{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:26:23Z","timestamp":1783542383537,"version":"3.55.0"},"reference-count":40,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"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>Phospholamban (PLN) is the natural inhibitor of the sarco\/endoplasmic reticulum Ca2+ ATP-ase (SERCA2a). Heterozygous PLN p.Arg14del mutation is associated with an arrhythmogenic dilated cardiomyopathy (DCM), whose pathogenesis has been attributed to SERCA2a \u201csuperinhibition\u201d. Aim: To test in cardiomyocytes (hiPSC-CMs) derived from a PLN p.Arg14del carrier whether (1) Ca2+ dynamics and protein localization were compatible with SERCA2a superinhibition and (2) if functional abnormalities could be reverted by pharmacological SERCA2a activation (PST3093). Methods: Ca2+ transients (CaT) were recorded at 36 \u00b0C in hiPSC-CMs clusters during field stimulation. SERCA2a and PLN where immunolabeled in single hiPSC-CMs. Mutant preparations (MUT) were compared to isogenic wild-type ones (WT), obtained by mutation reversal. Results: WT and MUT differed for the following properties: (1) CaT time to peak (tpeak) and half-time of CaT decay were shorter in MUT; (2) several CaT profiles were identified in WT, \u201chyperdynamic\u201d ones largely prevailed in MUT; (3) whereas tpeak rate-dependently declined in WT, it was shorter and rate-independent in MUT; (4) diastolic Ca2+ rate-dependently accumulated in WT, but not in MUT. When applied to WT, PST3093 turned all the above properties to resemble those of MUT; when applied to MUT, PST3093 had a smaller or negligible effect. Preferential perinuclear SERCA2a-PLN localization was lost in MUT hiPSC-CMs. Conclusions: Functional data converge to argue for PLN p.Arg14del incompetence in inhibiting SERCA2a in the tested case, thus weakening the rationale for therapeutic SERCA2a activation. Mechanisms alternative to SERCA2a superinhibition should be considered in the pathogenesis of DCM, possibly including dysregulation of Ca2+-dependent transcription.<\/jats:p>","DOI":"10.3390\/ijms222413500","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T11:27:36Z","timestamp":1639654056000},"page":"13500","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Characterization of the PLN p.Arg14del Mutation in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-4487","authenticated-orcid":false,"given":"Beatrice","family":"Badone","sequence":"first","affiliation":[{"name":"Laboratory of Cardiac Cellular Physiology, Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiac Cellular Physiology, Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3506-5619","authenticated-orcid":false,"given":"Francesco","family":"Lodola","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiac Cellular Physiology, Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika E.","family":"Knaust","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20249 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20249 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20249 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Zaza","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiac Cellular Physiology, Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1161\/CIRCRESAHA.111.259754","article-title":"Modulation of cardiac contractility by the phospholamban\/SERCA2a regulatome","volume":"110","author":"Kranias","year":"2012","journal-title":"Circ. 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