Disease relevance of Scn10a

• In recordings at approximately 22 days, a similar proportion of fibres were mechanosensitive in wild-type and Nav1.8 null neuromas (51 and 46%, respectively) [1].
• In this study, we used sensory neuron specific (SNS) sodium channel gene knockout (-/-) mice to ask whether SNS sodium channel produces the slow Na(+) current ("slow") in large (>40 microm diam) cutaneous afferent dorsal root ganglion (DRG) neurons [2].
• Together, these findings suggest that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na+ (Nav1.8) currents [3].
• Using recombinant lambda phage clones encoding a mouse 129/SV genomic library, we have determined the detailed structure of the mouse SNS gene (Scn10a), including the location of exon-intron boundaries and the nucleotide sequence of the exons [4].
• Here we compared visceral pain and referred hyperalgesia in Nav1.8-null mice and their wild-type littermates in five tests that differ in the degree to which behavior depends on spontaneous, ongoing firing in sensitized nociceptors [5].

Psychiatry related information on Scn10a

• Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds [6].

High impact information on Scn10a

• As this transgene failed to overcome embryonic lethality (unpublished data and ref. 3) in Gata3-/- mice, we hypothesized that a neuroendocrine deficiency in the sympathetic nervous system (SNS) might cause embryonic lethality in these mutants [7].
• We also demonstrate SNS mRNA and protein expression within Purkinje cells from tissue obtained postmortem from patients with MS, but not in control subjects with no neurological disease [8].
• Sensory Neuron-Specific sodium channel SNS displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels [8].
• Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis [8].
• SNS is selectively expressed in spinal sensory and trigeminal ganglion neurons within the peripheral nervous system and is not expressed within the normal brain [8].

Chemical compound and disease context of Scn10a

• However, Nav1.8-null mutants showed weak pain and no referred hyperalgesia to intracolonic capsaicin, a model in which behavior is sustained by ongoing activity in nociceptors sensitized by the initial application [5].
• To distinguish between a possible role for Nav1.8 in ongoing activity per se and ongoing activity after sensitization in the absence of additional stimuli, we tried a visceral model of tonic noxious chemical stimulation, cyclophosphamide cystitis [5].
• The low NE turnover in IBAT of MSG-treated mice prior to the onset of gross obesity suggests that low SNS activity may be an initial contributor to their high energy efficiency and resultant obesity [9].
• To clarify whether hyperinsulinemia accelerates sympathetic nervous system (SNS) activity, norepinephrine (NE) turnover, a reliable indicator of SNS activity, was measured in the interscapular brown adipose tissue (IBAT) and heart of hyperinsulinemic yellow KK and normoinsulinemic C57BL control mice at 12 weeks of age [10].
• We examined the impact of concurrent inhibition of RAS (captopril or losartan) and the SNS (prazosin) before and after acute nitric oxide (NO) synthase inhibition with L-nitro-L-arginine methyl ester (L-NAME) on renal cortical perfusion (RCF) and blood pressure (MAP) in healthy and acute ischemic renal failure (ARF) rats (n = 6) [11].

Biological context of Scn10a

• Scn11a is located on mouse chromosome 9, close to the two other TTX-R sodium channel genes, Scn5a and Scn10a [12].
• The tetrodotoxin-resistant sodium channel alpha subunit, Nav1.8, is exclusively expressed in primary sensory neurons and is suggested to play a role in the generation of ectopic action potentials after axonal injury and thereby contribute to neuropathic pain [1].
• At approximately 10 days, neither genotype showed spontaneous activity, but a significantly higher proportion of fibres were mechanosensitive in wild-type (54%) compared to Nav1.8 null neuromas (18%) [1].
• One current has physiological properties similar to those reported for SNS, while the other displays hyperpolarized voltage-dependence and persistent kinetics; a similar TTX-R current was recently identified in DRG neurons of sns-null mouse [13].
• The sizes of the exons and the exon-intron junction positions of the mouse SNS and the human skeletal muscle VGSC genes are remarkably conserved [4].

Anatomical context of Scn10a

• Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a [4].
• Two voltage gated sodium channel alpha-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain [6].
• Here we describe the generation of transgenic mouse lines which express Cre recombinase selectively in sensory ganglia using promoter elements of the Na(v)1.8 gene (Scn10a) [14].
• To assess whether muscle-derived NT-3 could prevent injury-induced neuronal death, neuron survival in the DRG was analyzed in mice 5 days after sciatic nerve crush on PN3 [15].
• Two tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels, SNS and NaN, are preferentially expressed in small dorsal root ganglia (DRG) and trigeminal ganglia neurons, most of which are nociceptive, of rat and mouse [13].

Associations of Scn10a with chemical compounds

• Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity [16].
• Nav1.8-null mice showed normal nociceptive behavior provoked by acute noxious stimulation of abdominal viscera (intracolonic saline or intraperitoneal acetylcholine) [5].
• This resulted in accumulation of large amounts of epinephrine in neurons of the sympathetic nervous system (SNS) and central nervous system (CNS) but did not reduce norepinephrine levels [17].
• Chemical SNS inactivation was achieved by prolonged daily treatment with guanethidine sulfate (GS) or by the introduction of propranolol in drinking water [18].
• These results indicate that central nervous system glucose metabolism may mediate diet-induced changes in SNS activity [19].

Physical interactions of Scn10a

• We show here that calmodulin coimmunoprecipitates with endogenous Nav1.8 channels from native DRG, suggesting that the two proteins can interact in vivo [20].

Regulatory relationships of Scn10a

• Calmodulin regulates current density and frequency-dependent inhibition of sodium channel Nav1.8 in DRG neurons [20].

Other interactions of Scn10a

• Novel isoforms of the sodium channels Nav1.8 and Nav1.5 are produced by a conserved mechanism in mouse and rat [21].
• Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse [22].
• Thus SNS and NaN channels appear to produce different currents in human DRG neurons [13].
• alpha-SNS produces the slow TTX-resistant sodium current in large cutaneous afferent DRG neurons [2].
• Using whole-cell patch-clamp recording, we observed a greater than two-fold reduction of tetrodotoxin-resistant (TTX-R) Nav1.8 and Nav1.9 current densities in IB4+ DRG neurons cultured from CNTN-/- vs. CNTN+/+ mice [23].

Analytical, diagnostic and therapeutic context of Scn10a

• These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects [24].
• The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen-induced arthritis (CIA) [25].
• Adrenalectomy reduced PNMT levels in the SNS and CNS, suggesting that the transgene is positively regulated by adrenal steroids [17].
• Immunoblotting and RT-PCR assays showed reduced Nav1.8 levels in aged mice [26].
• Unexpectedly, however, sympathectomy resulted in suppression of EAE in IL-4-/- mice, implying that control of actively induced EAE by the SNS depends on the genetic background of mice [27].

References