Cartoons describing possible views of inhibition of closed BK channels by paxilline. (A) Schematic BK channels are either closed (left pair) or open (right pair). The channels are diagrammed with an opening at the cytosolic end of the channel, which allows small molecules in and out of the inner cavity. Paxilline occludes the aperture to the inner cavity in the closed BK channel. Binding of paxilline to the closed channel (bottom left) occludes the aperture to the inner cavity. The open conformation either is unable to bind paxilline or does so with low affinity, without any occlusion of ion permeation. Dotted arrows indicate transitions that are either very low probability or do not occur. (B) Overall scheme is the same as in A, except for positions of inner-pore helices along alternative aqueous pathways for access of small molecules to the inner cavity. Thus, occlusion of the closed-channel aperture by paxilline may not impede access of small molecules to the inner cavity, such that MTS reagents can modify position A313C.