{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T13:43:22Z","timestamp":1725716602386},"reference-count":27,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,3,31]],"date-time":"2009-03-31T00:00:00Z","timestamp":1238457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:p>The pacemaker current, mediated by hyperpolarization\u2010activated cyclic nucleotide\u2010gated (HCN) channels, contributes to the initiation and regulation of cardiac rhythm. Previous experiments creating HCN\u2010based biological pacemakers <jats:italic>in vivo<\/jats:italic> found that an engineered HCN2\/HCN1 chimeric channel (HCN212) resulted in significantly faster rates than HCN2, interrupted by 1\u20135 s pauses. To elucidate the mechanisms underlying the differences in HCN212 and HCN2 <jats:italic>in vivo<\/jats:italic> functionality as biological pacemakers, we studied newborn rat ventricular myocytes over\u2010expressing either HCN2 or HCN212 channels. The HCN2\u2010 and HCN212\u2010over\u2010expressing myocytes manifest similar voltage dependence, current density and sensitivity to saturating cAMP concentrations, but HCN212 has faster activation\/deactivation kinetics. Compared with HCN2, myocytes expressing HCN212 exhibit a faster spontaneous rate and greater incidence of irregular rhythms (i.e. periods of rapid spontaneous rate followed by pauses). To explore these rhythm differences further, we imposed consecutive pacing and found that activation kinetics of the two channels are slower at faster pacing frequencies. As a result, time\u2010dependent HCN current flowing during diastole decreases for both constructs during a train of stimuli at a rapid frequency, with the effect more pronounced for HCN2. In addition, the slower deactivation kinetics of HCN2 contributes to more pronounced instantaneous current at a slower frequency. As a result of the frequency dependence of both instantaneous and time\u2010dependent current, HCN2 exhibits more robust negative feedback than HCN212, contributing to the maintenance of a stable pacing rhythm. These results illustrate the benefit of screening HCN constructs in spontaneously active myocyte cultures and may provide the basis for future optimization of HCN\u2010based biological pacemakers.<\/jats:p>","DOI":"10.1113\/jphysiol.2008.163444","type":"journal-article","created":{"date-parts":[[2009,1,27]],"date-time":"2009-01-27T01:13:44Z","timestamp":1233018824000},"page":"1513-1525","source":"Crossref","is-referenced-by-count":16,"title":["<i>In vitro<\/i> characterization of HCN channel kinetics and frequency dependence in myocytes predicts biological pacemaker functionality"],"prefix":"10.1113","volume":"587","author":[{"given":"Xin","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Bucchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronit V.","family":"Oren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yelena","family":"Kryukova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Dun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen E.","family":"Clancy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard B.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,3,31]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"32","article-title":"From funny current to HCN channels: 20 years of excitation","volume":"17","author":"Accili EA","year":"2002","journal-title":"News Physiol Sci"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.117.6.519"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.03.006"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BFb0032324"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.04.017"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.617613"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1984.sp015114"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.55.030193.002323"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.367ac.x"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601868"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00900.2001"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000055920.64384.FB"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2008.05.010"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-006-0095-0"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2007.09.028"},{"key":"e_1_2_5_17_1","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1161\/01.CIR.0000114527.10764.CC","article-title":"Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates","volume":"109","author":"Plotnikov AN","year":"2004","journal-title":"Circulation"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106974200"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200509389"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.277.3.H940"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-002-0860-7"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh1301.094395"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000059939.97249.2C"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2006.03.007"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb11353.x"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00968-6"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.3.237"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000151313.18547.A2"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.2008.163444","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.2008.163444","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T20:25:52Z","timestamp":1696969552000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.2008.163444"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,31]]},"references-count":27,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2009,4]]}},"alternative-id":["10.1113\/jphysiol.2008.163444"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.2008.163444","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,31]]}}}