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So, we aimed to examine the contribution of alterations in KCNQ1\/KCNE1\u2010current (I<jats:sub>Ks<\/jats:sub>) to the aging\u2010related remodeling of the heart as well as the role of insulin treatment on I<jats:sub>Ks<\/jats:sub>in the aged rats. Prolonged late\u2010phase action potential (AP) repolarization of ventricular cardiomyocytes from insulin\u2010resistant 24\u2010month\u2010old rats was significantly reversed by in vitro treatment of insulin or PKG inhibitor (in vivo, as well) via recovery in depressed I<jats:sub>Ks<\/jats:sub>. Although the protein level of either KCNQ1 or KCNE1 in cardiomyocytes was not affected with aging, PKG level was significantly increased in those cells. The inhibited I<jats:sub>Ks<\/jats:sub>in \u03b2<jats:sub>3<\/jats:sub>\u2010ARs\u2010stimulated cells could be reversed with a PKG inhibitor, indicating the correlation between PKG\u2010activation and \u03b2<jats:sub>3<\/jats:sub>\u2010ARs activation. Furthermore, in vivo treatment of aged rats, characterized by \u03b2<jats:sub>3<\/jats:sub>\u2010ARs activation, with either insulin or a PKG inhibitor for 2 weeks provided significant recoveries in I<jats:sub>Ks<\/jats:sub>, prolonged late phases of APs, prolonged QT\u2010intervals, and low heart rates without no effect on insulin resistance. In vivo insulin treatment provided also significant recovery in increased PKG and decreased PIP2 level, without the insulin effect on the KCNQ1 level in \u03b2<jats:sub>3<\/jats:sub>\u2010ARs overexpressed cells. The inhibition of I<jats:sub>Ks<\/jats:sub>in aged\u2010rat cardiomyocytes seems to be associated with activated \u03b2<jats:sub>3<\/jats:sub>\u2010ARs dependent remodeling in the interaction between KCNQ1 and KCNE1. Significant recoveries in ventricular\u2010repolarization of insulin\u2010treated aged cardiomyocytes via recovery in I<jats:sub>Ks<\/jats:sub>strongly emphasize two important issues: (1) I<jats:sub>Ks<\/jats:sub>can be a novel target in aging\u2010associated remodeling in the heart and insulin may be a cardioprotective agent in the maintenance of normal heart function during the aging process. (2) This study is one of the first to demonstrate insulin's\u00a0benefits on long\u2010QT in insulin\u2010resistant aged rats by accelerating the ventricular AP repolarization through reversing the depressed I<jats:sub>Ks<\/jats:sub>via affecting the \u03b2<jats:sub>3<\/jats:sub>\u2010ARs signaling pathway and particularly affecting activated PKG.<\/jats:p>","DOI":"10.1002\/jcp.30597","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T17:16:59Z","timestamp":1634145419000},"page":"1353-1371","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Insulin acts as an atypical KCNQ1\/KCNE1\u2010current activator and reverses long QT in insulin\u2010resistant aged rats by accelerating the ventricular action potential repolarization through affecting the \u03b2<sub>3<\/sub>\u2010adrenergic receptor signaling pathway"],"prefix":"10.1002","volume":"237","author":[{"given":"Yusuf","family":"Olgar","sequence":"first","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine Ankara University Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aysegul","family":"Durak","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine Ankara University Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ceylan V.","family":"Bitirim","sequence":"additional","affiliation":[{"name":"Stem Cell Institute Ankara University Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erkan","family":"Tuncay","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine Ankara University Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2583-9294","authenticated-orcid":false,"given":"Belma","family":"Turan","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine Ankara University Ankara Turkey"},{"name":"Department of Biophysics, Faculty of Medicine Lokman Hekim University Ankara Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00583"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005025"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu003"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv171"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.04.015"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/1567201811310010011"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000130409.72142.FE"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000107028.20478.8e"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvn093"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.90839.2008"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009191"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612811319320004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705983"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21124260"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/gly126"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.43.100901.140245"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.822403"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801547200"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2018.04.014"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406010200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.2.455"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2019.183148"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00074"},{"issue":"4","key":"e_1_2_8_25_1","first-page":"487","article-title":"Titin and CK2\u03b1 are new intracellular targets in acute insulin application\u2010associated benefits on electrophysiological parameters of left ventricular cardiomyocytes from insulin\u2010resistant metabolic syndrome rats. 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