{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:21:33Z","timestamp":1788481293634,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2017,7,4]],"date-time":"2017-07-04T00:00:00Z","timestamp":1499126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81370296"],"award-info":[{"award-number":["81370296"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81370297"],"award-info":[{"award-number":["81370297"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["11GRNT7270014"],"award-info":[{"award-number":["11GRNT7270014"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM102943"],"award-info":[{"award-number":["R01GM102943"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Outward and inward background currents across the cell membrane balance, determining resting membrane potential. Inward rectifier K<jats:sup>+<\/jats:sup> channel subfamily 2 (Kir2) channels primarily maintain the resting membrane potential of cardiomyocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Human cardiomyocytes exhibit two levels of resting membrane potential at subphysiological extracellular K<jats:sup>+<\/jats:sup> concentrations or pathological hypokalaemia, however, the underlying mechanism is unclear.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study, we show that human cardiomyocytes derived from induced pluripotent stem cells with enhanced expression of isoform 1 of Kir2 (Kir2.1) channels and mouse HL\u20101 cardiomyocytes with ectopic expression of two pore\u2010domain K<jats:sup>+<\/jats:sup> channel isoform 1 (K2P1) recapitulate two levels of resting membrane potential, indicating the contributions of Kir2.1 and K2P1 channels to the phenomenon.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In Chinese hamster ovary cells that express the channels, Kir2.1 currents non\u2010linearly counterbalance hypokalaemia\u2010induced K2P1 leak cation currents, reconstituting two levels of resting membrane potential.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings support the hypothesis that Kir2 currents non\u2010linearly counterbalance inward background cation currents, such as K2P1 currents, accounting for two levels of resting membrane potential in human cardiomyocytes and demonstrating a novel mechanism that regulates excitability.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Inward rectifier K<jats:sup>+<\/jats:sup> channel subfamily 2 (Kir2) channels primarily maintain the normal resting membrane potential of cardiomyocytes. At subphysiological extracellular K<jats:sup>+<\/jats:sup> concentrations or pathological hypokalaemia, human cardiomyocytes show both hyperpolarized and depolarized resting membrane potentials; these depolarized potentials cause cardiac arrhythmia; however, the underlying mechanism is unknown. In the present study, we show that inward rectifier K<jats:sup>+<\/jats:sup> channel subfamily 2 isoform 1 (Kir2.1) currents non\u2010linearly counterbalance hypokalaemia\u2010induced two pore\u2010domain K<jats:sup>+<\/jats:sup> channel isoform 1 (K2P1) leak cation currents, reconstituting two levels of resting membrane potential in cardiomyocytes. Under hypokalaemic conditions, both human cardiomyocytes derived from induced pluripotent stem cells with enhanced Kir2.1 expression and mouse HL\u20101 cardiomyocytes with ectopic expression of K2P1 channels recapitulate two levels of resting membrane potential. These cardiomyocytes display N\u2010shaped current\u2013voltage relationships that cross the voltage axis three times and the first and third zero\u2010current potentials match the two levels of resting membrane potential. Inhibition of K2P1 expression eliminates the phenomenon, indicating contributions of Kir2.1 and K2P1 channels to two levels of resting membrane potential. Second, in Chinese hamster ovary cells that heterologously express the channels, Kir2.1 currents non\u2010linearly counterbalance hypokalaemia\u2010induced K2P1 leak cation currents, yielding the N\u2010shaped current\u2013voltage relationships, causing the resting membrane potential to spontaneously jump from hyperpolarization at the first zero\u2010current potential to depolarization at the third zero\u2010current potential, again recapitulating two levels of resting membrane potential. These findings reveal ionic mechanisms of the two levels of resting membrane potential, demonstrating a previously unknown mechanism for the regulation of excitability, and support the hypothesis that Kir2 currents non\u2010linearly balance inward background cation currents, accounting for two levels of resting membrane potential of human cardiomyocytes.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274268","type":"journal-article","created":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T16:55:29Z","timestamp":1495731329000},"page":"5129-5142","source":"Crossref","is-referenced-by-count":20,"title":["Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes"],"prefix":"10.1113","volume":"595","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2243-9124","authenticated-orcid":false,"given":"Dongchuan","family":"Zuo","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University at Albany State University of New York  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