Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis

Neurology. 2003 Oct 14;61(7):914-8. doi: 10.1212/01.wnl.0000086820.54065.a0.


Background: The authors reported a mutation, P1158S, of the human skeletal muscle sodium channel gene (SCN4A) in a family with cold-induced hypokalemic periodic paralysis (hypoKPP) and myotonia.

Objective: To identify mechanisms of temperature dependency in this channelopathy.

Methods: Using the amphotericin B perforated patch clamp method, sodium currents were recorded at 22 and 32 degrees C from the wild-type (WT) and P1158S mutant SCN4A expressed in tsA201 cells. Computer simulation was performed, incorporating the gating parameters of the P1158S mutant SCN4A.

Results: P1158S mutant SCN4A exhibited hyperpolarizing shifts in voltage dependence of both activation and inactivation curves at a cold temperature and a slower rate of inactivation than the WT. Computer simulation reproduced the abnormal skeletal muscle electrical activities of both paralysis at a low potassium concentration in the cold and myotonia at a normal potassium concentration.

Conclusions: Both paralysis and myotonia are attributable to the biophysical properties of the SCN4A mutation associated with hypoKPP. This is the first report of an SCN4A mutation that exhibits temperature-dependent shifts of voltage dependence in sodium channel gating.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics
  • Action Potentials / physiology
  • Cell Line
  • Cold Temperature / adverse effects*
  • Computer Simulation
  • Humans
  • Hypokalemic Periodic Paralysis / etiology*
  • Hypokalemic Periodic Paralysis / genetics
  • Hypokalemic Periodic Paralysis / physiopathology*
  • Ion Channel Gating / genetics
  • Ion Channel Gating / physiology
  • Kidney / cytology
  • Kidney / metabolism
  • Mutagenesis, Site-Directed
  • Mutation
  • NAV1.4 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Sodium / metabolism*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • Temperature
  • Transfection


  • NAV1.4 Voltage-Gated Sodium Channel
  • SCN4A protein, human
  • Sodium Channels
  • Sodium