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- W2089968553 abstract "The tremorogenic fungal metabolite, paxilline, is widely used as a potent and relatively specific blocker of Ca2+- and voltage-activated Slo1 (or BK) K+ channels. Little is known about the mechanism of paxilline blockade, although paxilline has been proposed to act in an allosteric manner to influence the closed-open equilibrium and block by paxilline has been shown to be Ca2+ -dependent, with weakened block at more elevated Ca2+. Our previous study shows that block by paxilline is absolutely dependent on the presence of Glycine311 in the BK S6 helix, suggesting that block may occur within the BK central cavity. Here we provide new tests of the mechanism of block by paxilline. We show that block by paxilline is inhibited in an approximately competitive fashion by simultaneous application of the bulky pore blocker, bbTBA. Furthermore, we show that a pore lining cysteine is protected from being modified by cytosolically applied MTSET once the channel is blocked by paxilline. We also show that block is not strictly Ca2+-dependent, but strongly linked to channel open probability during paxilline application. By examining paxilline blockade at different open probabilities defined by either transmembrane potential, Ca2+, or chemical modifications, we show that paxilline only blocks closed BK channels, with essentially no ability to block the BK channel once it is open. We conclude that structural conformation of the BK channel necessary for block of closed channels by paxilline are disrupted by mutation of G311. The opening of the BK channel, which abolishes paxilline block, may produce an S6 conformation similar to that induced by mutation of G311.This work was supported by NIH grant GM-66215." @default.
- W2089968553 created "2016-06-24" @default.
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- W2089968553 date "2011-02-01" @default.
- W2089968553 modified "2023-09-26" @default.
- W2089968553 title "Paxilline, a Closed BK Channel Blocker" @default.
- W2089968553 doi "https://doi.org/10.1016/j.bpj.2010.12.1643" @default.
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