An SCN9A channelopathy causes congenital inability to experience pain

Cox, James J.; Reimann, Frank; Nicholas, Adeline K.; Thornton, Gemma; Roberts, Emma; Springell, Kelly; Karbani, G.; Jafri, Hussain; Mannan, Jovaria; Raashid, Yasmin; Al‐Gazali, Lihadh; Hamamy, Henan; Valente, Enza Maria; Gorman, Shaun; Williams, Richard A.; McHale, Duncan P.; Wood, John N.; Gribble, Fiona M.; Woods, C. Geoffrey

doi:10.1038/nature05413

Cited by 1,389 publications

(1,139 citation statements)

References 29 publications

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“…1 In 2006/7, biallelic null mutations in the transmembrane voltage-gated sodium channel Na V 1.7/SCN9A were discovered as a cause of CIP. 2,3 Recently, a new form of CIP was reported in two isolated unrelated cases. Both had recurrent injuries and self-mutilations secondary to feeling no pain, and identical de novo heterozygous p.L811P variants in the voltage-gated sodium channel Na V 1.9, encoded by SCN11A.…”

mentioning

confidence: 99%

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

et al. 2014

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mentioning

confidence: 99%

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

et al. 2014

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“…Capacitance transients were compensated and leak subtraction was performed with a P/8 protocol except during experiments using veratridine (to avoid subtraction of any 6 veratridine-induced steady state currents). Drugs were applied to cells by superfusion through gravity-fed flow pipes (250 µm diameter) positioned directly above the cell.…”

Section: Cell Culturementioning

confidence: 99%

“…In recent years Nav1.7 has emerged as an attractive drug target, with expression restricted to a subset of nociceptive neurons that is expected to limit on-target side effects of pharmacological modulators of Nav1.7 [5]. In addition, loss-of-function mutations in humans have highlighted the possibility that Nav1.7 inhibition could produce complete loss of pain sensations without dose-limiting side effects [6]. However, it remains unclear if such an effect can be translated to the clinic given the lack of subtype-specific Nav1.7 blockers in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of Nav types endogenously expressed in human SH-SY5Y neuroblastoma cells

Vetter

Mozar

Durek

et al. 2012

Biochemical Pharmacology

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Abbreviations: Nav, voltage-gated sodium channel; TTX, tetrodotoxin; ProTxII, β/ω-theraphotoxin-Tp2a; Ca 2+ , calcium ion; DMEM, Dulbecco's Modified Eagle's Medium; FBS, foetal bovine serum; PBS, phosphate buffered saline; PSS, physiological salt solution; HBS, HEPES-buffered saline; AFU, arbitrary fluorescence unit; SEM, standard error of the mean; Fluo-4 AM, Fluo-4 acetoxymethylester; RPMI, Roswell Park Memorial Institute; BSA, bovine serum albumin; CCD, charge-coupled device; DAPI, 4',6-diamidino-2-phenylindole 2 AbstractThe human neuroblastoma cell line SH-SY5Y is a potentially useful model for the identification and characterisation of Nav modulators, but little is known about the pharmacology of their endogenously expressed Navs. The aim of this study was to determine the expression of endogenous Nav α and β subunits in SH-SY5Y cells using PCR and immunohistochemical approaches, and pharmacologically characterise the Nav isoforms endogenously expressed in this cell line using electrophysiological and fluorescence approaches. SH-SY5Y human neuroblastoma cells were found to endogenously express several Nav isoforms including Nav1.2 and Nav1.7. Activation of endogenously expressed Navs with veratridine or the scorpion toxin OD1 caused membrane depolarization and subsequent Ca 2+ influx through voltage-gated L-and N-type calcium channels, allowing Nav activation to be detected with membrane potential and fluorescent Ca 2 dyes. -Conotoxin TIIIA and ProTxII identified Nav1.2 and Nav1.7 as the major contributors of this response. The Nav1.7-selective scorpion toxin OD1 in combination with veratridine produced a Nav1.7-selective response, confirming that endogenously expressed human Nav1.7 in SH-SY5Y cells is functional and can be synergistically activated, providing a new assay format for ligand screening.Key Words: SH-SY5Y; Ca 2+ ; Nav1.7; ProTxII; OD1 3 IntroductionVoltage-gated sodium channels (Nav) are complex transmembrane proteins comprised of a poreforming α subunit and accessory β subunits that play an essential role in the initiation and propagation of action potentials in excitable cells. To date, apart from the related Nax which appears to function as a sodium sensor [1,2], nine isoforms termed Nav1.1 -Nav1.9 have been functionally defined as sodium-selective ion channels [3]. Their distinct tissue distribution and amenability to modulation by toxins and drugs has led to significant interest in Nav as therapeutic targets in a number of poorly treated conditions ranging from epilepsy to cardiac arrhythmias and pain [4]. In recent years Nav1.7 has emerged as an attractive drug target, with expression restricted to a subset of nociceptive neurons that is expected to limit on-target side effects of pharmacological modulators of Nav1.7 [5]. In addition, loss-of-function mutations in humans have highlighted the possibility that Nav1.7 inhibition could produce complete loss of pain sensations without dose-limiting side effects [6]. However, it remains unclear if such an effect can be translated to the clinic...

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“…It is an essential sense to avoid a dangerous environment. Individuals lacking pain sensation sustain injuries, bite their tongue and lips, or get infections (Cox et al, 2006). When tissue damage (e.g., surgical incision) occurs, a reversible increase in pain sensitivity can be observed in the inflamed and surrounding tissue, which helps wound healing by avoiding any contact.…”

Section: Introductionmentioning

confidence: 99%

Do glial cells control pain?

Wen²,

et al. 2007

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Management of chronic pain is a real challenge, and current treatments focusing on blocking neurotransmission in the pain pathway have only resulted in limited success. Activation of glia cells has been widely implicated in neuroinflammation in the central nervous system, leading to neruodegeneration in many disease conditions such as Alzheimer's and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-α and interleukin-1β can not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as BDNF and bFGF that are produced by glia to protect neurons. Thus, glia cells can powerfully control pain when they are activated to produce various pain mediators. We will review accumulating evidence supporting an important role of microglia cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We will also discuss possible signaling mechanisms in particular MAP kinase pathways that are critical for glia control of pain. Investigating signaling mechanisms in microglia may lead to more effective management of devastating chronic pain.

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An SCN9A channelopathy causes congenital inability to experience pain

Cited by 1,389 publications

References 29 publications

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P

Characterisation of Nav types endogenously expressed in human SH-SY5Y neuroblastoma cells

Do glial cells control pain?

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