Poster Session B

III antiarrhythmic drug and exemplar blocker that facilitates.We propose that hERG channels blocked by nifekalant are biased toward their open state, and the supranormal conductance of facilitation is mediated by channels that were opened by nifekalant and then became unblocked.In the presence of nifekalant, similar negative voltages trap hERG in blocked and facilitated states, consistent with occupancy of the blocking site underlying facilitation.Rate-theory kinetics models identify the features necessary to produce facilitation.Atomistic models indicate block of the conduction path and suggest modulation of intracellular gate opening by nifekalant.We conclude that distinct binding modes of block and facilitation are not needed to explain facilitation by nifekalant.Rather, an agonism-while-blocking mechanism is sufficient.We speculate that the agonism-while-blocking mechanism contributes to the relative safety of some hERG blockers.