{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T18:13:09Z","timestamp":1778350389022,"version":"3.51.4"},"reference-count":88,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Robust, spontaneous pacemaker activity originating in the sinoatrial node (SAN) of the heart is essential for cardiovascular function. Anatomical, electrophysiological, and molecular methods as well as mathematical modeling approaches have quite thoroughly characterized the transmembrane fluxes of Na+, K+ and Ca2+ that produce SAN action potentials (AP) and \u2018pacemaker depolarizations\u2019 in a number of different in vitro adult mammalian heart preparations. Possible ionic mechanisms that are responsible for SAN primary pacemaker activity are described in terms of: (i) a Ca2+-regulated mechanism based on a requirement for phasic release of Ca2+ from intracellular stores and activation of an inward current-mediated by Na+\/Ca2+ exchange; (ii) time- and voltage-dependent activation of Na+ or Ca2+ currents, as well as a cyclic nucleotide-activated current, If; and\/or (iii) a combination of (i) and (ii). Electrophysiological studies of single spontaneously active SAN myocytes in both adult mouse and rabbit hearts consistently reveal significant expression of a rapidly activating time- and voltage-dependent K+ current, often denoted IKr, that is selectively expressed in the leading or primary pacemaker region of the adult mouse SAN. The main goal of the present study was to examine by combined experimental and simulation approaches the functional or physiological roles of this K+ current in the pacemaker activity. Our patch clamp data of mouse SAN myocytes on the effects of a pharmacological blocker, E4031, revealed that a rapidly activating K+ current is essential for action potential (AP) repolarization, and its deactivation during the pacemaker potential contributes a small but significant component to the pacemaker depolarization. Mathematical simulations using a murine SAN AP model confirm that well known biophysical properties of a delayed rectifier K+ current can contribute to its role in generating spontaneous myogenic activity.<\/jats:p>","DOI":"10.3390\/ijms22094761","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T05:10:55Z","timestamp":1619759455000},"page":"4761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Physiological Roles of the Rapidly Activated Delayed Rectifier K+ Current in Adult Mouse Heart Primary Pacemaker Activity"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4637-8995","authenticated-orcid":false,"given":"Wei","family":"Hu","sequence":"first","affiliation":[{"name":"Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert B.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne R.","family":"Giles","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erwin","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Physiology, Carver School of Medicine, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK"},{"name":"Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/1751035a0","article-title":"Production of membrane potential changes in the frog\u2019s heart by inhibitory nerve impulses","volume":"175","author":"Katz","year":"1955","journal-title":"Nature"},{"key":"ref_2","first-page":"283","article-title":"Ultramicroelectrode recording from the cardiac pacemaker","volume":"115","author":"West","year":"1955","journal-title":"J. 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