Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism.
Bottom Line: Measurements of Po times the number of channels at negative potentials support the idea that paxilline increases occupancy of closed states, effectively reducing the closed-open equilibrium constant, L(0).However, paxilline does not hinder MTSET modification of the inner cavity residue, A313C.We conclude that paxilline binds more tightly to the closed conformation, favoring occupancy of closed-channel conformations, and propose that it binds to a superficial position near the entrance to the central cavity, but does not hinder access of smaller molecules to this cavity.
Affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.Show MeSH
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Mentions: The ability of inhibition by paxilline to be reversed by changes in equilibration conditions, even in the constant presence of paxilline, was also confirmed in patches with large numbers of BK channels (Fig. 4). Specifically, after onset of block in 100 nM paxilline (Fig. 4 A), changing the equilibration conditions to those favoring unblocking can produce recovery from paxilline inhibition (Fig. 4, B and C). It may be noticed that the onset of paxilline inhibition appears variable during wash-in of paxilline. This is addressed below and appears to reflect variability in paxilline access to the patch, despite the rapidity of solution exchange with small charged molecules.
Affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110.