Revisiting voltage-dependent relief of block in ion channels: A mechanism independent of punchthrough

Voltage dependence of block was investigated in a simple model for permeation in a multiion pore. Internal blocker could bind to three states of the open channel that differed in the locations and number of permeant ion bound; blocker dissociation occurs exclusively to the internal solution, and the blocker does not itself enter the electric field. By changing the relative stability of blocker binding to these three states, block displayed voltage dependence with relief of block at high potentials. Similar patterns of block could also be generated in more detailed models of ion permeation. These results illustrate that the observation of relief of block at high potentials is not a sufficient criterion for establishing that a blocker is permeant in a channel that has a complex permeation cycle.