{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T21:42:59Z","timestamp":1758404579038,"version":"3.32.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,1,31]],"date-time":"2006-01-31T00:00:00Z","timestamp":1138665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2006,3]]},"abstract":"<jats:p><jats:italic>Background:<\/jats:italic>Transient outward current (I<jats:sub>to<\/jats:sub>) and L\u2010type calcium current (I<jats:sub>Ca<\/jats:sub>) are important repolarization currents in cardiac myocytes. These two currents often undergo disease\u2010related remodeling while other currents are spared, suggesting a functional coupling between them. Here, we investigated the effects of I<jats:sub>to<\/jats:sub>channel blockers, 4\u2010aminopyridine (4\u2010AP) and heteropodatoxin\u20102 (HpTx2), on I<jats:sub>Ca<\/jats:sub>in cardiac ventricular myocytes.<\/jats:p><jats:p><jats:italic>Methods and Results:<\/jats:italic>I<jats:sub>Ca<\/jats:sub>was recorded in enzymatically dissociated mouse and guinea pig ventricular myocytes using the whole\u2010cell voltage clamp method. In mouse ventricular myocytes, 4\u2010AP (2 mM) significantly facilitated I<jats:sub>Ca<\/jats:sub>by increasing current amplitude and slowing inactivation. These effects were not voltage\u2010dependent. Similar facilitating effects were seen when equimolar Ba<jats:sup>2+<\/jats:sup>was substituted for external Ca<jats:sup>2+<\/jats:sup>, indicating that Ca<jats:sup>2+<\/jats:sup>influx is not required. Measurements of Ca<jats:sup>2+<\/jats:sup>\/calmodulin\u2010dependent protein kinase (CaMKII) activity revealed significant increases in cells treated with 4\u2010AP. Pretreatment of cells with 10\u03bcM KN93, a specific inhibitor of CaMKII, abolished the effects of 4\u2010AP on I<jats:sub>Ca.<\/jats:sub>To test the requirement of I<jats:sub>to<\/jats:sub>, we studied guinea pig ventricular myocytes, which do not express I<jats:sub>to<\/jats:sub>channels. In these cells, 2 mM 4\u2010AP had no effect on I<jats:sub>Ca<\/jats:sub>amplitude or kinetics. In both cell types, Ca<jats:sup>2+<\/jats:sup>\u2010induced I<jats:sub>Ca<\/jats:sub>facilitation, a CaMKII\u2010dependent process, was observed. However, 4\u2010AP abolished Ca<jats:sup>2+<\/jats:sup>\u2010induced I<jats:sub>Ca<\/jats:sub>facilitation exclusively in mouse ventricular myocytes.<\/jats:p><jats:p><jats:italic>Conclusion:<\/jats:italic>4\u2010AP, an I<jats:sub>to<\/jats:sub>blocker, facilitates L\u2010type Ca<jats:sup>2+<\/jats:sup>current through a mechanism involving the I<jats:sub>to<\/jats:sub>channel and CaMKII activation. These data indicate a functional association of I<jats:sub>Ca<\/jats:sub>and I<jats:sub>to<\/jats:sub>in cardiac myocytes.<\/jats:p>","DOI":"10.1111\/j.1540-8167.2006.00362.x","type":"journal-article","created":{"date-parts":[[2006,1,31]],"date-time":"2006-01-31T09:31:32Z","timestamp":1138699892000},"page":"298-304","source":"Crossref","is-referenced-by-count":17,"title":["Transient\u2010Outward K<sup>+<\/sup>Channel Inhibition Facilitates L\u2010Type Ca<sup>2+<\/sup>Current in Heart"],"prefix":"10.1111","volume":"17","author":[{"given":"YANGGAN","family":"WANG","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JUN","family":"CHENG","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SAMVIT","family":"TANDAN","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MINJIE","family":"JIANG","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"DIANA T.","family":"McCLOSKEY","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JOSEPH A.","family":"HILL","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,1,31]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001573-200005000-00014"},{"key":"e_1_2_7_3_2","first-page":"384","article-title":"Effects of class III antiarrhythmic drugs on transient outward and ultra\u2010rapid delayed rectifier currents in human atrial myocytes","volume":"281","author":"Feng J","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.249151"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00178-9"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00013-9"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(01)00171-1"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.81.4.512"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc3901.095766"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.278.2.H452"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2828(03)00200-1"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.02.076"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.163aa.x"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021716"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.83.8.806"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2002.00927.x"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2002.2038"},{"key":"e_1_2_7_18_2","first-page":"H982","article-title":"Ca\u2010dependent facilitation of cardiac Ca current is due to Ca\u2010calmodulin\u2010dependent protein kinase","volume":"267","author":"Yuan W","year":"1994","journal-title":"Am J Physiol"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.57.030195.002221"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000064566.91495.0C"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199807000-00021"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00668-5"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00346.2003"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.00587.x"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.063347"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00044.2002"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00859-3"},{"key":"e_1_2_7_28_2","first-page":"2059","article-title":"Solution structure of hpTX2, a toxin from Heteropoda venatoria spider that blocks Kv4.2 potassium channel","volume":"9","author":"Bernard C","year":"2000","journal-title":"Protein Sci"},{"key":"e_1_2_7_29_2","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0026-895X(24)13491-8","article-title":"Heteropodatoxins: Peptides isolated from spider venom that block Kv4.2 potassium channels","volume":"51","author":"Sanguinetti MC","year":"1997","journal-title":"Mol Pharmacol"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(91)90369-M"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00494.2001"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2004.02.005"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000145361.50017.aa"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.020552"},{"key":"e_1_2_7_35_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.021881"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000012223.86441.A1"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.11.1067"},{"key":"e_1_2_7_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000148176.33730.3F"},{"key":"e_1_2_7_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.11.018"},{"key":"e_1_2_7_40_2","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.104.051508"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000033988.13062.7C"}],"container-title":["Journal of Cardiovascular Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1540-8167.2006.00362.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1540-8167.2006.00362.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T15:19:36Z","timestamp":1736263176000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1540-8167.2006.00362.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,31]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2006,3]]}},"alternative-id":["10.1111\/j.1540-8167.2006.00362.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1540-8167.2006.00362.x","archive":["Portico"],"relation":{},"ISSN":["1045-3873","1540-8167"],"issn-type":[{"type":"print","value":"1045-3873"},{"type":"electronic","value":"1540-8167"}],"subject":[],"published":{"date-parts":[[2006,1,31]]}}}