Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons

Herzog, Raimund I.; Cummins, Theodore R.; Ghassemi, Farshid; Dib‐Hajj, Sulayman D.; Waxman, Stephen G.

doi:10.1111/j.1469-7793.2003.00741.x

Cited by 120 publications

(199 citation statements)

References 43 publications

(62 reference statements)

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“…2C, top), the envelope of the peaks was monotonic, and a similar exponential time course was observed also at Ϫ60 and Ϫ50 mV with time constants rec (V m ), of 17.7 Ϯ 1.4, 26.9 Ϯ 1.5, and 25.7 Ϯ 2.2 ms, respectively (n ϭ 5). All of these control time constants agree with similar data reported for the rNa v 1.6 channel (29).…”

Section: Cn2supporting

confidence: 81%

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Schiavon

Sacco

Cassulini

et al. 2006

Journal of Biological Chemistry

109

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Resurgent currents are functionally crucial in sustaining the high frequency firing of cerebellar Purkinje neurons expressing Na v 1.6 channels. ␤-Scorpion toxins, such as CssIV, induce a left shift in the voltage-dependent activation of Na v 1.2 channels by "trapping" the IIS4 voltage sensor segment. We found that the dangerous Cn2 ␤-scorpion peptide induces both the left shift voltage-dependent activation and a transient resurgent current only in human Na v 1.6 channels (among 1.1-1.7), whereas CssIV did not induce the resurgent current. Cn2 also produced both actions in mouse Purkinje cells. These findings suggest that only distinct ␤-toxins produce resurgent currents. We suggest that the novel and unique selectivity of Cn2 could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease.

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Section: Cn2supporting

confidence: 81%

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Schiavon

Sacco

Cassulini

et al. 2006

Journal of Biological Chemistry

109

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“…Gating and kinetic properties of Nav1.7 channels are similar when the channel is expressed in DRG neurons or in the stable HEK293 cell line (19). Thus, the properties of WT and mutant channel derivatives in stable HEK293 cells reported in this study are likely to resemble those in native DRG neurons.…”

Section: Discussionmentioning

confidence: 67%

“…The slow closed-state inactivation of Nav1.7 permits this channel to produce relatively larger ramp currents compared with other sodium channels (19,22). HEK293 cells which express Nav1.7 R channels produced FIGURE 1.…”

Section: S241t Lowers Threshold For Activation Slows Deactivation Amentioning

confidence: 99%

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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“…Na v 1.6 channels produce a persistent current in addition to a transient current (33,37), and the persistent current produced by Na v 1.6 is much larger than the persistent current produced by Na v 1.2 (33). Herzog et al (38) performed patchclamp analysis on dorsal root ganglion neurons expressing recombinant Na v 1.6 channels and detected persistent Na v 1.6 currents in all cells that were studied. The present results from MS, like recent studies in EAE (31), show an association between expression of Na v 1.6, but not Na v 1.2, and axonal degeneration; Na v 1.6 and the NCX were both, in fact, detectable and colocalized in 60% of ␤-APP-labeled axons in MS but were found to be coexpressed in Ͻ20% of axons that were ␤-APP-negative.…”

Section: Discussionmentioning

confidence: 99%

“…Na v 1.2 channels produce rapidly activating and inactivating currents (32)(33)(34) and appear to support actionpotential conduction, which occurs before myelination (35,36), suggesting that newly produced Na v 1.2 channels can support conduction in demyelinated axons. Na v 1.6 channels, on the other hand, produce a persistent current in addition to rapidly activating and inactivating currents (33,37,38), and Na v 1.6 is coexpressed together with the Na ϩ ͞Ca 2ϩ exchanger (NCX) along degenerating axons in EAE (31).…”

mentioning

confidence: 99%

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger

Craner

Newcombe

Black

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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423

305

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Although voltage-gated sodium channels are known to be deployed along experimentally demyelinated axons, the molecular identities of the sodium channels expressed along axons in human demyelinating diseases such as multiple sclerosis (MS) have not been determined. Here we demonstrate changes in the expression of sodium channels in demyelinated axons in MS, with Nav1.6 confined to nodes of Ranvier in controls but with diffuse distribution of Nav1.2 and Nav1.6 along extensive regions of demyelinated axons within acute MS plaques. Using triple-labeled fluorescent immunocytochemistry, we also show that Nav1.6, which is known to produce a persistent sodium current, and the Na ؉ ͞Ca 2؉ exchanger, which can be driven by persistent sodium current to import damaging levels of calcium into axons, are colocalized with ␤-amyloid precursor protein, a marker of axonal injury, in acute MS lesions. Our results demonstrate the molecular identities of the sodium channels expressed along demyelinated and degenerating axons in MS and suggest that coexpression of Nav1.6 and Na ؉ ͞Ca 2؉ exchanger is associated with axonal degeneration in MS.demyelinating diseases ͉ action potential conduction ͉ axonal degeneration

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Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons

Cited by 120 publications

References 43 publications

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

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

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger

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Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons

Cited by 120 publications

References 43 publications

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

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

Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na v 1.2 and Na v 1.6 sodium channels and Na + /Ca 2 + exchanger

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Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Na _v 1.2 and Na _v 1.6 sodium channels and Na ⁺ /Ca ² + exchanger