{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:15:53Z","timestamp":1790835353264,"version":"4.1.0"},"reference-count":68,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T00:00:00Z","timestamp":1636070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["ES 569\/2-1"],"award-info":[{"award-number":["ES 569\/2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2020-116927RB-C21"],"award-info":[{"award-number":["PID2020-116927RB-C21"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Both, the decreased L-type Ca2+ current (ICa,L) density and increased spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3\u2032,5\u2032-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is linked to these compartment-specific changes (up- or down-regulation) in Ca2+-handling. Perforated patch-clamp experiments were performed in atrial myocytes from 53 patients with AF and 104 patients in sinus rhythm (Ctl). A significantly higher frequency of transient inward currents (ITI) activated by spontaneous Ca2+ release was confirmed in myocytes from AF patients. Next, inhibition of PKA by H-89 promoted a stronger effect on the ITI frequency in these myocytes compared to myocytes from Ctl patients (7.6-fold vs. 2.5-fold reduction), while the \u03b2-agonist isoproterenol (ISO) caused a greater increase in Ctl patients (5.5-fold vs. 2.1-fold). ICa,L density was larger in myocytes from Ctl patients at baseline (p &lt; 0.05). However, the effect of ISO on ICa,L density was only slightly stronger in AF than in Ctl myocytes (3.6-fold vs. 2.7-fold). Interestingly, a significant reduction of ICa,L and Ca2+ sparks was observed upon Ca2+\/Calmodulin-dependent protein kinase II inhibition by KN-93, but this inhibition had no effect on ITI. Fluorescence resonance energy transfer (FRET) experiments showed that although AF promoted cytosolic desensitization to \u03b2-adrenergic stimulation, ISO increased cAMP to similar levels in both groups of patients in the L-type Ca2+ channel and ryanodine receptor compartments. Basal cAMP signaling also showed compartment-specific regulation by phosphodiesterases in atrial myocytes from 44 Ctl and 43 AF patients. Our results suggest that AF is associated with opposite changes in compartmentalized PKA\/cAMP-dependent regulation of ICa,L (down-regulation) and ITI (up-regulation).<\/jats:p>","DOI":"10.3390\/cells10113042","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T10:33:09Z","timestamp":1636108389000},"page":"3042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling"],"prefix":"10.3390","volume":"10","author":[{"given":"Franziska","family":"Reinhardt","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg UKE, 20251 Hamburg, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira","family":"Beneke","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"},{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf (UKE), 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nefeli Grammatica","family":"Pavlidou","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"},{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf (UKE), 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenard","family":"Conradi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg UKE, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Reichenspurner","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg UKE, 20251 Hamburg, Germany"},{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf (UKE), 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif","family":"Hove-Madsen","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute Barcelona, IIBB-CSIC and IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-1568","authenticated-orcid":false,"given":"Cristina E.","family":"Molina","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 20251 Hamburg, Germany"},{"name":"Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf (UKE), 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1161\/01.CIR.0000141296.59876.87","article-title":"Atrial Fibrillation Is Associated with Increased Spontaneous Calcium Release From the Sarcoplasmic Reticulum in Human Atrial Myocytes","volume":"110","author":"Llach","year":"2004","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1161\/01.RES.85.5.428","article-title":"Atrial L-Type Ca2+ Currents and Human Atrial Fibrillation","volume":"85","author":"Pond","year":"1999","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1161\/01.CIR.0000162461.67140.4C","article-title":"Defective Cardiac Ryanodine Receptor Regulation during Atrial Fibrillation","volume":"111","author":"Vest","year":"2005","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Beneke, K., and Molina, C.E. (2021). Molecular Basis of Atrial Fibrillation Initiation and Maintenance. Hearts, 2.","DOI":"10.3390\/hearts2010014"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1093\/eurheartj\/ehq464","article-title":"Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Up-Regulation of Adenosine A2A Receptors","volume":"32","author":"Llach","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1161\/CIRCULATIONAHA.111.067306","article-title":"Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+-Ca2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients with Chronic Atrial Fibrillation","volume":"125","author":"Voigt","year":"2012","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1113\/jphysiol.2010.197715","article-title":"Sarcoplasmic Reticulum and L-Type Ca2+ Channel Activity Regulate the Beat-to-Beat Stability of Calcium Handling in Human Atrial Myocytes","volume":"589","author":"Llach","year":"2011","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1093\/eurheartj\/ehn140","article-title":"Downregulation of the Calcium Current in Human Right Atrial Myocytes from Patients in Sinus Rhythm but with a High Risk of Atrial Fibrillation","volume":"29","author":"Dinanian","year":"2008","journal-title":"Eur. Heart J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1161\/CIRCULATIONAHA.106.636845","article-title":"Molecular Determinants of Altered Ca2+ Handling in Human Chronic Atrial Fibrillation","volume":"114","author":"Boknik","year":"2006","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1161\/CIRCRESAHA.109.203836","article-title":"CaMKII-Dependent Diastolic SR Ca2+ Leak and Elevated Diastolic Ca2+ Levels in Right Atrial Myocardium of Patients with Atrial Fibrillation","volume":"106","author":"Neef","year":"2010","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1161\/01.CIR.0000145659.80212.6A","article-title":"L-Type Ca2+ Current Downregulation in Chronic Human Atrial Fibrillation Is Associated with Increased Activity of Protein Phosphatases","volume":"110","author":"Christ","year":"2004","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/24884","article-title":"Epac Is a Rap1 Guanine-Nucleotide-Exchange Factor Directly Activated by Cyclic AMP","volume":"396","author":"Zwartkruis","year":"1998","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1113\/jphysiol.2007.133066","article-title":"The CAMP Binding Protein Epac Modulates Ca2+ Sparks by a Ca2+ \/Calmodulin Kinase Signalling Pathway in Rat Cardiac Myocytes","volume":"583","author":"Pereira","year":"2007","journal-title":"J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1016\/j.jacc.2012.01.060","article-title":"Cyclic Adenosine Monophosphate Phosphodiesterase Type 4 Protects Against Atrial Arrhythmias","volume":"59","author":"Molina","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00210-020-01968-1","article-title":"Impact of Phosphodiesterases PDE3 and PDE4 on 5-Hydroxytryptamine Receptor4-Mediated Increase of CAMP in Human Atrial Fibrillation","volume":"394","author":"Dolce","year":"2020","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.ejphar.2006.09.023","article-title":"The Proarrhythmic Antihistaminic Drug Terfenadine Increases Spontaneous Calcium Release in Human Atrial Myocytes","volume":"553","author":"Llach","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/S0006-3495(99)77229-2","article-title":"Amplitude Distribution of Calcium Sparks in Confocal Images: Theory and Studies with an Automatic Detection Method","volume":"76","author":"Cheng","year":"1999","journal-title":"Biophys. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1093\/cvr\/cvy221","article-title":"Heart Failure Leads to Altered \u03922-Adrenoceptor\/Cyclic Adenosine Monophosphate Dynamics in the Sarcolemmal Phospholemman\/Na,K ATPase Microdomain","volume":"115","author":"Wright","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.celrep.2018.03.053","article-title":"Cardiomyocyte Membrane Structure and CAMP Compartmentation Produce Anatomical Variation in \u03922AR-CAMP Responsiveness in Murine Hearts","volume":"23","author":"Wright","year":"2018","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Berisha, F., G\u00f6tz, K.R., Wegener, J.W., Brandenburg, S., Subramanian, H., Molina, C.E., R\u00fcffer, A., Petersen, J., Bernhardt, A., and Girdauskas, E. (2021). CAMP Imaging at Ryanodine Receptors Reveals \u03b2 2 -Adrenoceptor Driven Arrhythmias. Circ. Res., 129.","DOI":"10.1161\/CIRCRESAHA.120.318234"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.14440\/jbm.2014.36","article-title":"Advanced Methods of Microscope Control Using \u039cManager Software","volume":"1","author":"Edelstein","year":"2014","journal-title":"J. Biol. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1111\/bph.13525","article-title":"In Permanent Atrial Fibrillation, PDE3 Reduces Force Responses to 5-HT, but PDE3 and PDE4 Do Not Cause the Blunting of Atrial Arrhythmias","volume":"173","author":"Berk","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Llach, A., Molina, C.E., Alvarez-Lacalle, E., Tort, L., Ben\u00edtez, R., and Hove-Madsen, L. (2011). Detection, Properties, and Frequency of Local Calcium Release from the Sarcoplasmic Reticulum in Teleost Cardiomyocytes. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023708"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1161\/CIRCULATIONAHA.104.506857","article-title":"Human Atrial Ion Channel and Transporter Subunit Gene-Expression Remodeling Associated With Valvular Heart Disease and Atrial Fibrillation","volume":"112","author":"Gaborit","year":"2005","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0735-1097(99)00008-X","article-title":"Down-Regulation of L-Type Calcium Channel and Sarcoplasmic Reticular Ca2+-ATPase MRNA in Human Atrial Fibrillation without Significant Change in the MRNA of Ryanodine Receptor, Calsequestrin and Phospholamban","volume":"33","author":"Lai","year":"1999","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"28063","DOI":"10.1074\/jbc.M704893200","article-title":"Atrial Glutathione Content, Calcium Current, and Contractility","volume":"282","author":"Carnes","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0092-8674(00)80847-8","article-title":"PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)","volume":"101","author":"Marx","year":"2000","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1161\/01.CIR.0000068316.53218.49","article-title":"\u03b2-Blockers Restore Calcium Release Channel Function and Improve Cardiac Muscle Performance in Human Heart Failure","volume":"107","author":"Reiken","year":"2003","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nm.2406","article-title":"Carvedilol and Its New Analogs Suppress Arrhythmogenic Store Overload\u2013Induced Ca2+ Release","volume":"17","author":"Zhou","year":"2011","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"H1245","DOI":"10.1152\/ajpheart.00650.2019","article-title":"Effect of Carvedilol on Atrial Excitation-Contraction Coupling, Ca2+ Release, and Arrhythmogenicity","volume":"318","author":"Blatter","year":"2020","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1016\/j.jacc.2007.01.064","article-title":"Scavenging Free Radicals by Low-Dose Carvedilol Prevents Redox-Dependent Ca2+Leak Via Stabilization of Ryanodine Receptor in Heart Failure","volume":"49","author":"Mochizuki","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0002-9149(03)00842-7","article-title":"Comparison of Effectiveness of Carvedilol versus Metoprolol or Atenolol for Atrial Fibrillation Appearing after Coronary Artery Bypass Grafting or Cardiac Valve Operation","volume":"92","author":"Merritt","year":"2003","journal-title":"Am. J. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/eurheartj\/ehs423","article-title":"Metoprolol vs. Carvedilol or Carvedilol plus N-Acetyl Cysteine on Post-Operative Atrial Fibrillation: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"34","author":"Ozaydin","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ijcard.2007.03.123","article-title":"Comparison of the Efficacy of Metoprolol and Carvedilol for Preventing Atrial Fibrillation after Coronary Bypass Surgery","volume":"126","author":"Acikel","year":"2008","journal-title":"Int. J. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.amjcard.2004.01.023","article-title":"Role of Carvedilol in Atrial Fibrillation: Insights from Clinical Trials","volume":"93","author":"Gheorghiade","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.ijcard.2016.12.029","article-title":"Aldosterone Pathway Blockade to Prevent Atrial Fibrillation: A Systematic Review and Meta-Analysis","volume":"231","author":"Neefs","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_37","first-page":"1111","article-title":"Dantrolene Reduces CaMKII\u03b4C-Mediated Atrial Arrhythmias","volume":"22","author":"Pabel","year":"2020","journal-title":"EP Eur."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1161\/CIRCULATIONAHA.113.006641","article-title":"Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients with Paroxysmal Atrial Fibrillation","volume":"129","author":"Voigt","year":"2014","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1161\/CIRCRESAHA.120.316710","article-title":"Atrial Myocyte NLRP3\/CaMKII Nexus Forms a Substrate for Postoperative Atrial Fibrillation","volume":"127","author":"Heijman","year":"2020","journal-title":"Circ. Res."},{"key":"ref_40","first-page":"1940","article-title":"Calmodulin Kinase II\u2013Mediated Sarcoplasmic Reticulum Ca2+ Leak Promotes Atrial Fibrillation in Mice","volume":"119","author":"Chelu","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.3389\/fphys.2018.01383","article-title":"Profibrotic, Electrical, and Calcium-Handling Remodeling of the Atria in Heart Failure Patients With and Without Atrial Fibrillation","volume":"9","author":"Molina","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1161\/CIRCRESAHA.113.301678","article-title":"Phospholamban Knockout Breaks Arrhythmogenic Ca2+ Waves and Suppresses Catecholaminergic Polymorphic Ventricular Tachycardia in Mice","volume":"113","author":"Bai","year":"2013","journal-title":"Circ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1161\/01.RES.0000246118.98832.04","article-title":"Compartmentation of Cyclic Nucleotide Signaling in the Heart","volume":"99","author":"Fischmeister","year":"2006","journal-title":"Circ. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1161\/CIRCULATIONAHA.119.042573","article-title":"Cardiac Overexpression of PDE4B Blunts \u03b2-Adrenergic Response and Maladaptive Remodeling in Heart Failure","volume":"142","author":"Karam","year":"2020","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pavlaki, N., de Jong, K.A., Geertz, B., Nikolaev, V.O., and Froese, A. (2021). Cardiac Hypertrophy Changes Compartmentation of CAMP in Non-Raft Membrane Microdomains. Cells, 10.","DOI":"10.3390\/cells10030535"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1126\/science.1185988","article-title":"Beta2-Adrenergic Receptor Redistribution in Heart Failure Changes CAMP Compartmentation","volume":"327","author":"Nikolaev","year":"2010","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wagner, M., Sadek, M.S., Dybkova, N., Mason, F.E., Klehr, J., Firneburg, R., Cachorro, E., Richter, K., Klapproth, E., and Kuenzel, S.R. (2021). Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094816"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15031","DOI":"10.1038\/ncomms15031","article-title":"FRET Biosensor Uncovers CAMP Nano-Domains at \u03b2-Adrenergic Targets That Dictate Precise Tuning of Cardiac Contractility","volume":"8","author":"Surdo","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11193","DOI":"10.1073\/pnas.1324132111","article-title":"Arrhythmias, Elicited by Catecholamines and Serotonin, Vanish in Human Chronic Atrial Fibrillation","volume":"111","author":"Christ","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00395-015-0525-2","article-title":"Prevention of Adenosine A2A Receptor Activation Diminishes Beat-to-Beat Alternation in Human Atrial Myocytes","volume":"111","author":"Molina","year":"2016","journal-title":"Basic Res. Cardiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.yjmcc.2021.02.006","article-title":"Mapping Genetic Changes in the CAMP-Signaling Cascade in Human Atria","volume":"155","author":"Garnier","year":"2021","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cell.2005.07.030","article-title":"Phosphodiesterase 4D Deficiency in the Ryanodine-Receptor Complex Promotes Heart Failure and Arrhythmias","volume":"123","author":"Lehnart","year":"2005","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1161\/01.CIR.0000020013.73106.D8","article-title":"Clinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia","volume":"106","author":"Priori","year":"2002","journal-title":"Circulation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1161\/CIRCULATIONAHA.12.148619","article-title":"Epac2 Mediates Cardiac \u03921-Adrenergic\u2013Dependent Sarcoplasmic Reticulum Ca2+ Leak and Arrhythmia","volume":"127","author":"Pereira","year":"2013","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Curran, J., Tang, L., Roof, S.R., Velmurugan, S., Millard, A., Shonts, S., Wang, H., Santiago, D., Ahmad, U., and Perryman, M. (2014). Nitric Oxide-Dependent Activation of CaMKII Increases Diastolic Sarcoplasmic Reticulum Calcium Release in Cardiac Myocytes in Response to Adrenergic Stimulation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087495"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/cvr\/cvt201","article-title":"NO-Dependent CaMKII Activation during \u03b2-Adrenergic Stimulation of Cardiac Muscle","volume":"100","author":"Gutierrez","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1073\/pnas.1416163112","article-title":"Novel Epac Fluorescent Ligand Reveals Distinct Epac1 vs. Epac2 Distribution and Function in Cardiomyocytes","volume":"112","author":"Pereira","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1469-7793.1997.003bo.x","article-title":"Measurement of Sarcoplasmic Reticulum Ca2+ Content and Sarcolemmal Ca2+ Fluxes in Isolated Rat Ventricular Myocytes during Spontaneous Ca2+ Release","volume":"501","author":"Trafford","year":"1997","journal-title":"J. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e61","DOI":"10.1161\/01.RES.0000125626.33738.E2","article-title":"Ca2+ \/Calmodulin-Dependent Protein Kinase II Phosphorylation Regulates the Cardiac Ryanodine Receptor","volume":"94","author":"Wehrens","year":"2004","journal-title":"Circ. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5972","DOI":"10.1073\/pnas.0806422106","article-title":"Calmodulin Kinase II Is Required for Fight or Flight Sinoatrial Node Physiology","volume":"106","author":"Wu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10274","DOI":"10.1073\/pnas.1005843107","article-title":"Role of CaMKII Phosphorylation of the Cardiac Ryanodine Receptor in the Force Frequency Relationship and Heart Failure","volume":"107","author":"Kushnir","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.yjmcc.2018.03.020","article-title":"The Novel CaMKII Inhibitor GS-680 Reduces Diastolic SR Ca Leak and Prevents CaMKII-Dependent pro-Arrhythmic Activity","volume":"118","author":"Lebek","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5923","DOI":"10.1113\/JP271965","article-title":"Calcium\/Calmodulin-Dependent Kinase II and Nitric Oxide Synthase 1-Dependent Modulation of Ryanodine Receptors during \u03b2-Adrenergic Stimulation Is Restricted to the Dyadic Cleft","volume":"594","author":"Dries","year":"2016","journal-title":"J. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1161\/01.RES.0000236756.06252.13","article-title":"Ca2+\/Calmodulin-Dependent Protein Kinase II Phosphorylation of Ryanodine Receptor Does Affect Calcium Sparks in Mouse Ventricular Myocytes","volume":"99","author":"Guo","year":"2006","journal-title":"Circ. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.yjmcc.2018.10.010","article-title":"Cardiac CaMKII Activation Promotes Rapid Translocation to Its Extra-Dyadic Targets","volume":"125","author":"Wood","year":"2018","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1161\/CIRCULATIONAHA.115.018131","article-title":"Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes","volume":"132","author":"Glukhov","year":"2015","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1161\/CIRCRESAHA.109.206276","article-title":"Ultrastructural and Functional Remodeling of the Coupling Between Ca2+ Influx and Sarcoplasmic Reticulum Ca2+ Release in Right Atrial Myocytes from Experimental Persistent Atrial Fibrillation","volume":"105","author":"Lenaerts","year":"2009","journal-title":"Circ. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1172\/JCI88241","article-title":"Axial Tubule Junctions Control Rapid Calcium Signaling in Atria","volume":"126","author":"Brandenburg","year":"2016","journal-title":"J. Clin. 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