Models for inward rectification mechanisms. Left: Two opposing subunits of Kir2.2 (PDB accession no. 5KUM) show the key structural features of the channel pore, including the SF, transmembrane inner cavity, and cytoplasmic pore regions, as well as residues that control polyamine-induced rectification (red). Right: Cartoon illustrations of the distinct proposed models for inward rectification. In the long pore plugging model, polyamines are assumed to cause very weak voltage-dependent block by interaction with negatively charged residues in the cytoplasmic pore (pale site), but cause steep voltage-dependent rectification by moving deep into the pore, beyond the rectification controller and into the selectivity filter (dark site), thereby moving substantial polyamine charge across the electric field and displacing K⁺ ions from the SF in the process. In the extended pore filing model, rectification is assumed to arise from movement of the polyamine into the cytoplasmic pore, and through the HBC towards the rectification controller (dark site), obligatorily “pushing” a single-file “chain” of K⁺ ions (blue) through the SF in the process. The cavity trapping model represents a hybrid model that assumes weak block arising from movement of the polyamine into the cytoplasmic pore (pale site), but with the major charge movement associated with steep rectification arising from displacement of K⁺ ions from the inner cavity through the SF, due to obligatory single file movement of positive charges above the G-loop, plus movement of polyamine charge itself into the electric field, as in the long pore plugging model. Redrawn from Nichols and Lee, 2018.