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 : 001542 ( Main/Exploration ); précédent : 001541; suivant : 001543Mechanisms 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 [Mexique] ; Iván A. Aréchiga-Figueroa [Mexique] ; Eloy G. Moreno-Galindo [Mexique] ; Daniela Ponce-Balbuena [Mexique] ; Martín Rodríguez-Martínez [Mexique] ; Tania Ferrer-Villada [Mexique] ; Aldo A. Rodríguez-Menchaca [Mexique] ; Marcel A G. Van Der Heyden [Pays-Bas] ; José A. Sánchez-Chapula [Mexique]Source :
- 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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Moreno-Galindo</name><affiliation wicri:level="1"><country xml:lang="fr">Mexique</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Colima</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Mexique</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Colima</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Mexique</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Colima</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Mexique</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Colima</wicri:noRegion></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. 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Sánchez-Chapula</name><affiliation wicri:level="1"><country xml:lang="fr">Mexique</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Colima</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Mexique</country></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><affiliations><list><country><li>Mexique</li><li>Pays-Bas</li></country><region><li>Utrecht (province)</li></region><settlement><li>Utrecht</li></settlement></list><tree><country name="Mexique"><noRegion><name sortKey="L Pez Izquierdo, Angelica" sort="L Pez Izquierdo, Angelica" uniqKey="L Pez Izquierdo A" first="Angélica" last="L Pez-Izquierdo">Angélica L Pez-Izquierdo</name></noRegion><name sortKey="Arechiga Figueroa, Ivan A" sort="Arechiga Figueroa, Ivan A" uniqKey="Arechiga Figueroa I" first="Iván A." last="Aréchiga-Figueroa">Iván A. Aréchiga-Figueroa</name><name sortKey="Ferrer Villada, Tania" sort="Ferrer Villada, Tania" uniqKey="Ferrer Villada T" first="Tania" last="Ferrer-Villada">Tania Ferrer-Villada</name><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><name sortKey="Ponce Balbuena, Daniela" sort="Ponce Balbuena, Daniela" uniqKey="Ponce Balbuena D" first="Daniela" last="Ponce-Balbuena">Daniela Ponce-Balbuena</name><name sortKey="Rodriguez Martinez, Martin" sort="Rodriguez Martinez, Martin" uniqKey="Rodriguez Martinez M" first="Martín" last="Rodríguez-Martínez">Martín Rodríguez-Martínez</name><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><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><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></country><country name="Pays-Bas"><region name="Utrecht (province)"><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></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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