Disease relevance of Scn10a

• Moreover, this hypothesis is supported by evidence demonstrating that selective "knock-down" of PN3 protein in the dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury [1].
• These results suggest the participation of Na(V)1.8 channels in the development and maintenance of chronic inflammatory hyperalgesia, and confirm their involvement in the acute inflammatory hypernociception [2].
• A non-angiogenic keratinocyte line, CL-2, derived from cultures of untreated epithelium and 3 lines of carcinogen-initiated keratinocytes, PN3, 5, and 7, of varying angiogenic potential were fused, using polyethylene glycol, to 3 tumorigenic, potently angiogenic, drug-resistant, hamster pouch carcinomas cell lines: HCPC-1, AW16E1-1, and AW16 E1-2 [3].

High impact information on Scn10a

• The endogenous Na(V)1.8 current in sensory neurons is inhibited by antisense downregulation of p11 expression [4].
• The tetrodotoxin-resistant sodium channel Na(V)1.8/SNS is expressed exclusively in sensory neurons and appears to have an important role in pain pathways [4].
• Unlike other sodium channels, Na(V)1.8 is poorly expressed in cell lines even in the presence of accessory beta-subunits [4].
• A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain [1].
• Although physiological and pharmacological evidence suggests the presence of multiple tetrodotoxin-resistant (TTX-R) Na channels in neurons of peripheral nervous system ganglia, only one, SNS/PN3, has been identified in these cells to date [5].

Biological context of Scn10a

• Functional expression in Xenopus oocytes showed that PN3 is a voltage-gated sodium channel with a depolarized activation potential, slow inactivation kinetics, and resistance to high concentrations of tetrodotoxin [6].
• 9. The binding of amino acids 74-103 of Na(V)1.8 to p11 residues 33-78 occurs in a random coiled region flanked by two EF hand motifs whose crystal structure has been established [7].
• The absence of a mutually exclusive alternative exon 17 was confirmed by sequencing 4.1 kilobases of genomic DNA spanning exons 16-18 of Scn10a [8].
• The transcription rate of the opsin gene increases to a similar extent over the same time course between PN3 and adulthood, suggesting that transcriptional activation is responsible for the increase in opsin expression [9].
• The novel sodium channel PN3/alpha-SNS, which was cloned from a rat dorsal root ganglion (DRG) cDNA library, is expressed predominantly in small sensory neurons and may contribute to the tetrodotoxin-resistant (TTXR) sodium current that is believed to be associated with central sensitization in chronic neuropathic pain states [10].

Anatomical context of Scn10a

• In situ hybridization to rat DRG indicated that PN3 is expressed primarily in small sensory neurons of the peripheral nervous system [6].
• The tetrodotoxin-resistant Na(+) channel (Na(V)1.8/SNS) is expressed in damage-sensing neurons (nociceptors) and plays an important role in pain pathways [11].
• Attenuating expression of Na(V)1.8 with antisense oligodeoxynucleotides prevented the redistribution of Na(V)1.8 in the sciatic nerve and reversed neuropathic pain [12].
• We recently demonstrated that antisense mediated "knock-down" of the sodium channel isoform, Na(V)1.8, reverses neuropathic pain behavior after L5/L6 spinal nerve ligation (SNL), implicating a critical functional role of Na(V)1.8 in the neuropathic state [12].
• Consistent with this, reverse transcription-PCR, single-cell profiling, and immunostaining experiments indicated that Na(V)1.9 transcripts and subunits, but not Na(V)1.8, were expressed in the enteric nervous system and restricted to myenteric sensory neurons [13].

Associations of Scn10a with chemical compounds

• In the TTX-binding site, a serine appears as in TTX-resistant SNS/PN3, instead of Cys (as in TTX-insensitive cardiac channels) and Tyr/Phe (as in TTX-sensitive sodium channels) [14].
• Astrocytes of oestradiol-treated females did not differ on PN3 from those of PN3-untreated males [15].
• Pentothal anesthesia on PN3 did not damage P cells [16].
• We found that yohimbine inhibited tetrodotoxin-sensitive Na(+) channels (Na(V)1.2), the tetrodotoxin-resistant Na(+) channels, including both slow inactivating (Na(V)1.8) and persistent (Na(V)1.9) Na(+) channels, and capsaicin-sensitive vanilloid VR1 receptors [17].
• On PN3 ethanol killed some P cells in 12 h, and the first ultrastructural change was a dilatation of the nuclear double membrane after 8 h [16].

Physical interactions of Scn10a

• Here we show that p11 binds to Na(V)1.8 but not to sodium channel isoforms Na(V)1.2, 1.5, 1.7 or Na(V)1 [7].

Other interactions of Scn10a

• Because direct association with p11 is required for functional expression of Na(V)1.8, disrupting this interaction may be a useful new approach to downregulating Na(V)1.8 and effecting analgesia [4].
• Identification of binding domains in the sodium channel Na(V)1.8 intracellular N-terminal region and annexin II light chain p11 [7].

Analytical, diagnostic and therapeutic context of Scn10a

• Immunoprecipitation (pull-down) assays confirm that some of the proteins interact with, and may hence regulate, Na(V)1.8 in vivo [11].
• We here study the effect of chronic axotomy of the inferior alveolar nerve on the expression of SNS/PN3 mRNA in trigeminal sensory neurons [18].
• At PN1 and PN3 immunofluorescence microscopy revealed weak labelling, mainly in radial processes (Bergmann fibres) and at the pial surface [19].
• In the PGE(2)-induced persistent hypernociception, but not in the single injection-induced acute hypernociception, the mRNA expression (RT-PCR) of Na(V)1.8 in dorsal root ganglia (DRG) was up-regulated [2].
• Subcutaneous injection of 5alpha-dihydrotestosterone as well as testosterone propionate to PN2 neonatal rats significantly increased p130 gene expression at PN3, whereas estradiol benzoate did not have a significant effect [20].

References