The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways

Akopian, Armen N.; Souslova, Veronika; England, Steven; Okuse, Kenji; Ogata, Nobukuni; Ure, Jan; Smith, Andrew M.; Kerr, Bradley J.; McMahon, Stephen B.; Boyce, S.; Hill, Ray; Stanfa, Louise C.; Dickenson, Anthony H.; Wood, John N.

doi:10.1038/9195

Cited by 736 publications

(583 citation statements)

References 38 publications

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“…Consistent with this notion, SCN5A is primarily expressed in cardiac tissue, while SCN10A and SCN11A transcripts are found in peripheral nociceptive sensory neurons (Akopian et al 1999;Dib-Hajj et al 1999a;Amaya et al 2000). SCN5A expression also occurs in central nervous system regions associated with the limbic system (Donahue et al 2000;Hartmann et al 1999).…”

Section: Scna Gene Expression In Teleosts and Mammalsmentioning

confidence: 52%

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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Section: Scna Gene Expression In Teleosts and Mammalsmentioning

confidence: 52%

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

Novak¹,

Jost

et al. 2006

J Mol Evol

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“…Tetrodotoxin-resistant voltage-dependent sodium channels Nav1.8 (SNS) and Nav1.9 (NaN or SNS2) are selectively expressed in small/medium-sized nociceptive neurons and contribute to the production of an action potential in these neurons. In addition, functional studies reveal that Nav1.8 and Nav1.9 have a specialized role in mediating pain [1,2,[15][16][17]. Thus, the level of gene expression and/or distribution of these channels may be altered in aging neurons that have lowered sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

Wang

Davis

Zwick³

et al. 2006

Neurobiology of Aging

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Sensory neurons in aging mammals undergo changes in anatomy, physiology and gene expression that correlate with reduced sensory perception. In this study we compared young and aged mice to identify proteins that might contribute to this loss of sensation. We first show using behavioral testing that thermal sensitivity in aged male and female mice is reduced. Expression of sodium channel (Nav1.8 and Nav1.9) and transient receptor potential vanilloid (TRPV) channels in DRG and peripheral nerves of young and old male mice was then examined. Immunoblotting and RT-PCR assays showed reduced Nav1.8 levels in aged mice. No change was measured in TRPV1 mRNA levels in DRG though TRPV1 protein appeared reduced in the DRG and peripheral nerves. The GFRα3 receptor, which binds the growth factor artemin and is expressed by TRPV1-positive neurons, was also decreased in the DRG of aged animals. These findings indicate that loss of thermal sensitivity in aging animals may result from a decreased level of TRPV1 and Nav1.8 and decreased trophic support that inhibits efficient transport of channel proteins to peripheral afferents.

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“…The depolarization of the membrane potential of 8‐month‐old IB4+ neurons is important, as it nears the activation potentials of the TTX‐R Nav1.8 isoform (~−40 mV), which was shown to be the main Na + channel isoform underlying the majority of the current during AP upstroke and key to enabling repetitive firing in mouse DRG neurons (Akopian et al., 1999; Renganathan et al., 2001). Indeed, we found that the IB4+ neurons from 8‐month‐old animals receive the highest contribution from the TTX‐R window current at rest (Figure 6b).…”

Section: Discussionmentioning

confidence: 99%

Differential aging‐related changes in neurophysiology and gene expression in IB4‐positive and IB4‐negative nociceptive neurons

et al. 2018

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SummaryDespite pain prevalence altering with age, the effects of aging on the properties of nociceptors are not well understood. Nociceptors, whose somas are located in dorsal root ganglia, are frequently divided into two groups based on their ability to bind isolectin B4 (IB4). Here, using cultured neurons from 1‐, 3‐, 5‐, 8‐, 12‐, and 18‐month‐old mice, we investigate age‐dependent changes in IB4‐positive and IB4‐negative neurons. Current‐clamp experiments at physiological temperature revealed nonlinear changes in firing frequency of IB4‐positive, but not IB4‐negative neurons, with a peak at 8 months. This was likely due to the presence of proexcitatory conductances activated at depolarized membrane potentials and significantly higher input resistances found in IB4‐positive neurons from 8‐month‐old mice. Repetitive firing in nociceptors is driven primarily by the TTX‐resistant sodium current, and indeed, IB4‐positive neurons from 8‐month‐old mice were found to receive larger contributions from the TTX‐resistant window current around the resting membrane potential. To further address the mechanisms behind these differences, we performed RNA‐seq experiments on IB4‐positive and IB4‐negative neurons from 1‐, 8‐, and 18‐month‐old mice. We found a larger number of genes significantly affected by age within the IB4‐positive than IB4‐negative neurons from 8‐month‐old mice, including known determinants of nociceptor excitability. The above pronounced age‐dependent changes at the cellular and molecular levels in IB4‐positive neurons point to potential mechanisms behind the reported increase in pain sensitivity in middle‐aged rodents and humans, and highlight the possibility of targeting a particular group of neurons in the development of age‐tailored pain treatments.

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The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways

Cited by 736 publications

References 38 publications

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

Gene Duplications and Evolution of Vertebrate Voltage-Gated Sodium Channels

Reduced thermal sensitivity and Nav1.8 and TRPV1 channel expression in sensory neurons of aged mice

Differential aging‐related changes in neurophysiology and gene expression in IB4‐positive and IB4‐negative nociceptive neurons

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