Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: S Wang, M J Morales, S Liu, H C Strauss, R L Rasmusson

Journal, date & volume: FEBS Lett., 1997 Nov 3 , 417, 43-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/9395071

Abstract
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.