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

FEBS Letters

Liu, Shuguang¹  Rasmusson, Randall L¹  Morales, Michael J¹  Strauss, Harold C¹  Wang, Shimin¹ 

[1] Departments of Medicine, Biomedical Engineering and Pharmacology, Duke University Medical Center, Durham, NC, USA

关键词: Potassium;    Delayed rectifier;    Repolarization;    Cardiac;   

DOI  :  10.1016/S0014-5793(97)01245-3

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown