Electrophysiological Properties of Mutant Na<sub>v</sub>1.7 Sodium Channels in a Painful Inherited Neuropathy

Cummins, Theodore R.; Dib‐Hajj, Sulayman D.; Waxman, Stephen G.

doi:10.1523/jneurosci.2695-04.2004

Cited by 363 publications

(332 citation statements)

References 42 publications

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“…All these changes would be expected to increase the excitability of nociceptive dorsal root ganglion neurons harboring the mutation, thus contributing to the pain in IEM (8,17). Slow inactivation, on the other hand, was enhanced in the S241T mutant channels, similar to previously reported IEM mutations (8,16,18), but its contribution to the pathophysiology of erythromelalgia is not known at this time. This change would theoretically render mutations expressing DRG neurons hypoexcitable.…”

Section: Discussionsupporting

confidence: 88%

“…Enhanced slow inactivation has been observed for several IEM mutations (16,18), including those showing increased neuronal excitability in dorsal root ganglion neurons (8,17,18). S241T enhances steady-state slow inactivation and shifts the V1 ⁄ 2 by Ϫ12.3 mV from Ϫ78.4 Ϯ 2.1 mV (n ϭ 21) for Nav1.7 R to Ϫ90.7 Ϯ 1.1 mV (n ϭ 12) for S241T (p Ͻ 0.001) (Fig.…”

Section: S241t Lowers Threshold For Activation Slows Deactivation Amentioning

confidence: 97%

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Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Lampert¹,

Dib‐Hajj

Tyrrell

et al. 2006

Journal of Biological Chemistry

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The Nav1.7 sodium channel is preferentially expressed in most nociceptive dorsal root ganglion neurons and in sympathetic neurons. Inherited erythromelalgia (IEM, also known as erythermalgia), an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth, has been linked to mutations in Nav1.7. Recently, a substitution of Ser-241 by threonine (S241T) in the domain I S4-S5 linker of Nav1.7 was identified in a family with IEM. To investigate the possible causative role of this mutation in the pathophysiology of IEM, we used whole-cell voltage-clamp analysis to study the effects of S241T on Nav1.7 gating in HEK293 cells. We found a hyperpolarizing shift of activation midpoint by 8.4 mV, an accelerated time to peak, slowing of deactivation, and an increase in the current in response to small, slow depolarizations. Additionally, S241T produced an enhancement of slow inactivation, shifting the midpoint by ؊12.3 mV. Because serine and threonine have similar biochemical properties, the S241T substitution suggested that the size of the side chain at this position affected channel gating. To test this hypothesis, we investigated the effect of S241A and S241L substitutions on the gating properties of Nav1.7. Although S241A did not alter the properties of the channel, S241L mimicked the effects of S241T. We conclude that the linker between S4 and S5 in domain I of Nav1.7 modulates gating of this channel, and that a larger side chain at position 241 interferes with its gating mechanisms.Naturally occurring mutations, frequent single amino acid substitutions, in voltage-gated sodium channels can cause disorders of excitable tissues such as epilepsy (1, 2), cardiac arrhythmia (3, 4), muscle diseases (5, 6), and the inherited painful neuropathy, inherited erythromelalgia (IEM, 3 also known as erythermalgia) (7). Recently, IEM was linked to mutations in the voltage-gated sodium channel Nav1.7 (8 -12). Nav1.7 is preferentially expressed in dorsal root and sympathetic ganglion neurons (13-15).The Nav1.7 IEM mutations, which have been investigated to date, shift the midpoint of activation to hyperpolarized potentials, except for F1449V, all slow channel deactivation time constants, and increase the response to small, slow depolarizations (ramp currents) (8, 11, 16 -18). Expression of F1449V and L858H mutant Nav1.7 channels in dorsal root ganglion neurons leads to an increase in excitability as measured by a reduced threshold and increased firing frequency, as would be expected from the changes in gating properties (8,17).The seven missense mutations in Nav1.7, which have been described to date (8 -12, 17), alter residues that are highly conserved among all sodium channels. Except for two mutations in S4 and S6 of domain I (DI), the other five mutations change residues in cytoplasmic linkers, with one mutation in the S4-S5 linker of domain I (DI S4-S5), three mutations in the DII S4-S5, and one mutation in the loop between DIII and DIV (7). Ser-241 to threonine (S241T) mutation in DI S4...

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Section: Discussionsupporting

confidence: 88%

Section: S241t Lowers Threshold For Activation Slows Deactivation Amentioning

confidence: 97%

Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Lampert¹,

Dib‐Hajj

Tyrrell

et al. 2006

Journal of Biological Chemistry

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“…72 Transfection of HEK293 cells with two different mutations of human DNA for Na V 1.7 that are associated with familial autosomal erythermalgia showed that the mutated channel produced a hyperpolarizing shift in activation, slowed deactivation of the channel and markedly increased the ramp current, with the net effect being a marked hyperexcitation of the cells. 73 These alterations would be consistent with enhanced nociception and sympathetic activity and could account for the etiology of erythermalgia. 73 More recently, voltage clamp studies performed on transfected mouse DRG cells showed that the human mutations lowered the thresholds for generation of action potentials and repetitive firing, thus provoking high-frequency firing of nociceptive small diameter sensory neurons in the DRG.…”

Section: Na V 13mentioning

confidence: 82%

“…73 These alterations would be consistent with enhanced nociception and sympathetic activity and could account for the etiology of erythermalgia. 73 More recently, voltage clamp studies performed on transfected mouse DRG cells showed that the human mutations lowered the thresholds for generation of action potentials and repetitive firing, thus provoking high-frequency firing of nociceptive small diameter sensory neurons in the DRG.…”

Section: Na V 13mentioning

confidence: 82%

Challenges in the development of novel treatment strategies for neuropathic pain

Ossipov

Porreca

2005

Neurotherapeutics

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Summary:Neuropathic pain might best be considered as a collection of various pain states with a common feature, that being symptoms suggestive of dysfunction of peripheral nerves. The development of therapeutic options for the treatment of neuropathic pain is complicated significantly by several factors. Neuropathic pain may arise from widely diverse etiologies such as physical trauma, disease, infection, or chemotherapy. Symptoms indicative of neuropathic pain may also arise in individuals with no evidence of any type of nerve trauma (idiopathic). Although neuropathic pain is a substantial health care issue, it is relatively uncommon and only occurs in a small fraction (Ͻ10%) of individuals with these initiating factors. Moreover, the efficacy of treatment protocols, even against the same type of symptoms, differ depending on the underlying initiating cause of the neuropathy. Although these observations strongly suggest that there are predisposing factors that may impart susceptibility to the development of neuropathic pain, no common predisposing factors or genetic markers have been satisfactorily identified. Because of these vagaries, treatment of neuropathic pain has been based on trial and error. However, recent progress in the understanding of neurophysiologic changes that accompany peripheral nerve dysfunction indicate that regulation of ion channels that maintain membrane potentials or generate action potentials may provide an important therapeutic approach. Neuropathic pain is accompanied by increased activity of peripheral nociceptors, which is produced in part by changes in levels of specific calcium and sodium channels. The identification of sodium and/or calcium channels subtypes that are expressed almost exclusively on nocicpetors may provide a way of regulating the activity of exaggerated nociceptor function without altering other sensory modalities. Thus, the selective targeting of ion channels may represent a viable therapeutic target for the management of the neuropathic pain state, regardless of etiology.

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“…Primary erythromelalgia and paroxysmal extreme pain disorder among painful inherited neuropathies are caused by several mutations in the SCN9A gene [4,5]. Met1627Lys mutation has been previously described in a sporadic case of paroxysmal extreme pain disorder from France [1], and then reported in an English family [2].…”

Section: Discussionmentioning

confidence: 99%

A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-ResistantParoxysmal Extreme Pain Disorder

Sablonniere¹,

Huin²

2015

J Pediatr Neurol Disord

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Paroxysmal extreme pain disorder is an autosomal dominant disorder caused by mutation of the SCN9A gene. In most cases, the pain is relieved by carbamazepine. We report on a novel SCN9A mutation associated with carbamazepine-resistant. The proband was a 7-month-old child who suffered from typical attacks from birth onwards. Sequencing of SCN9A revealed a heterozygous c.4880T>G substitution. Identification of this novel mutation and characterization of the associated carbamazepine-resistant phenotype may facilitate diagnosis and drug development.

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Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy

Cited by 363 publications

References 42 publications

Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Challenges in the development of novel treatment strategies for neuropathic pain

A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-ResistantParoxysmal Extreme Pain Disorder

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Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy

Cited by 363 publications

References 42 publications

Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Size Matters: Erythromelalgia Mutation S241T in Nav1.7 Alters Channel Gating

Challenges in the development of novel treatment strategies for neuropathic pain

A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-ResistantParoxysmal Extreme Pain Disorder

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Product

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Electrophysiological Properties of Mutant Na_v1.7 Sodium Channels in a Painful Inherited Neuropathy