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

Alison Gardner, Michael C Sanguinetti

Mol. Pharmacol., 2015 Jul , 88, 19-28

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 expression of channels in Xenopus oocytes to characterize the structural basis for the differential sensitivity of hERG1 and rERG2 channels to RPR. Analysis of hERG1-rERG2 chimeric channels indicated that the structural determinant of channel sensitivity to RPR was located within the cytoplasmic C-terminus. Analysis of a panel of mutant hERG1 and rERG2 channels further revealed that seven residues, five in the C-linker and two in the adjacent region of the cyclic nucleotide-binding homology domain, can fully account for the differential sensitivity of hERG1 and rERG2 channels to RPR. These findings provide further evidence that the C-linker is a key structural component of slow deactivation in ether-à-go-go-related gene channels.