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Br J Pharmacol. 2019 Aug;176(15):2708-2723. doi: 10.1111/bph.14693. Epub 2019 Jun 17.

Histidine at position 462 determines the low quinine sensitivity of ether-à-go-go channel superfamily member Kv 12.1.

Author information

1
Department of Neurophysiology, Institute of Physiology and Pathophysiology, Philipps-University Marburg, Marburg, Germany.
2
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
3
Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
4
Division of Physiology, Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck, Austria.

Abstract

BACKGROUND AND PURPOSE:

The ether-à-go-go (Eag) Kv superfamily comprises closely related Kv 10, Kv 11, and Kv 12 subunits. Kv 11.1 (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 Kv 11.1 can be explained by central drug-binding pockets that are absent in most other channels. Currently, it is unknown whether Kv 12 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 Kv 12.1 channels to quinine, a substituted quinoline that blocks Kv 10.1 and Kv 11.1 at low micromolar concentrations.

KEY RESULTS:

Quinine inhibited Kv 12.1, but its affinity was 10-fold lower than for Kv 11.1. Contrary to Kv 11.1, quinine inhibited Kv 12.1 in a largely voltage-independent manner and induced channel opening at more depolarised potentials. Low sensitivity of Kv 12.1 and characteristics of quinine-dependent inhibition were determined by histidine 462, as site-directed mutagenesis of this residue into the homologous tyrosine of Kv 11.1 conferred Kv 11.1-like quinine block to Kv 12.1(H462Y). Molecular modelling demonstrated that the low affinity of Kv 12.1 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 Kv 12.1(H462Y) and Kv 11.1 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.

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