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Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels

Rectification of macroscopic current through inward-rectifier K(+) (Kir) channels reflects strong voltage dependence of channel block by intracellular cations such as polyamines. The voltage dependence results primarily from the movement of K(+) ions across the transmembrane electric field, which ac...

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Autores principales: Guo, Donglin, Lu, Zhe
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229578/
https://www.ncbi.nlm.nih.gov/pubmed/14581581
http://dx.doi.org/10.1085/jgp.200308890
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author Guo, Donglin
Lu, Zhe
author_facet Guo, Donglin
Lu, Zhe
author_sort Guo, Donglin
collection PubMed
description Rectification of macroscopic current through inward-rectifier K(+) (Kir) channels reflects strong voltage dependence of channel block by intracellular cations such as polyamines. The voltage dependence results primarily from the movement of K(+) ions across the transmembrane electric field, which accompanies the binding–unbinding of a blocker. Residues D172, E224, and E299 in IRK1 are critical for high-affinity binding of blockers. D172 appears to be located somewhat internal to the narrow K(+) selectivity filter, whereas E224 and E299 form a ring at a more intracellular site. Using a series of alkyl-bis-amines of varying length as calibration, we investigated how the acidic residues in IRK1 interact with amine groups in the natural polyamines (putrescine, spermidine, and spermine) that cause rectification in cells. To block the pore, the leading amine of bis-amines of increasing length penetrates ever deeper into the pore toward D172, while the trailing amine in every bis-amine binds near a more intracellular site and interacts with E224 and E299. The leading amine in nonamethylene-bis-amine (bis-C9) makes the closest approach to D172, displacing the maximal number of K(+) ions and exhibiting the strongest voltage dependence. Cells do not synthesize bis-amines longer than putrescine (bis-C4) but generate the polyamines spermidine and spermine by attaching an amino-propyl group to one or both ends of putrescine. Voltage dependence of channel block by the tetra-amine spermine is comparable to that of block by the bis-amines bis-C9 (shorter) or bis-C12 (equally long), but spermine binds to IRK1 with much higher affinity than either bis-amine does. Thus, counterintuitively, the multiple amines in spermine primarily confer the high affinity but not the strong voltage dependence of channel block. Tetravalent spermine achieves a stronger interaction with the pore by effectively behaving like a pair of tethered divalent cations, two amine groups in its leading half interacting primarily with D172, whereas the other two in the trailing half interact primarily with E224 and E299. Thus, nature has optimized not only the blocker but also, in a complementary manner, the channel for producing rapid, high-affinity, and strongly voltage-dependent channel block, giving rise to exceedingly sharp rectification.
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spelling pubmed-22295782008-04-16 Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels Guo, Donglin Lu, Zhe J Gen Physiol Article Rectification of macroscopic current through inward-rectifier K(+) (Kir) channels reflects strong voltage dependence of channel block by intracellular cations such as polyamines. The voltage dependence results primarily from the movement of K(+) ions across the transmembrane electric field, which accompanies the binding–unbinding of a blocker. Residues D172, E224, and E299 in IRK1 are critical for high-affinity binding of blockers. D172 appears to be located somewhat internal to the narrow K(+) selectivity filter, whereas E224 and E299 form a ring at a more intracellular site. Using a series of alkyl-bis-amines of varying length as calibration, we investigated how the acidic residues in IRK1 interact with amine groups in the natural polyamines (putrescine, spermidine, and spermine) that cause rectification in cells. To block the pore, the leading amine of bis-amines of increasing length penetrates ever deeper into the pore toward D172, while the trailing amine in every bis-amine binds near a more intracellular site and interacts with E224 and E299. The leading amine in nonamethylene-bis-amine (bis-C9) makes the closest approach to D172, displacing the maximal number of K(+) ions and exhibiting the strongest voltage dependence. Cells do not synthesize bis-amines longer than putrescine (bis-C4) but generate the polyamines spermidine and spermine by attaching an amino-propyl group to one or both ends of putrescine. Voltage dependence of channel block by the tetra-amine spermine is comparable to that of block by the bis-amines bis-C9 (shorter) or bis-C12 (equally long), but spermine binds to IRK1 with much higher affinity than either bis-amine does. Thus, counterintuitively, the multiple amines in spermine primarily confer the high affinity but not the strong voltage dependence of channel block. Tetravalent spermine achieves a stronger interaction with the pore by effectively behaving like a pair of tethered divalent cations, two amine groups in its leading half interacting primarily with D172, whereas the other two in the trailing half interact primarily with E224 and E299. Thus, nature has optimized not only the blocker but also, in a complementary manner, the channel for producing rapid, high-affinity, and strongly voltage-dependent channel block, giving rise to exceedingly sharp rectification. The Rockefeller University Press 2003-11 /pmc/articles/PMC2229578/ /pubmed/14581581 http://dx.doi.org/10.1085/jgp.200308890 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Guo, Donglin
Lu, Zhe
Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title_full Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title_fullStr Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title_full_unstemmed Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title_short Interaction Mechanisms between Polyamines and IRK1 Inward Rectifier K(+) Channels
title_sort interaction mechanisms between polyamines and irk1 inward rectifier k(+) channels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229578/
https://www.ncbi.nlm.nih.gov/pubmed/14581581
http://dx.doi.org/10.1085/jgp.200308890
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