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Title: Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block

Abstract

Background: Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings: We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the TRS mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affectmore » blocker binding. Conclusions/Significance: The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [3];  [4];  [5];  [3];  [6]
  1. Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.
  2. Univ. degli Studi di Milano (Italy). Dipartimento di Biologia e Istituto di Biofisica del Consiglio Nazionale delle Ricerche
  3. Univ. degli Studi di Milano (Italy). Dipartimento di Biologia e Istituto di Biofisica del Consiglio Nazionale delle Ricerche
  4. Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology
  5. Technical Univ. of Darmstadt (Germany). Inst. fur Botanik
  6. Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology; Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics; Univ. of California, San Francisco, CA (United States). Dept. of California Inst. for Quantitative Biomedical Research; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI Identifier:
1627387
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 4; Journal Issue: 10; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics

Citation Formats

Chatelain, Franck C., Gazzarrini, Sabrina, Fujiwara, Yuichiro, Arrigoni, Cristina, Domigan, Courtney, Ferrara, Giuseppina, Pantoja, Carlos, Thiel, Gerhard, Moroni, Anna, and Minor, Daniel L. Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block. United States: N. p., 2009. Web. doi:10.1371/journal.pone.0007496.
Chatelain, Franck C., Gazzarrini, Sabrina, Fujiwara, Yuichiro, Arrigoni, Cristina, Domigan, Courtney, Ferrara, Giuseppina, Pantoja, Carlos, Thiel, Gerhard, Moroni, Anna, & Minor, Daniel L. Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block. United States. https://doi.org/10.1371/journal.pone.0007496
Chatelain, Franck C., Gazzarrini, Sabrina, Fujiwara, Yuichiro, Arrigoni, Cristina, Domigan, Courtney, Ferrara, Giuseppina, Pantoja, Carlos, Thiel, Gerhard, Moroni, Anna, and Minor, Daniel L. Fri . "Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block". United States. https://doi.org/10.1371/journal.pone.0007496. https://www.osti.gov/servlets/purl/1627387.
@article{osti_1627387,
title = {Selection of Inhibitor-Resistant Viral Potassium Channels Identifies a Selectivity Filter Site that Affects Barium and Amantadine Block},
author = {Chatelain, Franck C. and Gazzarrini, Sabrina and Fujiwara, Yuichiro and Arrigoni, Cristina and Domigan, Courtney and Ferrara, Giuseppina and Pantoja, Carlos and Thiel, Gerhard and Moroni, Anna and Minor, Daniel L.},
abstractNote = {Background: Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs. Methodology/Principal Findings: We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the TRS mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding. Conclusions/Significance: The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features.},
doi = {10.1371/journal.pone.0007496},
journal = {PLoS ONE},
number = 10,
volume = 4,
place = {United States},
year = {Fri Oct 16 00:00:00 EDT 2009},
month = {Fri Oct 16 00:00:00 EDT 2009}
}

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Novel Neuroprotective K + Channel Inhibitor Identified by High-Throughput Screening in Yeast
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Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor
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Tethered Protein Display Identifies a Novel Kir3.2 (GIRK2) Regulator from Protein Scaffold Libraries
journal, July 2014

  • Bagriantsev, Sviatoslav N.; Chatelain, Franck C.; Clark, Kimberly A.
  • ACS Chemical Neuroscience, Vol. 5, Issue 9
  • DOI: 10.1021/cn5000698

The voltage-sensing domain of a phosphatase gates the pore of a potassium channel
journal, February 2013

  • Arrigoni, Cristina; Schroeder, Indra; Romani, Giulia
  • Journal of General Physiology, Vol. 141, Issue 3
  • DOI: 10.1085/jgp.201210940

Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa
journal, February 2012


Engineering a Ca++-Sensitive (Bio)Sensor from the Pore-Module of a Potassium Channel
journal, February 2015

  • DiFrancesco, Mattia; Gazzarrini, Sabrina; Arrigoni, Cristina
  • Sensors, Vol. 15, Issue 3
  • DOI: 10.3390/s150304913

Genes for Membrane Transport Proteins: Not So Rare in Viruses
journal, August 2018

  • Greiner, Timo; Moroni, Anna; Van Etten, James
  • Viruses, Vol. 10, Issue 9
  • DOI: 10.3390/v10090456

A small viral potassium ion channel with an inherent inward rectification
text, January 2019