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Effects of the ventilatory stimulant, doxapram on human TASK-3 (KCNK9, K2P9.1) channels and TASK-1 (KCNK3, K2P3.1) channels

Cunningham, Kevin P., MacIntyre, D. Euan, Mathie, Alistair, Veale, Emma L. (2019) Effects of the ventilatory stimulant, doxapram on human TASK-3 (KCNK9, K2P9.1) channels and TASK-1 (KCNK3, K2P3.1) channels. Acta physiologica, 228 (2). ISSN 1748-1708. E-ISSN 1748-1716. (doi:10.1111/apha.13361)

Abstract

Aims: The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK-1 and TASK-1/TASK-3 heterodimer channels, than TASK-3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK-1 and TASK-3.

Methods: Whole-cell patch-clamp electrophysiology on tSA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK-1, TASK-3 and TASK-2 channels. Mutations of amino acids in the pore-lining region of TASK-3 channels were introduced using site-directed mutagenesis.

Results: Doxapram was an equipotent inhibitor of human TASK-1 and TASK-3 channels, compared with mouse channel variants, where it was more selective for TASK-1 and heterodimers of TASK-1 and TASK-3. The effect of doxapram could be attenuated by either the removal of the C-terminus of human TASK-3 channels or mutations of particular hydrophobic residues in the pore-lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK-3, zinc. The positive enantiomer of doxapram, GAL-054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL-053, had little inhibitory effect.

Conclusion: These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK-1 and TASK-3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents. This article is protected by copyright. All rights reserved.

Item Type: Article
DOI/Identification number: 10.1111/apha.13361
Uncontrolled keywords: doxapram enantiomers heterodimers K2P channels respiratory stimulant TASK‐1 channels TASK‐3 channels, Medway school of pharmacy
Subjects: R Medicine
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 12 Nov 2019 08:32 UTC
Last Modified: 26 Feb 2020 11:52 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/75921 (The current URI for this page, for reference purposes)
Mathie, Alistair: https://orcid.org/0000-0001-6094-2890
Veale, Emma L.: https://orcid.org/0000-0002-6778-9929
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