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Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.

Cregg R, Cox JJ, Bennett DL, Wood JN, Werdehausen R - Br. J. Pharmacol. (2014)

Bottom Line: Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties.Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents.Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, London, UK; UCL Centre for Anaesthesia, Critical Care and Pain Medicine, London, UK.

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Analysis of window currents in whole-cell voltage-clamp configuration of NaV1.7-expressing HEK293 cells. Combined superimposed fitted curves of steady-state activation and fast inactivation kinetics in cells expressing NaV1.7 channels (controls or L858F mutant) with NaVβ1 and NaVβ2 subunits. Window currents of cell population expressing wild-type channels (green striped area) were reduced by mexiletine (500 μM; green solid area). Mexiletine treatment (500 μM; red solid area) also reduced window currents of cells expressing L858F mutant channels (red striped area). All data are presented are as means.
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fig05: Analysis of window currents in whole-cell voltage-clamp configuration of NaV1.7-expressing HEK293 cells. Combined superimposed fitted curves of steady-state activation and fast inactivation kinetics in cells expressing NaV1.7 channels (controls or L858F mutant) with NaVβ1 and NaVβ2 subunits. Window currents of cell population expressing wild-type channels (green striped area) were reduced by mexiletine (500 μM; green solid area). Mexiletine treatment (500 μM; red solid area) also reduced window currents of cells expressing L858F mutant channels (red striped area). All data are presented are as means.

Mentions: A composite graph showing Boltzmann fits of mean activation and steady-state inactivation curves of L858F mutant versus WT channels showed an increase in the window current (Figure 5). Maximum window currents for WT NaV1.7 channels were 4.5% of the peak currents (AUC = 0.82) as opposed to 11.5% seen in the mutant channel population of cells (AUC = 2.49). Following the application of mexiletine (500 μM) and after a steady state had been reached, there was a reduction in the maximum window current to 5.5% of peak currents in L858F channels and a reduction in the window current AUC by 48% (AUC = 1.29).


Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.

Cregg R, Cox JJ, Bennett DL, Wood JN, Werdehausen R - Br. J. Pharmacol. (2014)

Analysis of window currents in whole-cell voltage-clamp configuration of NaV1.7-expressing HEK293 cells. Combined superimposed fitted curves of steady-state activation and fast inactivation kinetics in cells expressing NaV1.7 channels (controls or L858F mutant) with NaVβ1 and NaVβ2 subunits. Window currents of cell population expressing wild-type channels (green striped area) were reduced by mexiletine (500 μM; green solid area). Mexiletine treatment (500 μM; red solid area) also reduced window currents of cells expressing L858F mutant channels (red striped area). All data are presented are as means.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209151&req=5

fig05: Analysis of window currents in whole-cell voltage-clamp configuration of NaV1.7-expressing HEK293 cells. Combined superimposed fitted curves of steady-state activation and fast inactivation kinetics in cells expressing NaV1.7 channels (controls or L858F mutant) with NaVβ1 and NaVβ2 subunits. Window currents of cell population expressing wild-type channels (green striped area) were reduced by mexiletine (500 μM; green solid area). Mexiletine treatment (500 μM; red solid area) also reduced window currents of cells expressing L858F mutant channels (red striped area). All data are presented are as means.
Mentions: A composite graph showing Boltzmann fits of mean activation and steady-state inactivation curves of L858F mutant versus WT channels showed an increase in the window current (Figure 5). Maximum window currents for WT NaV1.7 channels were 4.5% of the peak currents (AUC = 0.82) as opposed to 11.5% seen in the mutant channel population of cells (AUC = 2.49). Following the application of mexiletine (500 μM) and after a steady state had been reached, there was a reduction in the maximum window current to 5.5% of peak currents in L858F channels and a reduction in the window current AUC by 48% (AUC = 1.29).

Bottom Line: Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties.Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents.Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, London, UK; UCL Centre for Anaesthesia, Critical Care and Pain Medicine, London, UK.

Show MeSH
Related in: MedlinePlus