Altered gating and conductance of Na+ channels in hyperkalemic periodic paralysis

Horn, F. Lehmann; Iaizzo, Paul A.; Hatt, H.; Franke, Ch.

doi:10.1007/bf00370530

Cited by 65 publications

(12 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2C), whereas the second time constant and its weight were not different between the mutants and WT. The occurrence of late channel reopenings in a steady-state has been shown to account for a persistent macroscopic Na + current for many Na + channel mutants causing myotonia and/or paralysis [4,5,17,19,20,24,25]. Compatible with our whole-cell data, late channel openings were increased significantly for F1473S channels (Fig.…”

Section: Single-channel Studiessupporting

confidence: 81%

Effects of temperature and mexiletine on the F1473S Na + channel mutation causing paramyotonia congenita

Fleischhauer¹,

Mitrović²,

Deymeer

et al. 1998

Pfl�gers Archiv European Journal of Physiology

View full text Add to dashboard Cite

The F1473S mutation of the adult human skeletal muscle Na+ channel causes paramyotonia congenita, a disease characterized by muscle stiffness sometimes followed by weakness in a cold environment. The symptoms are relieved by the local anaesthetic mexiletine. This mutation, which resides in the cytoplasmic S4-S5 loop in domain IV of the alpha-subunit, was studied by heterologous expression in HEK293 cells using standard patch-clamp techniques. Compared to wild-type (WT) channels, those with the F1473S mutation exhibit a twofold slowing of fast inactivation, an increased persistent Na+ current, a +18-mV shift in steady-state inactivation and a fivefold acceleration of recovery from fast inactivation; slow inactivation was similar for both clones. Single-channel recordings for the F1473S mutation revealed a prolonged mean open time and an increased number of channel reopenings that increased further upon cooling. The pharmacological effects of mexiletine on cells expressing either WT, F1473S or G1306E channels were studied. G1306E is a myotonia-causing mutation located within the inactivation gate that displays similar but stronger inactivation defects than F1473S. The hyperpolarizing shift in steady-state inactivation induced by mexiletine was almost identical for all three clones. In contrast, this agent had a reduced effectiveness on the phasic (use-dependent) block of Na+ currents recorded from the mutants: the relative order of block was WT>F1473S>G1306E. We suggest that the relative effectiveness of mexiletine is associated with the degree of abnormal channel inactivation and that the relative binding affinity of mexiletine is not substantially different between the mutations or the WT.

show abstract

Section: Single-channel Studiessupporting

confidence: 81%

Effects of temperature and mexiletine on the F1473S Na + channel mutation causing paramyotonia congenita

Fleischhauer¹,

Mitrović²,

Deymeer

et al. 1998

Pfl�gers Archiv European Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…1; for review see 40]. The mutations disturb channel inactivation and produce a persistent sodium current [10,13,14,36,38,62]. Based on the same mechanism of pathogenesis and distribution of mutations, the reader may draw two conclusions, both of which are correct: 1.)…”

Section: Molecular Pathogenesismentioning

confidence: 97%

Skeletal muscle channelopathies

Jurkat‐Rott

Lerche

Lehmann‐Horn

2002

Journal of Neurology

111

View full text Add to dashboard Cite

show abstract

“…2); any malformation may reduce the affinity between the "latch bar and the catch." The mutant channels avoid the fast inactivated state and, in contrast to normal Na ϩ channels, reopen or flicker between the inactivated and the open state 23 (FIG. 3), corresponding to a gain-of-function defect.…”

Section: 16mentioning

confidence: 99%

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Jurkat‐Rott¹,

Lehmann‐Horn²

2007

Neurotherapeutics

View full text Add to dashboard Cite

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.

show abstract

Altered gating and conductance of Na+ channels in hyperkalemic periodic paralysis

Cited by 65 publications

References 7 publications

Effects of temperature and mexiletine on the F1473S Na + channel mutation causing paramyotonia congenita

Effects of temperature and mexiletine on the F1473S Na + channel mutation causing paramyotonia congenita

Skeletal muscle channelopathies

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Contact Info

Product

Resources

About