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Mechanism of inhibition of mouse S lo3 ( K Ca 5.1) potassium channels by quinine, quinidine and barium
Author(s) -
Wrighton David C,
Muench Stephen P,
Lippiat Jonathan D
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13214
Subject(s) - quinidine , potassium channel , chemistry , biophysics , barium , extracellular , potassium channel blocker , patch clamp , inward rectifier potassium ion channel , quinine , xenopus , pharmacology , ion channel , biochemistry , biology , receptor , inorganic chemistry , malaria , gene , immunology
Background and Purpose The Slo 3 (K Ca 5.1) channel is a major component of mammalian KSper (sperm potassium conductance) channels and inhibition of these channels by quinine and barium alters sperm motility. The aim of this investigation was to determine the mechanism by which these drugs inhibit Slo 3 channels. Experimental Approach Mouse (m) Slo3 (K Ca 5.1) channels or mutant forms were expressed in Xenopus oocytes and currents recorded with 2‐electrode voltage‐clamp. Gain‐of‐function mSlo 3 mutations were used to explore the state‐dependence of the inhibition. The interaction between quinidine and mSlo 3 channels was modelled by in silico docking. Key Results Several drugs known to block KSper also affected m Slo 3 channels with similar levels of inhibition. The inhibition induced by extracellular barium was prevented by increasing the extracellular potassium concentration. R196Q and F304Y mutations in the mSlo 3 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 10‐fold; this effect was not observed with the R196Q mutation. Conclusions and Implications Block of mSlo 3 channels by quinine, quinidine and barium is not state‐dependent. Barium inhibits mSlo 3 outside the cell by interacting with the selectivity filter, whereas quinine and quinidine act from the inside, by binding in a hydrophobic pocket formed by the S 6 segment of each subunit. Furthermore, we propose that the Slo 3 channel activation gate lies deep within the pore between F 304 in the S6 segment and the selectivity filter.