Gating pore current in an inherited ion channelopathy

Nature. 2007 Mar 1;446(7131):76-8. doi: 10.1038/nature05598.


Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Electric Conductivity
  • Hypokalemic Periodic Paralysis / congenital*
  • Hypokalemic Periodic Paralysis / genetics*
  • Ion Channel Gating
  • Ion Transport
  • Membrane Potentials
  • Muscle, Skeletal / metabolism
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Oocytes / metabolism
  • Sodium / metabolism
  • Sodium Channels / genetics*
  • Sodium Channels / metabolism*
  • Xenopus


  • Mutant Proteins
  • Sodium Channels
  • Sodium