Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2

Biophys J. 2010 Nov 3;99(9):L72-4. doi: 10.1016/j.bpj.2010.08.069.

Abstract

The effects on the structural and functional properties of the Kv1.2 voltage-gated ion channel, caused by selective mutation of voltage sensor domain residues, have been investigated using classical molecular dynamics simulations. Following experiments that have identified mutations of voltage-gated ion channels involved in state-dependent omega currents, we observe for both the open and closed conformations of the Kv1.2 that specific mutations of S4 gating-charge residues destabilize the electrostatic network between helices of the voltage sensor domain, resulting in the formation of hydrophilic pathways linking the intra- and extracellular media. When such mutant channels are subject to transmembrane potentials, they conduct cations via these so-called "omega pores." This study provides therefore further insight into the molecular mechanisms that lead to omega currents, which have been linked to certain channelopathies.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Biophysical Phenomena
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • In Vitro Techniques
  • Ion Channel Gating
  • Kv1.2 Potassium Channel / chemistry*
  • Kv1.2 Potassium Channel / genetics*
  • Kv1.2 Potassium Channel / metabolism
  • Membrane Potentials
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Protein Conformation
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Static Electricity

Substances

  • Kv1.2 Potassium Channel
  • Mutant Proteins