{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:45:21Z","timestamp":1776872721147,"version":"3.51.2"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2012,5]]},"abstract":"\n Background\u2014<\/jats:title>\n G-protein\u2013coupled receptor kinase 2 (GRK2) is a primary regulator of \u03b2-adrenergic signaling in the heart. G-protein\u2013coupled receptor kinase 2 ablation impedes heart failure development, but elucidation of the cellular mechanisms has not been achieved, and such elucidation is the aim of this study.<\/jats:p>\n <\/jats:sec>\n \n Methods and Results\u2014<\/jats:title>\n \n Myocyte contractility, Ca\n 2+<\/jats:sup>\n handling and excitation-contraction coupling were studied in isolated cardiomyocytes from wild-type and GRK2 knockout (GRK2KO) mice without (sham) or with myocardial infarction (MI). In cardiac myocytes isolated from unstressed wild-type and GRK2KO hearts, myocyte contractions and Ca\n 2+<\/jats:sup>\n transients were similar, but GRK2KO myocytes had lower sarcoplasmic reticulum (SR) Ca\n 2+<\/jats:sup>\n content because of increased sodium-Ca\n 2+<\/jats:sup>\n exchanger activity and inhibited SR Ca\n 2+<\/jats:sup>\n ATPase by local protein kinase A\u2013mediated activation of phosphodiesterase 4 resulting in hypophosphorylated phospholamban. This Ca\n 2+<\/jats:sup>\n handling phenotype is explained by a higher fractional SR Ca\n 2+<\/jats:sup>\n release induced by increased L-type Ca\n 2+<\/jats:sup>\n channel currents. After \u03b2-adrenergic stimulation, GRK2KO myocytes revealed significant increases in contractility and Ca\n 2+<\/jats:sup>\n transients, which were not mediated through cardiac L-type Ca\n 2+<\/jats:sup>\n channels but through an increased SR Ca\n 2+<\/jats:sup>\n . Interestingly, post-MI GRK2KO mice showed better cardiac function than post-MI control mice, which is explained by an improved Ca\n 2+<\/jats:sup>\n handling phenotype. The SR Ca\n 2+<\/jats:sup>\n content was better maintained in post-MI GRK2KO myocytes than in post-MI control myocytes because of better-maintained L-type Ca\n 2+<\/jats:sup>\n channel current density and no increase in sodium-Ca\n 2+<\/jats:sup>\n exchanger in GRK2KO myocytes. An L-type Ca\n 2+<\/jats:sup>\n channel blocker, verapamil, reversed some beneficial effects of GRK2KO.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions\u2014<\/jats:title>\n \n These data argue for novel differential regulation of L-type Ca\n 2+<\/jats:sup>\n channel currents and SR load by GRK2. G-protein\u2013coupled receptor kinase 2 ablation represents a novel beneficial Ca\n 2+<\/jats:sup>\n handling phenotype resisting adverse remodeling after MI.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circulationaha.111.044255","type":"journal-article","created":{"date-parts":[[2012,4,11]],"date-time":"2012-04-11T03:15:21Z","timestamp":1334114121000},"page":"2108-2118","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Cardiac G-Protein\u2013Coupled Receptor Kinase 2 Ablation Induces a Novel Ca\n 2+<\/sup>\n Handling Phenotype Resistant to Adverse Alterations and Remodeling After Myocardial Infarction"],"prefix":"10.1161","volume":"125","author":[{"given":"Philip W.","family":"Raake","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoying","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leif E.","family":"Vinge","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henriette","family":"Brinks","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naser","family":"Jaleel","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingxin","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxin","family":"Tang","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Most","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"II","given":"Gerald W.","family":"Dorn","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven R.","family":"Houser","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugo A.","family":"Katus","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiongwen","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter J.","family":"Koch","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany (P.W.R., H.A.K.); Cardiovascular Research Center\/Department of Physiology (X.Z., N.J., Y.L., M.T., S.R.H., X.C.), and Center for Translational Medicine, Department of Pharmacology (E.G., W.J.K.), Temple University; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University (L.E.V., H.B., P.M.), Philadelphia, PA; and Center for Pharmacogenomics, Washington University, St..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000062469.83985.9B"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1206"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00019.2006"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000033988.13062.7c"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.70.113006.100455"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198409273111303"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/415206a"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.091102398"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.7000"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.107.168336"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.110.225201"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.803999"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000247932.71270.2c"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.622415"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11642"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.10.969"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-004-0928-3"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00265.2010"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.08.014"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000060027.40275.a6"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.171736"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.064444"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.1.140"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31060"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.11.012"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.111.044255","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:59:20Z","timestamp":1715579960000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.111.044255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5]]},"references-count":26,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2012,5]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.111.044255"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.111.044255","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5]]},"assertion":[{"value":"2011-06-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-03-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2012-04-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}