Article date: August 2019
By: Marlen Dierich, Willem B. Ham, Anna Stary‐Weinzinger, Michael G. Leitner in Volume 176, Issue 15, pages 2708-2723
Background and Purpose
The ether‐à‐go‐go (Eag) Kv superfamily comprises closely related Kv10, Kv11, and Kv12 subunits. Kv11.1 (termed hERG in humans) gained much attention, as drug‐induced inhibition of these channels is a frequent cause of sudden death in humans. The exclusive drug sensitivity of Kv11.1 can be explained by central drug‐binding pockets that are absent in most other channels. Currently, it is unknown whether Kv12 channels are equipped with an analogous drug‐binding pocket and whether drug‐binding properties are conserved in all Eag superfamily members.
Experimental Approach
We analysed sensitivity of recombinant Kv12.1 channels to quinine, a substituted quinoline that blocks Kv10.1 and Kv11.1 at low micromolar concentrations.
Key Results
Quinine inhibited Kv12.1, but its affinity was 10‐fold lower than for Kv11.1. Contrary to Kv11.1, quinine inhibited Kv12.1 in a largely voltage‐independent manner and induced channel opening at more depolarised potentials. Low sensitivity of Kv12.1 and characteristics of quinine‐dependent inhibition were determined by histidine 462, as site‐directed mutagenesis of this residue into the homologous tyrosine of Kv11.1 conferred Kv11.1‐like quinine block to Kv12.1(H462Y). Molecular modelling demonstrated that the low affinity of Kv12.1 was determined by only weak interactions of residues in the central cavity with quinine. In contrast, more favourable interactions can explain the higher quinine sensitivity of Kv12.1(H462Y) and Kv11.1 channels.
Conclusions and Implications
The quinoline‐binding “motif” is not conserved within the Eag superfamily, although the overall architecture of these channels is apparently similar. Our findings highlight functional and pharmacological diversity in this group of evolutionary‐conserved channels.
DOI: 10.1111/bph.14693
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