Potentiation of the Kv1 family K(+) channel by cortisone analogues

ACS Chem Biol. 2012 Oct 19;7(10):1641-6. doi: 10.1021/cb300233y. Epub 2012 Jul 23.


The Kv1 family voltage-dependent K(+) channels are essential for termination of action potentials in neurons and myocytes. These channels form a stable complex with their beta subunits (Kvβ), some of which inhibit channel activity. Cortisone potentiates Kv1 channel by binding to Kvβ and promoting its dissociation from the channel, but its half-maximum effective concentration is ∼46 μM. To identify corticosteroids that are more efficient than cortisone, we examined 25 cortisone analogues and found that fluticasone propionate potentiates channel current with a half-maximum effective concentration (EC(50)) of 37 ± 1.1 nM. Further studies showed that fluticasone propionate potentiates channel current by inducing dissociation of Kvβ, and docking of fluticasone propionate into the cortisone binding site reveals potential interactions that enhance the EC(50) value. Thus, fluticasone propionate provides a starting point for rational design of more efficient small-molecule compounds that increase Kv1 activity and affect the integrity of the Kv1-Kvβ complex.

Publication types

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

MeSH terms

  • Adrenal Cortex Hormones / pharmacology*
  • Androstadienes / pharmacology
  • Binding Sites / drug effects
  • Cortisone / analogs & derivatives*
  • Cortisone / pharmacology*
  • Drug Design
  • Fluticasone
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Shaker Superfamily of Potassium Channels / agonists*
  • Small Molecule Libraries


  • Adrenal Cortex Hormones
  • Androstadienes
  • Shaker Superfamily of Potassium Channels
  • Small Molecule Libraries
  • Fluticasone
  • Cortisone