and E15 only; (Dib-Hajj et al 1999b;George et al 1993;Plummer et al 1998;Souslova et al 1997;Wang et al 1996;Plummer and Meisler 1999). Because the genomic databases were not sufficiently annotated in the relevant regions, we performed RT-PCR analyses.…”

Section: Exon Organization Of Scna Genesmentioning

confidence: 99%

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Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

Novak¹,

Jost

et al. 2006

J Mol Evol

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Abstract.Voltage-gated sodium channels underlie action potential generation in excitable tissue.To establish the evolutionary mechanisms that shaped the vertebrate sodium channel a-subunit (SCNA) gene family and their encoded Na v 1 proteins, we identified all SCNA genes in several teleost species. Molecular cloning revealed that teleosts have eight SCNA genes, comparable to the number in another vertebrate lineage, mammals.Prior phylogenetic analyses had indicated that teleosts and tetrapods share four monophyletic groups of SCNA genes and that tandem duplications selectively expanded the number of genes in two of the four mammalian groups. However, the number of genes in each group varies between teleosts and tetrapods suggesting different evolutionary histories in the two vertebrate lineages. Our findings from phylogenetic analysis and chromosomal mapping of Danio rerio genes indicate that tandem duplications are an unlikely mechanism for generation of the extant teleost SCNA genes. Instead, analysis of other closely mapped genes in D. rerio supports the hypothesis that a whole genome duplication was involved in expansion of the SCNA gene family in teleosts. Interestingly, despite their different evolutionary histories, mRNA analyses demonstrated a conservation of expression patterns for SCNA orthologues in teleosts and tetrapods, suggesting functional conservation.

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Cloning and Characterization of a Mouse Sensory Neuron Tetrodotoxin-Resistant Voltage-Gated Sodium Channel Gene, Scn10a

Cited by 59 publications

References 69 publications

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

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Cloning and Characterization of a Mouse Sensory Neuron Tetrodotoxin-Resistant Voltage-Gated Sodium Channel Gene, Scn10a

Cited by 59 publications

References 69 publications

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-α

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

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Product

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Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain