Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation

FEBS Lett. 1997 Nov 3;417(1):43-7. doi: 10.1016/s0014-5793(97)01245-3.


Rectification of HERG is due to a rapid inactivation process that has been labeled C-type inactivation and is believed to be due to closure of the external mouth of the pore. We examined the effects of mutation of extracellular residues that remove C-type inactivation on binding of the intracellularly acting methanesulfonanilide drug E-4031. Removal of inactivation through mutation reduced drug affinity by more than an order of magnitude. Elevation of [K+]o in the wild-type channel reduces channel affinity for E-4031. Elevation of [K+]o also interferes with the extracellular pore mouth closure associated with C-type inactivation through a 'foot in the door' mechanism. We examined the possibility that [K+]o elevation reduces drug binding through inhibition of C-type inactivation by comparing drug block in the wild-type and inactivation-removed mutant channels. Elevation of [K+]o decreased affinity in both channel constructs by a roughly equal amount. These results suggest that [K+]o alters drug binding affinity independently of its effects on C-type inactivation. They further suggest that inhibition of pore mouth closure by elevated [K+]o does not have same effect on drug affinity as mutations removing C-type inactivation.

Publication types

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

MeSH terms

  • Animals
  • Cation Transport Proteins*
  • Electrophysiology
  • Ether-A-Go-Go Potassium Channels
  • Patch-Clamp Techniques
  • Piperidines / metabolism*
  • Potassium / metabolism*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Potassium Channels / physiology
  • Potassium Channels, Voltage-Gated*
  • Pyridines / metabolism*
  • Xenopus laevis


  • Cation Transport Proteins
  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Piperidines
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Pyridines
  • E 4031
  • Potassium