{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:35:46Z","timestamp":1791012946425,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2006,8,15]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Abnormal Ca\n            <jats:sup>2+<\/jats:sup>\n            handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca\n            <jats:sup>2+<\/jats:sup>\n            handling and contractility in cAF patients.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Total and phosphorylation levels of Ca\n            <jats:sup>2+<\/jats:sup>\n            -handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca\n            <jats:sup>2+<\/jats:sup>\n            -calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35\u2013phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            Altered Ca\n            <jats:sup>2+<\/jats:sup>\n            handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum\u2013associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.106.636845","type":"journal-article","created":{"date-parts":[[2006,8,8]],"date-time":"2006-08-08T00:39:20Z","timestamp":1154997560000},"page":"670-680","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":237,"title":["Molecular Determinants of Altered Ca\n            <sup>2+<\/sup>\n            Handling in Human Chronic Atrial Fibrillation"],"prefix":"10.1161","volume":"114","author":[{"given":"Ali","family":"El-Armouche","sequence":"first","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Boknik","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Knaut","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Ravens","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dobromir","family":"Dobrev","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Mu\u0308nster (P.B.), Mu\u0308nster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/415219a"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000125626.33738.e2"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.11.009"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000145659.80212.6a"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00013.2003"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.1.173"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.12.4124-4135.2002"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0057fje"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000161256.85833.fa"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M007197200"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1000"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00045-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.1999.tb00712.x"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(99)00008-X"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.104.2.174"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00453-9"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000138849.03311.c6"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.104.506857"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000162461.67140.4c"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000141296.59876.87"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.103.5.691"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000145155.60288.71"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2005.07.002"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.11.005"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.146.3.631"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002100000283"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1991.tb15871.x"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(92)90359-5"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.21.5682"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1976.tb11032.x"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2004.01422.x"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000253200"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.85.9.810"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00036-X"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.07.030"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.85.9.848"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2004.12.022"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000127175.21818.c2"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2003.08.014"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.22.5.699"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25713"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(02)00851-1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.64.1.9"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000165480.82737.33"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405770200"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.89.11.997"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000204575.94040.d1"},{"key":"e_1_3_2_49_2","first-page":"H1151","volume":"271","year":"1996","unstructured":"Benardeau A, Hatem SN, Rucker-Martin C, Le Grand B, Mace L, Dervanian P, Mercadier JJ, Coraboeuf E. 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