C-Linker Accounts for Differential Sensitivity of ERG1 and ERG2 K+ Channels to RPR260243-Induced Slow Deactivation.

ABSTRACT: Compounds can activate human ether-à-go-go-related gene 1 (hERG1) channels by several different mechanisms, including a slowing of deactivation, an increase in single channel open probability, or a reduction in C-type inactivation. The first hERG1 activator to be discovered, RPR260243 ((3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid) (RPR) induces a pronounced, voltage-dependent slowing of hERG1 deactivation. The putative binding site for RPR, previously mapped to a hydrophobic pocket located between two adjacent subunits, is fully conserved in the closely related rat ether-à-go-go-related gene 2 (rERG2), yet these channels are relatively insensitive to RPR. Here, we use site-directed mutagenesis and heterologous ex

SUBMITTER: Gardner A 

PROVIDER: S-EPMC4468633 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature