A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita
DE Featherstone, E Fujimoto… - The Journal of …, 1998 - Wiley Online Library
DE Featherstone, E Fujimoto, PC Ruben
The Journal of physiology, 1998•Wiley Online Library1 Paramyotonia congenita (PC) is a human hereditary disorder wherein missense mutations
in the skeletal muscle sodium channel lead to cold‐exacerbated muscle hyperexcitability.
The most common site for PC mutations is the outermost arginine of domain IV segment 4
(human R1448, rat R1441). 2 We examined the rat homologues of two PC mutants with
changes at this site: R1441P and R1441C. The R→ P mutation leads to the most clinically
severe form of the disease. Since PC has so far been attributed to defects in fast inactivation …
in the skeletal muscle sodium channel lead to cold‐exacerbated muscle hyperexcitability.
The most common site for PC mutations is the outermost arginine of domain IV segment 4
(human R1448, rat R1441). 2 We examined the rat homologues of two PC mutants with
changes at this site: R1441P and R1441C. The R→ P mutation leads to the most clinically
severe form of the disease. Since PC has so far been attributed to defects in fast inactivation …
- 1Paramyotonia congenita (PC) is a human hereditary disorder wherein missense mutations in the skeletal muscle sodium channel lead to cold‐exacerbated muscle hyperexcitability. The most common site for PC mutations is the outermost arginine of domain IV segment 4 (human R1448, rat R1441).
- 2We examined the rat homologues of two PC mutants with changes at this site: R1441P and R1441C. The R→P mutation leads to the most clinically severe form of the disease. Since PC has so far been attributed to defects in fast inactivation, we expected the R→P substitution to have a more dramatic effect on fast inactivation than R→C. Both mutants (R1441P and R1441C), however, had identical rates and voltage dependence of fast inactivation and activation.
- 3R1441P and R1441C also had slowed deactivation, compared with wild‐type, raising the possibility that slowed deactivation, in combination with defective fast inactivation, might be a contributing cause of paramyotonia congenita. Furthermore, deactivation was slower in R1441P than in R1441C, suggesting that the worse phenotype of the human R→P mutation is due to a greater effect on deactivation, and supporting our hypothesis that slowed sodium channel deactivation contributes to paramyotonia congenita.
- 4We show that the downstroke of the muscle action potential produced a sodium tail current, and thus slowed deactivation opposes repolarization and therefore leads to hyperexcitability. Hyperexcitability due to slowed deactivation, which has previously been overlooked, also predicts the temperature sensitivity of PC, which has otherwise not been adequately explained.
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