Block of the Kir2.1 channel pore by alkylamine analogues of endogenous polyamines

Inward rectification induced by mono- and diaminoalkane application to inside-out membrane patches was studied in Kir2.1 (IRK1) channels expressed in Xenopus oocytes. Both monoamines and diamines block Ki2.1 channels, with potency increasing as the alkyl chain length increases (from 2 to 12 methylene groups), indicating a strong hydrophobic interaction with the blocking site. For diamines, but not monoamines, increasing the alkyl chain also increases the steepness of the voltage dependence, at any concentration, from a limiting minimal value of similar to 1.5 (n = 2 methylene groups) to similar to 4 (n = 10 methylene groups). These observations lead us to hypothesize that monoamines and diamines block inward rectifier K+ channels by entering deeply into a long, narrow pore, displacing K+ ions to the outside of the membrane, with this displacement of K+ ions contributing to "extra" charge movement. All monoamines are proposed to lie with the "head" amine at a fixed position in the pore, determined by electrostatic interaction, so that z delta is independent of monoamine alkyl chain length. The head amine of diamines is proposed to lie progressively further into the pore as alkyl chain length increases, thus displacing more K+ ions to the outside, resulting in charge movement (z delta) increasing with the increase in alkyl chain length.