Properties and molecular determinants of the natural flavone acacetin for blocking hKv4.3 channels
The natural flavone acacetin has been demonstrated to inhibit transient outward potassium current (Ito) in human atrial myocytes. However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of t...
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| description | The natural flavone acacetin has been demonstrated to inhibit transient outward potassium current (Ito) in human atrial myocytes. However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of this compound for blocking hKv4.3 channels (coding Ito) stably expressed in HEK 293 cells using the approaches of whole-cell patch voltage-clamp technique and mutagenesis. It was found that acacetin inhibited hKv4.3 current by binding to both the closed and open channels, and decreased the recovery from inactivation. The blockade of hKv4.3 channels by acacetin was use- and frequency-dependent, and IC50s of acacetin for inhibiting hKv4.3 were 7.9, 6.1, 3.9, and 3.2 µM, respectively, at 0.2, 0.5, 1, and 3.3 Hz. The mutagenesis study revealed that the hKv4.3 mutants T366A and T367A in the P-loop helix, and V392A, I395A and V399A in the S6-segment had a reduced channel blocking efficacy of acacetin (IC50, 44.5 µM for T366A, 25.8 µM for T367A, 17.6 µM for V392A, 16.2 µM for I395A, and 19.1 µM for V399A). These results demonstrate the novel information that acacetin may inhibit the closed channels and block the open state of the channels by binding to their P-loop filter helix and S6 domain. The use- and rate-dependent blocking of hKv4.3 by acacetin is likely beneficial for managing atrial fibrillation. |
| doi_str_mv | 10.1371/journal.pone.0057864 |
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However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of this compound for blocking hKv4.3 channels (coding Ito) stably expressed in HEK 293 cells using the approaches of whole-cell patch voltage-clamp technique and mutagenesis. It was found that acacetin inhibited hKv4.3 current by binding to both the closed and open channels, and decreased the recovery from inactivation. The blockade of hKv4.3 channels by acacetin was use- and frequency-dependent, and IC50s of acacetin for inhibiting hKv4.3 were 7.9, 6.1, 3.9, and 3.2 µM, respectively, at 0.2, 0.5, 1, and 3.3 Hz. The mutagenesis study revealed that the hKv4.3 mutants T366A and T367A in the P-loop helix, and V392A, I395A and V399A in the S6-segment had a reduced channel blocking efficacy of acacetin (IC50, 44.5 µM for T366A, 25.8 µM for T367A, 17.6 µM for V392A, 16.2 µM for I395A, and 19.1 µM for V399A). These results demonstrate the novel information that acacetin may inhibit the closed channels and block the open state of the channels by binding to their P-loop filter helix and S6 domain. The use- and rate-dependent blocking of hKv4.3 by acacetin is likely beneficial for managing atrial fibrillation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0057864</identifier><identifier>PMID: 23526953</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Atrial fibrillation ; Binding ; Binding Sites - genetics ; Biology ; Blocking ; Cardiac arrhythmia ; Cardiomyocytes ; Deactivation ; Fibrillation ; Flavones - metabolism ; Flavones - pharmacology ; Frequency dependence ; HEK293 Cells ; Humans ; Inactivation ; Kinetics ; Medicine ; Mutagenesis ; Mutagenesis, Site-Directed ; Mutants ; Mutation ; Myocytes ; Open channels ; Patch-Clamp Techniques ; Potassium ; Potassium Channel Blockers - metabolism ; Potassium Channel Blockers - pharmacology ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - genetics ; Recombinant Proteins - metabolism ; Shal Potassium Channels - antagonists & inhibitors ; Shal Potassium Channels - genetics ; Shal Potassium Channels - metabolism</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e57864</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Wu et al 2013 Wu et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-4bb24866a2f55bae3afd90497d04a695092dde1b5b9b8e6a9e32b826a1c7c4ed3</citedby><cites>FETCH-LOGICAL-c692t-4bb24866a2f55bae3afd90497d04a695092dde1b5b9b8e6a9e32b826a1c7c4ed3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603988/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603988/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23526953$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>van Raaij, Mark J.</contributor><creatorcontrib>Wu, Hui-Jun</creatorcontrib><creatorcontrib>Sun, Hai-Ying</creatorcontrib><creatorcontrib>Wu, Wei</creatorcontrib><creatorcontrib>Zhang, Yan-Hui</creatorcontrib><creatorcontrib>Qin, Guo-Wei</creatorcontrib><creatorcontrib>Li, Gui-Rong</creatorcontrib><title>Properties and molecular determinants of the natural flavone acacetin for blocking hKv4.3 channels</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The natural flavone acacetin has been demonstrated to inhibit transient outward potassium current (Ito) in human atrial myocytes. However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of this compound for blocking hKv4.3 channels (coding Ito) stably expressed in HEK 293 cells using the approaches of whole-cell patch voltage-clamp technique and mutagenesis. It was found that acacetin inhibited hKv4.3 current by binding to both the closed and open channels, and decreased the recovery from inactivation. The blockade of hKv4.3 channels by acacetin was use- and frequency-dependent, and IC50s of acacetin for inhibiting hKv4.3 were 7.9, 6.1, 3.9, and 3.2 µM, respectively, at 0.2, 0.5, 1, and 3.3 Hz. The mutagenesis study revealed that the hKv4.3 mutants T366A and T367A in the P-loop helix, and V392A, I395A and V399A in the S6-segment had a reduced channel blocking efficacy of acacetin (IC50, 44.5 µM for T366A, 25.8 µM for T367A, 17.6 µM for V392A, 16.2 µM for I395A, and 19.1 µM for V399A). These results demonstrate the novel information that acacetin may inhibit the closed channels and block the open state of the channels by binding to their P-loop filter helix and S6 domain. The use- and rate-dependent blocking of hKv4.3 by acacetin is likely beneficial for managing atrial fibrillation.</description><subject>Atrial fibrillation</subject><subject>Binding</subject><subject>Binding Sites - genetics</subject><subject>Biology</subject><subject>Blocking</subject><subject>Cardiac arrhythmia</subject><subject>Cardiomyocytes</subject><subject>Deactivation</subject><subject>Fibrillation</subject><subject>Flavones - metabolism</subject><subject>Flavones - pharmacology</subject><subject>Frequency dependence</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Kinetics</subject><subject>Medicine</subject><subject>Mutagenesis</subject><subject>Mutagenesis, Site-Directed</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Myocytes</subject><subject>Open channels</subject><subject>Patch-Clamp Techniques</subject><subject>Potassium</subject><subject>Potassium Channel Blockers - metabolism</subject><subject>Potassium Channel Blockers - pharmacology</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - metabolism</subject><subject>Shal Potassium Channels - antagonists & inhibitors</subject><subject>Shal Potassium Channels - genetics</subject><subject>Shal Potassium Channels - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkm2L1DAQx4so3nn6DUQLguCLXdMmTds3B8fhw-LBiU9vwySZbrO2yZqki357c27v2AUFyYuEyW_-M_xnsuxpQZYFrYvXGzd5C8Ny6ywuCanqhrN72WnR0nLBS0LvH7xPskchbBJEG84fZiclrUreVvQ0kx-926KPBkMOVuejG1BNA_hcY0Q_Ggs2htx1eewxtxAnD0PeDbBLZXNQoDAam3fO53Jw6rux67z_sGNLmqserMUhPM4edDAEfDLfZ9nXt2--XL5fXF2_W11eXC0Ub8u4YFKWLLUHZVdVEpBCp1vC2loTBqlZ0pZaYyEr2coGObRIS9mUHApVK4aanmXP97rbwQUx2xNEQSlpmpJynojVntAONmLrzQj-l3BgxJ-A82sByQo1oGhZTRrCNO9YyajUkmteIBAmG94CqqR1Pleb5IhaoY3JmSPR4x9rerF2O0E5oW3TJIEXs4B3PyYM8R8tz9QaUlfGdi6JqdEEJS5Y3aQJk4olavkXKh2No1FpUp1J8aOEV0cJiYn4M65hCkGsPn_6f_b62zH78oDtEYbYBzdM0TgbjkG2B5V3IXjs7pwriLjZ71s3xM1-i3m_U9qzQ9fvkm4Xmv4GeM72bQ</recordid><startdate>20130320</startdate><enddate>20130320</enddate><creator>Wu, Hui-Jun</creator><creator>Sun, Hai-Ying</creator><creator>Wu, Wei</creator><creator>Zhang, Yan-Hui</creator><creator>Qin, Guo-Wei</creator><creator>Li, Gui-Rong</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130320</creationdate><title>Properties and molecular determinants of the natural flavone acacetin for blocking hKv4.3 channels</title><author>Wu, Hui-Jun ; Sun, Hai-Ying ; Wu, Wei ; Zhang, Yan-Hui ; Qin, Guo-Wei ; Li, Gui-Rong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-4bb24866a2f55bae3afd90497d04a695092dde1b5b9b8e6a9e32b826a1c7c4ed3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Atrial fibrillation</topic><topic>Binding</topic><topic>Binding Sites - 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However, the molecular determinants of acacetin for blocking Ito are unknown. The present study was designed to investigate the properties and molecular determinants of this compound for blocking hKv4.3 channels (coding Ito) stably expressed in HEK 293 cells using the approaches of whole-cell patch voltage-clamp technique and mutagenesis. It was found that acacetin inhibited hKv4.3 current by binding to both the closed and open channels, and decreased the recovery from inactivation. The blockade of hKv4.3 channels by acacetin was use- and frequency-dependent, and IC50s of acacetin for inhibiting hKv4.3 were 7.9, 6.1, 3.9, and 3.2 µM, respectively, at 0.2, 0.5, 1, and 3.3 Hz. The mutagenesis study revealed that the hKv4.3 mutants T366A and T367A in the P-loop helix, and V392A, I395A and V399A in the S6-segment had a reduced channel blocking efficacy of acacetin (IC50, 44.5 µM for T366A, 25.8 µM for T367A, 17.6 µM for V392A, 16.2 µM for I395A, and 19.1 µM for V399A). These results demonstrate the novel information that acacetin may inhibit the closed channels and block the open state of the channels by binding to their P-loop filter helix and S6 domain. The use- and rate-dependent blocking of hKv4.3 by acacetin is likely beneficial for managing atrial fibrillation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23526953</pmid><doi>10.1371/journal.pone.0057864</doi><tpages>e57864</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Atrial fibrillation Binding Binding Sites - genetics Biology Blocking Cardiac arrhythmia Cardiomyocytes Deactivation Fibrillation Flavones - metabolism Flavones - pharmacology Frequency dependence HEK293 Cells Humans Inactivation Kinetics Medicine Mutagenesis Mutagenesis, Site-Directed Mutants Mutation Myocytes Open channels Patch-Clamp Techniques Potassium Potassium Channel Blockers - metabolism Potassium Channel Blockers - pharmacology Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - genetics Recombinant Proteins - metabolism Shal Potassium Channels - antagonists & inhibitors Shal Potassium Channels - genetics Shal Potassium Channels - metabolism |
| title | Properties and molecular determinants of the natural flavone acacetin for blocking hKv4.3 channels |
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