{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:38:35Z","timestamp":1790836715164,"version":"4.1.0"},"reference-count":70,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,1,20]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              PKA (protein kinase A)\u2013mediated phosphorylation of cardiac RyR2 (ryanodine receptor 2) has been extensively studied for decades, but the physiological significance of PKA phosphorylation of RyR2 remains poorly understood. Recent determination of high-resolution 3-dimensional structure of RyR2 in complex with CaM (calmodulin) reveals that the major PKA phosphorylation site in RyR2, serine-2030 (S2030), is located within a structural pathway of CaM-dependent inactivation of RyR2. This novel structural insight points to a possible role of PKA phosphorylation of RyR2 in CaM-dependent inactivation of RyR2, which underlies the termination of Ca\n              <jats:sup>2+<\/jats:sup>\n              release and induction of cardiac Ca\n              <jats:sup>2+<\/jats:sup>\n              alternans.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We performed single-cell endoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              imaging to assess the impact of S2030 mutations on Ca\n              <jats:sup>2+<\/jats:sup>\n              release termination in human embryonic kidney 293 cells. Here we determined the role of the PKA site RyR2-S2030 in a physiological setting, we generated a novel mouse model harboring the S2030L mutation and carried out confocal Ca\n              <jats:sup>2+<\/jats:sup>\n              imaging.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We found that mutations, S2030D, S2030G, S2030L, S2030V, and S2030W reduced the endoplasmic reticulum luminal Ca\n              <jats:sup>2+<\/jats:sup>\n              level at which Ca\n              <jats:sup>2+<\/jats:sup>\n              release terminates (the termination threshold), whereas S2030P and S2030R increased the termination threshold. S2030A and S2030T had no significant impact on release termination. Furthermore, CaM\u2013wild-type increased, whereas Ca\n              <jats:sup>2+<\/jats:sup>\n              binding deficient CaM mutant (CaM-M [a loss-of-function CaM mutation with all 4 EF-hand motifs mutated]), PKA, and Ca\n              <jats:sup>2+<\/jats:sup>\n              \/CaMKII (CaM-dependent protein kinase II) reduced the termination threshold. The S2030L mutation abolished the actions of CaM\u2013wild-type, CaM-M, and PKA, but not CaMKII, in Ca\n              <jats:sup>2+<\/jats:sup>\n              release termination. Moreover, we showed that isoproterenol and CaM-M suppressed pacing-induced Ca\n              <jats:sup>2+<\/jats:sup>\n              alternans and accelerated Ca\n              <jats:sup>2+<\/jats:sup>\n              transient recovery in intact working hearts, whereas CaM\u2013wild-type exerted an opposite effect. The impact of isoproterenol was partially and fully reversed by the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide and the CaMKII inhibitor N-[2-[N-(4-chlorocinnamyl)-N-methylaminomethyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide individually and together, respectively. S2030L abolished the impact of CaM\u2013wild-type, CaM-M, and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide\u2013sensitive component, but not the N-[2-[N-(4-chlorocinnamyl)-N-methylaminomethyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide\u2013sensitive component, of isoproterenol.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.122.321177","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T10:01:12Z","timestamp":1672394472000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["RyR2 Serine-2030 PKA Site Governs Ca\n            <sup>2+<\/sup>\n            Release Termination and Ca\n            <sup>2+<\/sup>\n            Alternans"],"prefix":"10.1161","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5251-9192","authenticated-orcid":true,"given":"Jinhong","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."},{"name":"School of Medicine, Northwest University, Xi \u2018an, China (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1370-7764","authenticated-orcid":true,"given":"Wenting","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiwu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Paul Estillore","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell","family":"Belke","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Xiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Libin Cardiovascular Institute, University of Calgary, Alberta T2N 4N1, Canada (J.W., W.G., R.W., J.P.E., D.B., Y.-X.C., S.R.W.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7149-9385","authenticated-orcid":true,"given":"Alexander","family":"Vallmitjana","sequence":"additional","affiliation":[{"name":"School of Medicine, Northwest University, Xi \u2018an, China (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Benitez","sequence":"additional","affiliation":[{"name":"Department of Automatic Control, Universitat Polit\u00e8cnica de Catalunya, 08034 Barcelona, Spain (A.V., R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5493-3998","authenticated-orcid":true,"given":"Leif","family":"Hove-Madsen","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Barcelona IIBB-CSIC, IIB Sant Pau and CIBERCV, Hospital de Sant Pau, 08025, Barcelona, Spain (L.H.-M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5808-0304","authenticated-orcid":true,"given":"S.R. 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