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 Kir2.1 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 ∼1.5 (n = 2 methylene groups) 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 zδ 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 (zδ) increasing with the increase in alkyl chain length.
Block of the Kir2.1 Channel Pore by Alkylamine Analogues of Endogenous Polyamines
Address correspondence to C.G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Fax: 314-362-7463; E-mail: [email protected]
Many of the mono- and diaminoalkanes were gifts from Dr. Carl Romano. The Kir2.1 (IRK1) clone was a gift from Lou Philipson and Dorothy Hanck (University of Chicago, Chicago, IL).
Given that the blocking moiety in the polyamines is probably an unsubstituted amine (diameter ∼2 Å, similar to dehydrated K+), deeper access into the permeation pathway may be possible than for a tetramethylammonium group (diameter ∼8 Å, similar to hydrated K+).
Portions of this work were previously published in abstract form (Pearson, W.L., and C.G. Nichols. 1997. Biophys. J. 72:A254).
Alternatively, the current in the presence of the blocker was fit as the product of two single exponential equations, one rising exponential attributable to the unblocking process, and one falling exponential attributable to deactivation. The unblock time constants determined by either method were very similar.
W.L. Pearson, C.G. Nichols; Block of the Kir2.1 Channel Pore by Alkylamine Analogues of Endogenous Polyamines . J Gen Physiol 1 September 1998; 112 (3): 351–363. doi: https://doi.org/10.1085/jgp.112.3.351
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