Initial steps of inactivation at the K+ channel selectivity filter

Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):E1713-22. doi: 10.1073/pnas.1317573111. Epub 2014 Apr 14.


K(+) efflux through K(+) channels can be controlled by C-type inactivation, which is thought to arise from a conformational change near the channel's selectivity filter. Inactivation is modulated by ion binding near the selectivity filter; however, the molecular forces that initiate inactivation remain unclear. We probe these driving forces by electrophysiology and molecular simulation of MthK, a prototypical K(+) channel. Either Mg(2+) or Ca(2+) can reduce K(+) efflux through MthK channels. However, Ca(2+), but not Mg(2+), can enhance entry to the inactivated state. Molecular simulations illustrate that, in the MthK pore, Ca(2+) ions can partially dehydrate, enabling selective accessibility of Ca(2+) to a site at the entry to the selectivity filter. Ca(2+) binding at the site interacts with K(+) ions in the selectivity filter, facilitating a conformational change within the filter and subsequent inactivation. These results support an ionic mechanism that precedes changes in channel conformation to initiate inactivation.

Keywords: calcium; dynamics; energetics; gating; permeation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Calcium / metabolism
  • Cations, Divalent / pharmacology
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Ion Channel Gating* / drug effects
  • Ions / metabolism
  • Models, Biological
  • Molecular Dynamics Simulation
  • Potassium / metabolism
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels / metabolism*
  • Proton-Motive Force
  • Thermodynamics


  • Cations, Divalent
  • Ions
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium
  • Calcium