Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis

Cummins, Theodore R.; Zhou, Jianxiong; Sigworth, Frederick J.; Ukomadu, Chinwe; Stephan, Megan M.; Ptáčk, Louis J.; Agnew, William S.

doi:10.1016/0896-6273(93)90168-q

Cited by 160 publications

(90 citation statements)

References 29 publications

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“…The Na v 1.4 mutants T704M in DII/S5 and I1495F in DIV/S5, which have been linked to hyperkalemic periodic paralysis (Cannon and Strittmatter, 1993;Cummins et al, 1993;Bendahhou et al, 1999), shift voltage dependence of activation in a hyperpolarizing direction, whereas L266V in DI/S5 produces a depolarizing shift in steady-state inactivation but no effect on activation (Wu et al, 2001). Mutation F1344S in DIII/S5 in Na v 1.5 causes Brugada syndrome and shifts activation in a depolarizing direction (Keller et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Harty¹,

Dib‐Hajj²,

Tyrrell³

et al. 2006

J. Neurosci.

139

122

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Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Na v 1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na v 1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Na v 1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by Ϫ8 mV, whereas steady-state fast inactivation was shifted by ϩ10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by ϩ6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.

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Section: Discussionmentioning

confidence: 99%

Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Harty¹,

Dib‐Hajj²,

Tyrrell³

et al. 2006

J. Neurosci.

139

122

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“…All of these mutations shift the voltage dependence of activation in a hyperpolarizing direction. The Na v 1.4 mutations are thought to induce muscle weakness as a result of an enhanced persistent current (possibly attributable to window currents that result from the negative shift in the voltage dependence of activation) that depolarizes the muscle 5-10 mV, causing inactivation of the sodium currents and decreasing the ability of the muscle to fire action potentials (Lehmann-Horn et al, 1987;Cummins et al, 1993). The hNa v 1.4-I693T and hNa v 1.4-T704M mutations also significantly impair slow inactivation, and this impairment is thought to contribute to muscle weakness associated with these mutations (Ruff, 1994).…”

Section: Discussionmentioning

confidence: 99%

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

Cummins¹,

Dib‐Hajj²,

Waxman³

2004

J. Neurosci.

357

289

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Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of Na v 1.7, a sodium channel that produces a tetrodotoxinsensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. Na v 1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from inactivation and by slow closed-state inactivation that results in relatively large responses to small, subthreshold depolarizations. Here we show that these mutations in Na v 1.7 produce a hyperpolarizing shift in activation and slow deactivation. We also show that these mutations cause an increase in amplitude of the current produced by Na v 1.7 in response to slow, small depolarizations. These observations provide the first demonstration of altered sodium channel function associated with an inherited painful neuropathy and suggest that these physiological changes, which confer hyperexcitability on peripheral sensory and sympathetic neurons, contribute to symptom production in hereditary erythermalgia.

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“…The pipette solution contained (in mM): 140 CsF, 10 NaCl, 1 EGTA, and 10 HEPES; 302 mosmol (pH 7.4, adjusted with CsOH), and the extracellular bath contained (in mM): 140 NaCl, 3 KCl, 10 glucose, 10 HEPES, 1 MgCl 2 , 1 CaCl 2 , 0.0003 TTX; 310 mosmol (pH 7.4, adjusted with NaOH). TTX was added to the bath solution to block all endogenous voltage-gated sodium currents that might be present in HEK 293 cells (36) and thereby permitted study of Na v 1.7 R in isolation. All recordings were conducted at room temperature (ϳ21°C).…”

Section: Methodsmentioning

confidence: 99%

A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation

Lampert

O’Reilly

Dib‐Hajj

et al. 2008

Journal of Biological Chemistry

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Sodium channel Na v 1.7 has recently elicited considerable interest as a key contributor to human pain. Gain-of-function mutations of Na v 1.7 produce painful disorders, whereas loss-offunction Na v 1.7 mutations produce insensitivity to pain. The inherited erythromelalgia Na v 1.7/F1449V mutation, within the C terminus of domain III/transmembrane helix S6, shifts channel activation by ؊7.2 mV and accelerates time to peak, leading to nociceptor hyperexcitability. We constructed a homology model of Na v 1.7, based on the KcsA potassium channel crystal structure, which identifies four phylogenetically conserved aromatic residues that correspond to DIII/F1449 at the C-terminal end of each of the four S6 helices. The model predicted that changes in side-chain size of residue 1449 alter the pore's cytoplasmic aperture diameter and reshape inter-domain contact surfaces that contribute to closed state stabilization. To test this hypothesis, we compared activation of wild-type and mutant Na v 1.7 channels F1449V/L/Y/W by whole cell patch clamp analysis. All but the F1449V mutation conserve the voltage dependence of activation. Compared with wild type, time to peak was shorter in F1449V, similar in F1449L, but longer for F1449Y and F1449W, suggesting that a bulky, hydrophobic residue is necessary for normal activation. We also substituted the corresponding aromatic residue of S6 in each domain individually with valine, to mimic the naturally occurring Na v 1.7 mutation. We show that DII/F960V and DIII/F1449V, but not DI/Y405V or DIV/F1752V, regulate Na v 1.7 activation, consistent with well established conformational changes in DII and DIII. We propose that the four aromatic residues contribute to the gate at the cytoplasmic pore aperture, and that their ring side chains form a hydrophobic plug which stabilizes the closed state of Na v 1.7.

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Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis

Cited by 160 publications

References 29 publications

Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

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

A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation

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Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis

Cited by 160 publications

References 29 publications

Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

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

A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation

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Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

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