Wrighton, DC, Muench, SP and Lippiat, JD (2015) Mechanism of inhibition of mouse Slo3 (KCa5.1) potassium channels by quinine, quinidine, and barium. British Journal of Pharmacology, 172 (17). pp. 4355-4363. ISSN 0007-1188
Abstract
Background and Purpose: Slo3 is a major component of the membrane potassium conductance, KSper, of mammalian spermatozoa and inhibition by quinine and barium alters their motility. The aim of this investigation was to determine the mechanism by which these drugs inhibit Slo3. Experimental approach: We studied block of mouse Slo3 (mSlo3) potassium channels expressed in Xenopus oocytes by quinine, quinidine, and barium. Gain-of-function mSlo3 mutations were generated in order to explore state-dependence of inhibition. The interaction between quinidine and mSlo3 channels was modelled by in silico docking. Key results: We found that inhibition by several drugs known to block KSper also affected Slo3 with similar levels of inhibition. Inhibition by extracellular barium was prevented by increasing the extracellular potassium concentration. R196Q and F304Y mutations in the mSlo3 voltage-sensor and pore, respectively, both increased channel activity. The F304Y mutation did not alter the effects of barium, but increased the potency of inhibition by both quinine and quinidine approximately tenfold. This effect, however, was not observed with the R196Q mutation. Conclusions and Implications: Block of mSlo3 by quinine, quinidine, and barium is not state dependent. External barium inhibits mSlo3 by interacting with the selectivity filter, whilst quinine and quinidine block via the intracellular side by binding in a hydrophobic pocket formed by the S6 segment of each subunit. Furthermore, we propose that the Slo3 channel activation gate lies deep within the pore between F304 in the S6 segment and the selectivity filter.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Jun 2015 13:46 |
Last Modified: | 23 Jun 2023 21:48 |
Published Version: | http://dx.doi.org/10.1111/bph.13214 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/bph.13214 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:86674 |