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Three RyR2 phosphorylation sites have taken prominence in excitation\u2013contraction coupling: S2808 and S2030 are described as protein kinase A specific and S2814 as a Ca\n 2+<\/jats:sup>\n \/calmodulin kinase type\u20102\u2010specific site. To examine the contribution of these phosphosites to Ca\n 2+<\/jats:sup>\n signalling, we generated double knock\u2010in (DKI) mice in which Ser2808 and Ser2814 phosphorylation sites have both been replaced by alanine (RyR2\u2010S2808A\/S2814A). These mice did not exhibit an overt phenotype. Heart morphology and haemodynamic parameters were not altered. However, they had a higher susceptibility to arrhythmias. We performed confocal Ca\n 2+<\/jats:sup>\n \u00a0imaging and electrophysiology experiments. Isoprenaline was used to stimulate \u03b2\u2010ARs. Measurements of Ca\n 2+<\/jats:sup>\n waves and latencies in myocytes revealed an increased propensity for spontaneous Ca\n 2+<\/jats:sup>\n releases in DKI myocytes, both in control conditions and during \u03b2\u2010AR stimulation. In DKI cells, waves were initiated from a lower threshold concentration of Ca\n 2+<\/jats:sup>\n inside the sarcoplasmic reticulum, suggesting higher Ca\n 2+<\/jats:sup>\n sensitivity of the RyRs. The refractoriness of Ca\n 2+<\/jats:sup>\n spark triggering depends on the Ca\n 2+<\/jats:sup>\n sensitivity of the RyR2. We found that RyR2\u2010S2808A\/S2814A channels were more Ca\n 2+<\/jats:sup>\n sensitive in control conditions. Isoprenaline further shortened RyR refractoriness in DKI cardiomyocytes. Together, our results suggest that ablation of both the RyR2\u2010Ser2808 and RyR2\u2010S2814\u00a0sites increases the propensity for pro\u2010arrhythmic spontaneous Ca\n 2+<\/jats:sup>\n releases, as previously suggested for hyperphosphorylated RyRs. Given that the DKI cells present a full response to isoprenaline, the data suggest that phosphorylation of Ser2030\u00a0might be sufficient for \u03b2\u2010AR\u2010mediated sensitization of RyRs.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n Phosphorylation of cardiac sarcoplasmic reticulum Ca\n 2+<\/jats:sup>\n \u2010release channels (ryanodine receptors, RyRs) is involved in the regulation of cardiac function.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Ablation of both the RyR2\u2010Ser2808 and RyR2\u2010Ser2814\u00a0sites increases the propensity for pro\u2010arrhythmic spontaneous Ca\n 2+<\/jats:sup>\n releases, as previously suggested for hyperphosphorylated RyRs.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The intra\u2010sarcoplasmic reticulum Ca\n 2+<\/jats:sup>\n threshold for spontaneous Ca\n 2+<\/jats:sup>\n wave generation is lower in RyR2\u2010double\u2010knock\u2010in cells.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The RyR2 from double\u2010knock\u2010in cells exhibits increased Ca\n 2+<\/jats:sup>\n sensitivity.\n <\/jats:p>\n <\/jats:list-item>\n \n Phosphorylation of Ser2808 and Ser2814\u00a0might be important for basal activity of the channel.<\/jats:p>\n <\/jats:list-item>\n \n Phosphorylation of Ser2030\u00a0might be sufficient for a \u03b2\u2010adrenergic response.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp286453","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T15:38:48Z","timestamp":1727192328000},"page":"5179-5201","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Dual ablation of the RyR2\u2010Ser2808 and RyR2\u2010Ser2814\u00a0sites increases propensity for pro\u2010arrhythmic spontaneous Ca\n 2+<\/sup>\n releases"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8924-1024","authenticated-orcid":false,"given":"Radoslav","family":"Janicek","sequence":"first","affiliation":[{"name":"Department of Physiology University of Bern Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel M.","family":"Camors","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Cardiology University of Tennessee Health Science Center Le Bonheur Children's Hospital Research Center Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duilio M.","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Bern Bern 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