Polyamine block models. (A) Classical model where voltage dependence of the block comes from charged polyamines moving in the membrane electric field to reach the blocking site in the pore (right). (B) Model from Suma et al. (2020), where voltage-dependent movement of permeant ions upward in the selectivity filter (top right) is needed to free up the blocking site (S4) for the polyamine to bind (bottom). Voltage drop (V) across the whole channel is shown in A, while in B a more realistic depiction of the voltage across the membrane dropping mostly across the selectivity filter. K ions are shown in purple. Spermidine in chemical representation and MthK structure in gray (PDB accession no. 3LDC), where only two opposing subunits are shown.