The distribution of low-threshold TTX-resistant Na+ currents in rat trigeminal ganglion cells

Scroggs, Reese S.

doi:10.1016/j.neuroscience.2012.07.012

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…1f) -suggest that Na V 1.9 channels do not contribute much to the amplitude of action potentials, but rather that they may act as threshold channels by contributing a sodium conductance that regulates resting potential and that prolongs the depolarizing response to subthreshold stimuli 17,22 , lowering the threshold for single action potentials and increasing repetitive firing 29 . Although the degree of hyperpolarization of the voltage dependence of activation of Na V 1.9 is dependent on the ionic composition of the pipette solution during recording 24,25 , computer simulations and current-clamp studies using physiological solutions in the recording pipette support the conclusion that this channel acts as a threshold channel 17,29 . Computer simulations show that, even at densities as low as 20% of the density estimated to be present in DRG neurons, Na V 1.9 conductance depolarizes the resting potential of the cell 17 .…”

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confidence: 96%

“…Although instability of the Na V 1.9 current has been encountered by almost all investigators who have studied this channel, methods and protocols have been designed to minimize this instability and to generate reproducible data [22][23][24][25] . The inactivation of Na V 1.9 is unusually 'ultra-slow' and results in the persistence of the sodium current after activation (FIG.…”

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confidence: 99%

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NaV1.9: a sodium channel linked to human pain

Dib‐Hajj¹,

Black²,

Waxman³

2015

Nat Rev Neurosci

169

128

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The voltage-gated sodium channel Na(V)1.9 is preferentially expressed in nociceptors and has been shown in rodent models to have a major role in inflammatory and neuropathic pain. These studies suggest that by selectively targeting Na(V)1.9, it might be possible to ameliorate pain without inducing adverse CNS side effects such as sedation, confusion and addictive potential. Three recent studies in humans--two genetic and functional studies in rare genetic disorders, and a third study showing a role for Na(V)1.9 in painful peripheral neuropathy--have demonstrated that Na(V)1.9 plays an important part both in regulating sensory neuron excitability and in pain signalling. With this human validation, attention is turning to this channel as a potential therapeutic target for pain.

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confidence: 96%

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confidence: 99%

NaV1.9: a sodium channel linked to human pain

Dib‐Hajj¹,

Black²,

Waxman³

2015

Nat Rev Neurosci

169

128

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“…Previous studies in Scn11a knockout mice have confirmed that Na v 1.9 is an important molecule in generating hyperalgesia in infammatory pain states, 18,19 suggesting that Na v 1.9 channels may play an important role in nociception. 26,27 We herein provided the genetic evidence that mutations in SCN11A were directly involved in human episodic pain. In addition, Lolignier et al reported that Na v 1.9 channel plays an important role in the generation of heat and mechanical pain hypersensitivity in both subacute and chronic inflammatory models.…”

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confidence: 99%

Gain-of-Function Mutations in SCN11A Cause Familial Episodic Pain

Zhang

Wen

Wei

et al. 2013

The American Journal of Human Genetics

166

172

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Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.81 Mb region on chromosome 3p22.3-p21.32. By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Nav1.9 (SCN11A): c.673C>T (p.Arg225Cys) and c.2423C>G (p.Ala808Gly) (one in each family). Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1,021 normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Nav1.9 channel. We expressed the two SCN11A mutants in mouse dorsal root ganglion (DRG) neurons and showed that both mutations enhanced the channel's electrical activities and induced hyperexcitablity of DRG neurons. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder.

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“…Most nociceptive neurons in DRG are small-sized, mainly accepting nociceptive C-fibers, and expressing TTX-R isoforms, and are more closely related to neuropathic pain, compared with large-sized neurons which mainly express TTX-S VGSCs [3][4][5]17]. In this context, we specifically chose small-sized DRG neurons to investigate TTX-R I Na .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, numerous studies have shown that the abnormalities of VGSCs and/or sodium currents (I Na ) could induce the hyperexcitability of DRG neurons and increase the occurrence of DNP [4]. The majority of nociceptive DRG neurons are in small size accepting Aδ-fibers and C-fibers, and mainly express TTX-resistant (TTX-R) sodium channel isoforms, among which Nav1.8 and Nav1.9 are tightly related to neuropathic pain [5]. Furthermore, it has been reported that DNP is associated with differential changes in VGSCs and I Na of DRG neurons [4,6].…”

Section: Introductionmentioning

confidence: 99%