Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative

Desaphy, Jean-François; Luca, Annamaria De; Tortorella, Paolo; Vito, Danila De; George, Alfred L.; Camerino, Diana Conte

doi:10.1212/wnl.57.10.1849

Cited by 51 publications

(93 citation statements)

References 41 publications

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“…Nonetheless, the combination of theoretical prediction and experimental verification has led to the identification of a novel mechanism through which altered Na ϩ channel activity can account for prolonged QT intervals in mutation carriers. Although the waveform of the cardiac action potential and the electrical properties that define its plateau phase are unique, this integrative approach is applicable to understanding the molecular basis of other congenital diseases, such as myotonia and epilepsy, in which subtle changes in Na ϩ channel gating may increase the contribution of channel reopenings to myotonic discharge (myotonias) [25][26][27][28] or bursts of neural activity (epilepsy and seizure disorders). 5,29 …”

Section: Discussionmentioning

confidence: 99%

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

et al. 2003

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Background— Many long-QT syndrome (LQTS) mutations in the cardiac Na + channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (I sus ) during depolarization. However, some Na + channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase I sus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. Methods and Results— We developed new experimental approaches based on theoretical analyses to investigate Na + channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. Conclusions— Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.

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Section: Discussionmentioning

confidence: 99%

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

et al. 2003

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“…The reduction in the rate of I Na decay 26,27 and the enhanced rate of recovery from inactivation 7,8 exhibited by R1448 mutant channels are features which may increase excitability and contribute to myotonia.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Ranolazine block of human Na_v1.4 sodium channels and paramyotonia congenita mutants

El-Bizri¹,

Kahlig²,

Shyrock³

et al. 2011

Channels

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“…Hence, a pharmacogenetic strategy for mutation-specific treatment is needed. 57,58 Another unclear issue is whether the cardiac arrests reported in the premolecular era 5,6,7 occurred in patients with hyperkalemic PP or Andersen-Tawil syndrome. Last but not least, the question of why certain mutations cause hyperkalemic PP in some families or family members and PC in others has not yet been clarified.…”

Section: Hyperkalemic Pp: Naturally Occurring and Experimental Modelsmentioning

confidence: 99%

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Jurkat‐Rott¹,

Lehmann‐Horn²

2007

Neurotherapeutics

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Summary:Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.

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Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative

Cited by 51 publications

References 41 publications

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

Ranolazine block of human Na_v1.4 sodium channels and paramyotonia congenita mutants

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

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Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative

Cited by 51 publications

References 41 publications

Non-Equilibrium Gating in Cardiac Na + Channels

Non-Equilibrium Gating in Cardiac Na + Channels

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Contact Info

Product

Resources

About

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

Non-Equilibrium Gating in Cardiac Na ⁺ Channels

Ranolazine block of human Na_v1.4 sodium channels and paramyotonia congenita mutants