{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:24:49Z","timestamp":1791473089156,"version":"4.3.4"},"reference-count":70,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T00:00:00Z","timestamp":1553040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL110791"],"award-info":[{"award-number":["R01HL110791"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL096669"],"award-info":[{"award-number":["R01HL096669"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL121796"],"award-info":[{"award-number":["R01HL121796"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["RO1HL135236"],"award-info":[{"award-number":["RO1HL135236"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["Aid 15GRNT25650002"],"award-info":[{"award-number":["Aid 15GRNT25650002"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18POST33960456"],"award-info":[{"award-number":["18POST33960456"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2020,7]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Small\u2010conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (SK) channels expressed in ventricular myocytes are dormant in health, yet become functional in cardiac disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>SK channels are voltage independent and their gating is controlled by intracellular [Ca<jats:sup>2+<\/jats:sup>] in a biphasic manner. Submicromolar [Ca<jats:sup>2+<\/jats:sup>] activates the channel via constitutively\u2010bound calmodulin, whereas higher [Ca<jats:sup>2+<\/jats:sup>] exerts inhibitory effect during depolarization.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by protein kinase A (PKA) phosphorylation. Using site\u2010directed mutagenesis, we identified serine\u2010465 as the site conferring PKA\u2010dependent effects on SK2 channel function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PKA phosphorylation attenuates <jats:italic>I<\/jats:italic><jats:sub>SK<\/jats:sub> rectification by reducing the Ca<jats:sup>2+<\/jats:sup>\/voltage\u2010dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This mechanism underlies the functional recruitment of SK channels not only in cardiac disease, but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Small\u2010conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> (SK) channels expressed in ventricular myocytes (VMs) are dormant in health, yet become functional in cardiac disease. We aimed to test the hypothesis that post\u2010translational modification of SK channels under conditions accompanied by enhanced adrenergic drive plays a central role in disease\u2010related activation of the channels. We investigated this phenomenon using a rat model of hypertrophy induced by thoracic aortic banding (TAB). Western blot analysis using anti\u2010pan\u2010serine\/threonine antibodies demonstrated enhanced phosphorylation of immunoprecipitated SK2 channels in VMs from TAB rats <jats:italic>vs<\/jats:italic>. Shams, which was reversible by incubation of the VMs with PKA inhibitor H89 (1\u00a0\u03bcmol\u00a0L<jats:sup>\u20131<\/jats:sup>). Patch clamped VMs under basal conditions from TABs but not Shams exhibited outward current sensitive to the specific SK inhibitor apamin (100\u00a0nmol\u00a0L<jats:sup>\u20131<\/jats:sup>), which was eliminated by inhibition of PKA (1\u00a0\u03bcmol\u00a0L<jats:sup>\u20131<\/jats:sup>). Beta\u2010adrenergic stimulation (isoproterenol, 100\u00a0nmol\u00a0L<jats:sup>\u20131<\/jats:sup>) evoked <jats:italic>I<\/jats:italic><jats:sub>SK<\/jats:sub> in VMs from Shams, resulting in shortening of action potentials in VMs and <jats:italic>ex vivo<\/jats:italic> optically mapped Sham hearts. Using adenoviral gene transfer, wild\u2010type and mutant SK2 channels were overexpressed in adult rat VMs, revealing serine\u2010465 as the site that elicits PKA\u2010dependent phosphorylation effects on SK2 channel function. Concurrent confocal Ca<jats:sup>2+<\/jats:sup> imaging experiments established that PKA phosphorylation lessens rectification of <jats:italic>I<\/jats:italic><jats:sub>SK<\/jats:sub> via reduction Ca<jats:sup>2+<\/jats:sup>\/voltage\u2010dependent inhibition of the channels at high [Ca<jats:sup>2+<\/jats:sup>] without affecting their sensitivity to activation by Ca<jats:sup>2+<\/jats:sup> in the submicromolar range. In conclusion, upregulation of SK channels in diseased VMs is mediated by hyperadrenergic drive in cardiac hypertrophy, with functional effects on the channel conferred by PKA\u2010dependent phosphorylation at serine\u2010465.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277618","type":"journal-article","created":{"date-parts":[[2019,2,16]],"date-time":"2019-02-16T12:14:11Z","timestamp":1550319251000},"page":"2847-2873","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts"],"prefix":"10.1113","volume":"598","author":[{"given":"Shanna","family":"Hamilton","sequence":"first","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"},{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University  Columbus OH USA"},{"name":"Department of Physiology and Cell Biology College of Medicine The Ohio State University  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliia","family":"Polina","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"},{"name":"Medical University of South Carolina Department of Medicine Division of Nephrology  Charleston SC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radmila","family":"Terentyeva","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"},{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University  Columbus OH USA"},{"name":"Department of Physiology and Cell Biology College of Medicine The Ohio State University  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bronk","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Yun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Roder","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard T.","family":"Clements","sequence":"additional","affiliation":[{"name":"Department of Surgery The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"},{"name":"Vascular Research Laboratory Providence Veterans Affairs Medical Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Koren","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bum\u2010Rak","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-7384","authenticated-orcid":false,"given":"Dmitry","family":"Terentyev","sequence":"additional","affiliation":[{"name":"Department of Medicine The Warren Alpert Medical School of Brown University Rhode Island Hospital Cardiovascular Research Center  Providence RI USA"},{"name":"Dorothy M. Davis Heart and Lung Research Institute College of Medicine The Ohio State University  Columbus OH USA"},{"name":"Department of Physiology and Cell Biology College of Medicine The Ohio State University  Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,20]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-020911-153336"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3565-06.2007"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.202663"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000558"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-374841-6.00001-3"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.08.033"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3310"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108824"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.03.058"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.07.003"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.112.004713"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP275681"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703516200"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8235594"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272883"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.238386"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1435-5"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-15-0015"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00035.2001"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.170613"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004240050444"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00820.2011"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270818"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.117.005776"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.00323.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707281"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.111.000152"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.12.011"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.10.003"},{"key":"e_1_2_5_31_1","first-page":"343","article-title":"SK channel enhancers attenuate Ca2+\u2010dependent arrhythmia in hypertrophic hearts by regulating mito\u2010ROS\u2010dependent oxidation and activity of RyR","volume":"113","author":"Kim TY","year":"2017","journal-title":"Cardiovasc Res"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/jce.12176"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2008.167718"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1103090108"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200910295"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908207106"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000253095.44186.72"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2014.03.045"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.049072"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00825.2014"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986711796642463"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-013-1785-5"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2003.12.002"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513125200"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm970571a"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2004.03.017"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/35074145"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.104.047449"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu121"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(01)76193-0"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75264-8"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2004.07.006"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1516"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00636.2017"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00621.2013"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020991"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.215269"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00534.2005"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2006.00567.x"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh0202.103940"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.212324"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/26758"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307508200"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-015-9839-0"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096691"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1592"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22843-3"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt262"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272942"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1469-3"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000163981.97262.3b"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2FJP277618","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP277618","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP277618","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP277618","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,5]],"date-time":"2023-09-05T18:48:23Z","timestamp":1693939703000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP277618"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,20]]},"references-count":70,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2020,7]]}},"alternative-id":["10.1113\/JP277618"],"URL":"https:\/\/doi.org\/10.1113\/jp277618","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,20]]},"assertion":[{"value":"2018-12-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}