Nav1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?

@article{Lossin2013Nav14SI,
  title={Nav1.4 slow‐inactivation: Is it a player in the warm‐up phenomenon of myotonic disorders?},
  author={Christoph Lossin},
  journal={Muscle \& Nerve},
  year={2013},
  volume={47}
}
Myotonia is a heritable disorder in which patients are unable to willfully relax their muscles. The physiological basis for myotonia lies in well‐established deficiencies of skeletal muscle chloride and sodium conductances. What is unclear is how normal muscle function can temporarily return with repeated movement, the so‐called “warm‐up” phenomenon. Electrophysiological analyses of the skeletal muscle voltage‐gated sodium channel Nav1.4 (gene name SCN4A), a key player in myotonia, have… 
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References

SHOWING 1-10 OF 32 REFERENCES
Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III‐IV linker.
TLDR
Electrophysiological and molecular genetic studies strongly suggest that three dominant point mutations discovered at the same nucleotide position of the SCN4A gene encoding the adult skeletal muscle Na+ channel alpha‐subunit cause myotonia.
Altered fast and slow inactivation of the N440K Nav1.4 mutant in a periodic paralysis syndrome
TLDR
N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation, and produces a significant depolarizing shift in the voltage dependence of fast in activation and increased persistent current and acceleration in fast inactivation recovery.
Drug‐induced myotonia in human intercostal muscle
TLDR
The myotonia‐inducing effects of furosemide and clofibrate and anthracene‐9‐carboxylic acid, two widely used pharmaceutical agents, were investigated in excised human external intercostal muscle and the potency of these drugs was correlated with the decreased chloride conductance.
Inactivation of muscle chloride channel by transposon insertion in myotonic mice
TLDR
In ADR mice a transposon of the ETn family has been inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains, which strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.
Myotonia congenita.
Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro.
  • N. Yang, S. Ji, A. George
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
TLDR
Findings help to explain the phenotypic differences between HYPP and PC at the molecular and biophysical level and contribute to the understanding of Na+ channel structure and function.
Clinical and electrophysiological observations in patients with myotonic muscle disease and the therapeutic effect of N-propyl-ajmalin
TLDR
Almost all muscle cells investigated showed myotonic activity which was completely abolished by addition of 10−5 g/ml N-propyl-ajmalin to the bathing fluid, which seems to be due to the increased after-depolarization observed in myOTonic fibres which causes partial inactivation of the Na-carrying system.
The skeletal muscle chloride channel in dominant and recessive human myotonia.
TLDR
An unusual restriction site in the CLC-1 locus in two GM families identified a mutation associated with that disease, a phenylalanine-to-cysteine substitution in putative transmembrane domain D8, which suggests that different mutations in C LC-1 may cause dominant or recessive myotonia.
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