Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels
Identifieur interne : 000820 ( Istex/Corpus ); précédent : 000819; suivant : 000821Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels
Auteurs : Angélica L Pez-Izquierdo ; Iván A. Aréchiga-Figueroa ; Eloy G. Moreno-Galindo ; Daniela Ponce-Balbuena ; Martín Rodríguez-Martínez ; Tania Ferrer-Villada ; Aldo A. Rodríguez-Menchaca ; Marcel A G. Van Der Heyden ; José A. Sánchez-ChapulaSource :
- Pflügers Archiv - European Journal of Physiology [ 0031-6768 ] ; 2011-10-01.
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Abstract
Abstract: Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.
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DOI: 10.1007/s00424-011-0995-5
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Aréchiga-Figueroa</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Moreno Galindo, Eloy G" sort="Moreno Galindo, Eloy G" uniqKey="Moreno Galindo E" first="Eloy G." last="Moreno-Galindo">Eloy G. Moreno-Galindo</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Ponce Balbuena, Daniela" sort="Ponce Balbuena, Daniela" uniqKey="Ponce Balbuena D" first="Daniela" last="Ponce-Balbuena">Daniela Ponce-Balbuena</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Rodriguez Martinez, Martin" sort="Rodriguez Martinez, Martin" uniqKey="Rodriguez Martinez M" first="Martín" last="Rodríguez-Martínez">Martín Rodríguez-Martínez</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Ferrer Villada, Tania" sort="Ferrer Villada, Tania" uniqKey="Ferrer Villada T" first="Tania" last="Ferrer-Villada">Tania Ferrer-Villada</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Rodriguez Menchaca, Aldo A" sort="Rodriguez Menchaca, Aldo A" uniqKey="Rodriguez Menchaca A" first="Aldo A." last="Rodríguez-Menchaca">Aldo A. Rodríguez-Menchaca</name><affiliation><mods:affiliation>Departamento de Fisiología, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico</mods:affiliation></affiliation></author><author><name sortKey="Van Der Heyden, Marcel A G" sort="Van Der Heyden, Marcel A G" uniqKey="Van Der Heyden M" first="Marcel A G" last="Van Der Heyden">Marcel A G. Van Der Heyden</name><affiliation><mods:affiliation>Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Sanchez Chapula, Jose A" sort="Sanchez Chapula, Jose A" uniqKey="Sanchez Chapula J" first="José A." last="Sánchez-Chapula">José A. Sánchez-Chapula</name><affiliation><mods:affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: sancheza@ucol.mx</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Pflügers Archiv - European Journal of Physiology</title><title level="j" type="sub">European Journal of Physiology</title><title level="j" type="abbrev">Pflugers Arch - Eur J Physiol</title><idno type="ISSN">0031-6768</idno><idno type="eISSN">1432-2013</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="2011-10-01">2011-10-01</date><biblScope unit="volume">462</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="505">505</biblScope><biblScope unit="page" to="517">517</biblScope></imprint><idno type="ISSN">0031-6768</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0031-6768</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Inward rectifier potassium channels</term><term>Kir2.1</term><term>Kir2.3</term><term>Kir6.2</term><term>Phosphatidylinositol 4,5-bisphosphate, PIP2</term><term>Quinacrine</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.</div></front></TEI><istex><corpusName>springer-journals</corpusName><author><json:item><name>Angélica López-Izquierdo</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Iván A. Aréchiga-Figueroa</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Eloy G. Moreno-Galindo</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Daniela Ponce-Balbuena</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Martín Rodríguez-Martínez</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Tania Ferrer-Villada</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string></affiliations></json:item><json:item><name>Aldo A. Rodríguez-Menchaca</name><affiliations><json:string>Departamento de Fisiología, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico</json:string></affiliations></json:item><json:item><name>Marcel A G van der Heyden</name><affiliations><json:string>Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands</json:string></affiliations></json:item><json:item><name>José A. Sánchez-Chapula</name><affiliations><json:string>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</json:string><json:string>E-mail: sancheza@ucol.mx</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Quinacrine</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Inward rectifier potassium channels</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Phosphatidylinositol 4,5-bisphosphate, PIP2</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Kir2.1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Kir2.3</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Kir6.2</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CADs : Cationic amphiphilic drugs</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IK1 : Inward rectifier K+ current</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IKATP : ATP-sensitive inward rectifier K+ current</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HP : Holding potential</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Kir : Inward rectifier K+ channels</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PIP2 : Phosphatidylinositol 4,5-bisphosphate</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>T1/2 : Half-maximal inhibitory time</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TP : Test pulses</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>WT : Wild type</value></json:item></subject><articleId><json:string>995</json:string><json:string>s00424-011-0995-5</json:string></articleId><arkIstex>ark:/67375/VQC-GJBTFBF6-6</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>OriginalPaper</json:string></originalGenre><abstract>Abstract: Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.</abstract><qualityIndicators><score>9.868</score><pdfWordCount>6522</pdfWordCount><pdfCharCount>42335</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>13</pdfPageCount><pdfPageSize>595.276 x 790.866 pts</pdfPageSize><refBibsNative>false</refBibsNative><abstractWordCount>239</abstractWordCount><abstractCharCount>1684</abstractCharCount><keywordCount>15</keywordCount></qualityIndicators><title>Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels</title><genre><json:string>research-article</json:string></genre><host><title>Pflügers Archiv - European Journal of 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xml:id="author-0000"><persName><forename type="first">Angélica</forename><surname>López-Izquierdo</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Iván</forename><surname>Aréchiga-Figueroa</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Eloy</forename><surname>Moreno-Galindo</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Daniela</forename><surname>Ponce-Balbuena</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0004"><persName><forename type="first">Martín</forename><surname>Rodríguez-Martínez</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Tania</forename><surname>Ferrer-Villada</surname></persName><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Aldo</forename><surname>Rodríguez-Menchaca</surname></persName><affiliation>Departamento de Fisiología, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Marcel</forename><surname>van der Heyden</surname></persName><affiliation>Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands</affiliation></author><author xml:id="author-0008" corresp="yes"><persName><forename type="first">José</forename><surname>Sánchez-Chapula</surname></persName><email>sancheza@ucol.mx</email><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation></author><idno type="istex">78656B70A5538C4ED5F64457A52953B517728A7F</idno><idno type="ark">ark:/67375/VQC-GJBTFBF6-6</idno><idno type="DOI">10.1007/s00424-011-0995-5</idno><idno type="article-id">995</idno><idno type="article-id">s00424-011-0995-5</idno></analytic><monogr><title level="j">Pflügers Archiv - European Journal of Physiology</title><title level="j" type="sub">European Journal of Physiology</title><title level="j" type="abbrev">Pflugers Arch - Eur J Physiol</title><idno type="pISSN">0031-6768</idno><idno type="eISSN">1432-2013</idno><idno type="journal-ID">true</idno><idno type="issue-article-count">11</idno><idno type="volume-issue-count">6</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="2011-10-01"></date><biblScope unit="volume">462</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="505">505</biblScope><biblScope unit="page" to="517">517</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2011-05-04</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Quinacrine</term></item><item><term>Inward rectifier potassium channels</term></item><item><term>Phosphatidylinositol 4,5-bisphosphate, PIP2</term></item><item><term>Kir2.1</term></item><item><term>Kir2.3</term></item><item><term>Kir6.2</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>CADs</term><term>Cationic amphiphilic drugs</term></item><item><term>IK1</term><term>Inward rectifier K+ current</term></item><item><term>IKATP</term><term>ATP-sensitive inward rectifier K+ current</term></item><item><term>HP</term><term>Holding potential</term></item><item><term>Kir</term><term>Inward rectifier K+ channels</term></item><item><term>PIP2</term><term>Phosphatidylinositol 4,5-bisphosphate</term></item><item><term>T1/2</term><term>Half-maximal inhibitory time</term></item><item><term>TP</term><term>Test pulses</term></item><item><term>WT</term><term>Wild type</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Biomedicine</head><item><term>Human Physiology</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2011-05-04">Created</change><change when="2011-10-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-GJBTFBF6-6/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//Springer-Verlag//DTD A++ V2.4//EN" URI="http://devel.springer.de/A++/V2.4/DTD/A++V2.4.dtd" name="istex:docType"></istex:docType><istex:document><Publisher><PublisherInfo><PublisherName>Springer-Verlag</PublisherName><PublisherLocation>Berlin/Heidelberg</PublisherLocation></PublisherInfo><Journal OutputMedium="All"><JournalInfo JournalProductType="ArchiveJournal" NumberingStyle="Unnumbered"><JournalID>424</JournalID><JournalPrintISSN>0031-6768</JournalPrintISSN><JournalElectronicISSN>1432-2013</JournalElectronicISSN><JournalTitle>Pflügers Archiv - European Journal of Physiology</JournalTitle><JournalSubTitle>European Journal of Physiology</JournalSubTitle><JournalAbbreviatedTitle>Pflugers Arch - Eur J Physiol</JournalAbbreviatedTitle><JournalSubjectGroup><JournalSubject Type="Primary">Biomedicine</JournalSubject><JournalSubject Type="Secondary">Human Physiology</JournalSubject></JournalSubjectGroup></JournalInfo><Volume OutputMedium="All"><VolumeInfo TocLevels="0" VolumeType="Regular"><VolumeIDStart>462</VolumeIDStart><VolumeIDEnd>462</VolumeIDEnd><VolumeIssueCount>6</VolumeIssueCount></VolumeInfo><Issue IssueType="Regular" OutputMedium="All"><IssueInfo IssueType="Regular" TocLevels="0"><IssueIDStart>4</IssueIDStart><IssueIDEnd>4</IssueIDEnd><IssueArticleCount>11</IssueArticleCount><IssueHistory><OnlineDate><Year>2011</Year><Month>9</Month><Day>10</Day></OnlineDate><PrintDate><Year>2011</Year><Month>9</Month><Day>9</Day></PrintDate><CoverDate><Year>2011</Year><Month>10</Month></CoverDate><PricelistYear>2011</PricelistYear></IssueHistory><IssueCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>2011</CopyrightYear></IssueCopyright></IssueInfo><Article ID="s00424-011-0995-5" OutputMedium="All"><ArticleInfo ArticleType="OriginalPaper" ContainsESM="No" Language="En" NumberingStyle="Unnumbered" TocLevels="0"><ArticleID>995</ArticleID><ArticleDOI>10.1007/s00424-011-0995-5</ArticleDOI><ArticleCitationID>505</ArticleCitationID><ArticleSequenceNumber>2</ArticleSequenceNumber><ArticleTitle Language="En">Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP<Subscript>2</Subscript> interaction with Kir2.x and Kir6.2 channels</ArticleTitle><ArticleCategory>Cardiovascular Physiology</ArticleCategory><ArticleFirstPage>505</ArticleFirstPage><ArticleLastPage>517</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2011</Year><Month>7</Month><Day>10</Day></RegistrationDate><Received><Year>2011</Year><Month>5</Month><Day>4</Day></Received><Revised><Year>2011</Year><Month>7</Month><Day>8</Day></Revised><Accepted><Year>2011</Year><Month>7</Month><Day>8</Day></Accepted><OnlineDate><Year>2011</Year><Month>7</Month><Day>22</Day></OnlineDate></ArticleHistory><ArticleCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>2011</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Angélica</GivenName><FamilyName>López-Izquierdo</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Iván</GivenName><GivenName>A.</GivenName><FamilyName>Aréchiga-Figueroa</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Eloy</GivenName><GivenName>G.</GivenName><FamilyName>Moreno-Galindo</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Daniela</GivenName><FamilyName>Ponce-Balbuena</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Martín</GivenName><FamilyName>Rodríguez-Martínez</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Tania</GivenName><FamilyName>Ferrer-Villada</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff3"><AuthorName DisplayOrder="Western"><GivenName>Aldo</GivenName><GivenName>A.</GivenName><FamilyName>Rodríguez-Menchaca</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Marcel</GivenName><GivenName>A</GivenName><GivenName>G</GivenName><Particle>van der</Particle><FamilyName>Heyden</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1" CorrespondingAffiliationID="Aff1"><AuthorName DisplayOrder="Western"><GivenName>José</GivenName><GivenName>A.</GivenName><FamilyName>Sánchez-Chapula</FamilyName></AuthorName><Contact><Phone>+52-312-3161129</Phone><Fax>+52-312-3161129</Fax><Email>sancheza@ucol.mx</Email></Contact></Author><Affiliation ID="Aff1"><OrgDivision>Unidad de Investigación</OrgDivision><OrgName>“Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima</OrgName><OrgAddress><Street>Av. 25 de Julio 965</Street><Postcode>CP 28045</Postcode><City>Colima</City><State>Colima</State><Country Code="MX">Mexico</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Department of Medical Physiology, Division Heart & Lungs</OrgDivision><OrgName>University Medical Center Utrecht</OrgName><OrgAddress><City>Utrecht</City><Country Code="NL">The Netherlands</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgDivision>Departamento de Fisiología</OrgDivision><OrgName>Universidad Autónoma de San Luis Potosí</OrgName><OrgAddress><City>San Luis Potosí</City><Country Code="MX">Mexico</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En" OutputMedium="All"><Heading>Abstract</Heading><Para TextBreak="No">Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, I<Subscript>K1</Subscript> and I<Subscript>KATP</Subscript>, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited I<Subscript>KATP</Subscript> > I<Subscript>K1</Subscript>. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP<Subscript>2</Subscript>–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP<Subscript>2</Subscript> is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP<Subscript>2</Subscript> and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP<Subscript>2</Subscript> increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP<Subscript>2</Subscript> lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.</Para></Abstract><KeywordGroup Language="En" OutputMedium="All"><Heading>Keywords</Heading><Keyword>Quinacrine</Keyword><Keyword>Inward rectifier potassium channels</Keyword><Keyword>Phosphatidylinositol 4,5-bisphosphate, PIP<Subscript>2</Subscript></Keyword><Keyword>Kir2.1</Keyword><Keyword>Kir2.3</Keyword><Keyword>Kir6.2</Keyword></KeywordGroup><AbbreviationGroup><Heading>Abbreviations</Heading><DefinitionList><DefinitionListEntry><Term>CADs</Term><Description><Para TextBreak="No">Cationic amphiphilic drugs</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>I<Subscript>K1</Subscript></Term><Description><Para TextBreak="No">Inward rectifier K<Superscript>+</Superscript> current</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>I<Subscript>KATP</Subscript></Term><Description><Para TextBreak="No">ATP-sensitive inward rectifier K<Superscript>+</Superscript> current</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>HP</Term><Description><Para TextBreak="No">Holding potential</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>Kir</Term><Description><Para TextBreak="No">Inward rectifier K<Superscript>+</Superscript> channels</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>PIP<Subscript>2</Subscript></Term><Description><Para TextBreak="No">Phosphatidylinositol 4,5-bisphosphate</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>T<Subscript>1/2</Subscript></Term><Description><Para TextBreak="No">Half-maximal inhibitory time</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>TP</Term><Description><Para TextBreak="No">Test pulses</Para></Description></DefinitionListEntry><DefinitionListEntry><Term>WT</Term><Description><Para TextBreak="No">Wild type</Para></Description></DefinitionListEntry></DefinitionList></AbbreviationGroup><ArticleNote Type="Misc"><SimplePara>Angélica López-Izquierdo and Iván A. Aréchiga-Figueroa contributed equally to this study.</SimplePara></ArticleNote></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels</title></titleInfo><name type="personal"><namePart type="given">Angélica</namePart><namePart type="family">López-Izquierdo</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Iván</namePart><namePart type="given">A.</namePart><namePart type="family">Aréchiga-Figueroa</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eloy</namePart><namePart type="given">G.</namePart><namePart type="family">Moreno-Galindo</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniela</namePart><namePart type="family">Ponce-Balbuena</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martín</namePart><namePart type="family">Rodríguez-Martínez</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Tania</namePart><namePart type="family">Ferrer-Villada</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aldo</namePart><namePart type="given">A.</namePart><namePart type="family">Rodríguez-Menchaca</namePart><affiliation>Departamento de Fisiología, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marcel</namePart><namePart type="given">A</namePart><namePart type="given">G</namePart><namePart type="family">van der Heyden</namePart><affiliation>Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">José</namePart><namePart type="given">A.</namePart><namePart type="family">Sánchez-Chapula</namePart><affiliation>Unidad de Investigación, “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima, Mexico</affiliation><affiliation>E-mail: sancheza@ucol.mx</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Springer-Verlag</publisher><place><placeTerm type="text">Berlin/Heidelberg</placeTerm></place><dateCreated encoding="w3cdtf">2011-05-04</dateCreated><dateIssued encoding="w3cdtf">2011-10-01</dateIssued><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: Cardiac inward rectifier potassium currents determine the resting membrane potential and contribute repolarization capacity during phase 3 repolarization. Quinacrine is a cationic amphiphilic drug. In this work, the effects of quinacrine were studied on cardiac Kir channels expressed in HEK 293 cells and on the inward rectifier potassium currents, IK1 and IKATP, in cardiac myocytes. We found that quinacrine differentially inhibited Kir channels, Kir6.2 ∼ Kir2.3 > Kir2.1. In addition, we found in cardiac myocytes that quinacrine inhibited IKATP > IK1. We presented evidence that quinacrine displays a double action towards strong inward rectifier Kir2.x channels, i.e., direct pore block and interference in phosphatidylinositol 4,5-bisphosphate, PIP2–Kir channel interaction. Pore block is evident in Kir2.1 and 2.3 channels as rapid block; channel block involves residues E224 and E299 facing the cytoplasmic pore of Kir2.1. The interference of the drug with the interaction of Kir2.x and Kir6.2/SUR2A channels and PIP2 is suggested from four sources of evidence: (1) Slow onset of current block when quinacrine is applied from either the inside or the outside of the channel. (2) Mutation of Kir2.3(I213L) and mutation of Kir6.2(C166S) increase their affinity for PIP2 and lowers its sensitivity for quinacrine. (3) Mutations of Kir2.1(L222I and K182Q) which decreased its affinity for PIP2 increased its sensitivity for quinacrine. (4) Co-application of quinacrine with PIP2 lowers quinacrine-mediated current inhibition. In conclusion, our data demonstrate how an old drug provides insight into a dual a blocking mechanism of Kir carried inward rectifier channels.</abstract><note>Cardiovascular Physiology</note><subject lang="en"><genre>Keywords</genre><topic>Quinacrine</topic><topic>Inward rectifier potassium channels</topic><topic>Phosphatidylinositol 4,5-bisphosphate, PIP2</topic><topic>Kir2.1</topic><topic>Kir2.3</topic><topic>Kir6.2</topic></subject><subject><genre>Abbreviations</genre><topic>CADs : Cationic amphiphilic drugs</topic><topic>IK1 : Inward rectifier K+ current</topic><topic>IKATP : ATP-sensitive inward rectifier K+ current</topic><topic>HP : Holding potential</topic><topic>Kir : Inward rectifier K+ channels</topic><topic>PIP2 : Phosphatidylinositol 4,5-bisphosphate</topic><topic>T1/2 : Half-maximal inhibitory time</topic><topic>TP : Test pulses</topic><topic>WT : Wild type</topic></subject><relatedItem type="host"><titleInfo><title>Pflügers Archiv - European Journal of Physiology</title><subTitle>European Journal of Physiology</subTitle></titleInfo><titleInfo type="abbreviated"><title>Pflugers Arch - Eur J Physiol</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>Springer</publisher><dateIssued encoding="w3cdtf">2011-09-10</dateIssued><copyrightDate encoding="w3cdtf">2011</copyrightDate></originInfo><subject><genre>Biomedicine</genre><topic>Human Physiology</topic></subject><identifier type="ISSN">0031-6768</identifier><identifier type="eISSN">1432-2013</identifier><identifier type="JournalID">424</identifier><identifier type="IssueArticleCount">11</identifier><identifier type="VolumeIssueCount">6</identifier><part><date>2011</date><detail type="volume"><number>462</number><caption>vol.</caption></detail><detail type="issue"><number>4</number><caption>no.</caption></detail><extent unit="pages"><start>505</start><end>517</end></extent></part><recordInfo><recordOrigin>Springer-Verlag, 2011</recordOrigin></recordInfo></relatedItem><identifier type="istex">78656B70A5538C4ED5F64457A52953B517728A7F</identifier><identifier type="ark">ark:/67375/VQC-GJBTFBF6-6</identifier><identifier type="DOI">10.1007/s00424-011-0995-5</identifier><identifier type="ArticleID">995</identifier><identifier type="ArticleID">s00424-011-0995-5</identifier><accessCondition type="use and reproduction" contentType="copyright">Springer-Verlag, 2011</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-3XSW68JL-F">springer</recordContentSource><recordOrigin>Springer-Verlag, 2011</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/VQC-GJBTFBF6-6/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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