Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons

Dib‐Hajj, Sulayman D.; Rush, Anthony M.; Cummins, Theodore R.; Hisama, Fuki M.; Novella, Steven; Tyrrell, Lynda; Marshall, L.; Waxman, Stephen G.

doi:10.1093/brain/awh514

Cited by 429 publications

(364 citation statements)

References 24 publications

Supporting

Mentioning

336

Contrasting

Unclassified

Order By: Relevance

“…Individuals with loss of function and gain of mutations in NaV1.7 have been identified (Dib-Hajj et al, 2005;Goldberg et al, 2007). These people suffer from a congenital insensitivity to pain or erythomelalgia, respectively.…”

Section: Discussionmentioning

confidence: 99%

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

Kočmálová

Kollárik

Canning

et al. 2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Little is known about the neuronal voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the a subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species. Gene expression analysis showed that that NaV 1.7 was virtually the only tetrodotoxin-sensitive NaV1 gene expressed in guinea pig and human airway parasympathetic ganglia, where mouse ganglia expressed NaV1.1, 1.3, and 1.7. Using selective pharmacological blockers supported the gene expression results, showing that blocking NaV1.7 alone can abolish the responses in guinea pig and human bronchi, but not in mouse airways. To block the responses in mouse airways requires that NaV1.7 along with NaV1.1 and/or NaV1.3 is blocked. These results may suggest novel indications for NaV1.7-blocking drugs, in which there is an overactive parasympathetic drive, such as in asthma. The data also raise the potential concern of antiparasympathetic side effects for systemic NaV1.7 blockers.

show abstract

Section: Discussionmentioning

confidence: 99%

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

Kočmálová

Kollárik

Canning

et al. 2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The input current can simply be increased in a stepwise manner or defined by the previously determined current threshold. See Figure 3, e.g., results from a study examining how a gain of function inherited erythromelalgia mutation in Na v 1.7-impacted DRG neuron excitability 37 .…”

Section: |mentioning

confidence: 99%

Voltage-clamp and current-clamp recordings from mammalian DRG neurons

et al. 2009

View full text Add to dashboard Cite

We provide here detailed electrophysiological protocols to study voltage-gated sodium channels and to investigate how wild-type and mutant channels influence firing properties of transfected mammalian dorsal root ganglion (DRG) neurons. Whole-cell voltage-clamp recordings permit us to analyze kinetic and voltage-dependence properties of ion channels and to determine the effect and mode of action of pharmaceuticals on specific channel isoforms. They also permit us to analyze the role of individual sodium channels and their mutant derivatives in regulating firing of DRG neurons. Five to ten cells can be recorded daily, depending on the extent of analysis that is required. Because of different internal solutions that are used in voltage-clamp and current-clamp recordings, only limited information can be obtained from recording the same neuron in both modes. These electrophysiological studies help to elucidate the role of specific channels in setting threshold and suprathreshold responses of neurons, under normal and pathological conditions.

show abstract

“…Expression of Na V 1.7 is increased in rats with carrageenan-induced inflammatory pain (Black et al, 2004), and transgenic mice with a selective knock-out of Na V 1.7 expression in DRG neurons abolished pain behaviors evoked by a range of stimuli including formalin, carrageenan, and nerve growth factor (Nassar et al, 2004). Mutations in the SCN9A gene coding for Na V 1.7 have been identified in patients with the inherited painful neuropathy erythromelalgia (Yang et al, 2004;Dib-Hajj et al, 2005;Choi et al, 2006) and in the dominantly inherited paroxysmal extreme pain disorder (Fertleman et al, 2006). Mutations in SCN9A that lead to loss of Na V 1.7 function in nerve result in a syndrome of congenital inability to experience pain (Cox et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

Chattopadhyay

Mata²,

Fink³

2008

Journal of Neuroscience

121

108

View full text Add to dashboard Cite

The Na V 1.7 tetrodotoxin-sensitive voltage-gated sodium channel isoform plays a critical role in nociception. In rodent models of diabetic neuropathy, increased Na V 1.7 in dorsal root ganglia (DRG) neurons correlates with the emergence of pain-related behaviors characteristic of painful diabetic neuropathy (PDN). We examined the effect of transgene-mediated expression of enkephalin on pain-related behaviors and their biochemical correlates in DRG neurons. Transfection of DRG neurons by subcutaneous inoculation of a herpes simplex virus-based vector expressing proenkephalin reversed nocisponsive behavioral responses to heat, cold, and mechanical pressure characteristic of PDN. Vector-mediated enkephalin production in vivo prevented the increase in DRG Na V 1.7 observed in PDN, an effect that correlated with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC). Primary DRG neurons in vitro exposed to 45 mM glucose for 18 h also demonstrated an increase in Na V 1.7 and increased phosphorylation of p38 and PKC; these changes were prevented by transfection in vitro with the enkephalin-expressing vector. The effect of hyperglycemia on Na V 1.7 production in vitro was mimicked by exposure to PMA and blocked by the myristolated PKC inhibitor 20-28 or the p38 inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]; the effect of vector-mediated enkephalin on Na V 1.7 levels was prevented by naltrindole. The results of these studies suggest that activation of the presynaptic ␦-opioid receptor by enkephalin prevents the increase in neuronal Na V 1.7 in DRG through inhibition of PKC and p38. These results establish a novel interaction between the ␦-opioid receptor and voltage-gated sodium channels.

show abstract

Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons

Cited by 429 publications

References 24 publications

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves

Voltage-clamp and current-clamp recordings from mammalian DRG neurons

Continuous -Opioid Receptor Activation Reduces Neuronal Voltage-Gated Sodium Channel (NaV1.7) Levels through Activation of Protein Kinase C in Painful Diabetic Neuropathy

Contact Info

Product

Resources

About