{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:14:30Z","timestamp":1790709270047,"version":"4.1.0"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["675351"],"award-info":[{"award-number":["675351"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Naunyn-Schmiedeberg's Arch Pharmacol"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Atrial fibrillation (AF)\u2013associated remodeling includes contractile dysfunction whose reasons are only partially resolved. Serotonin (5-HT) increases contractile force and causes arrhythmias in atrial trabeculae from patients in sinus rhythm (SR). In persistent atrial fibrillation (peAF), the force responses to 5-HT are blunted and arrhythmic effects are abolished. Since force but not arrhythmic responses to 5-HT in peAF could be restored by PDE3 + PDE4 inhibition, we sought to perform real-time measurements of cAMP to understand whether peAF alters PDE3 + PDE4-mediated compartmentation of 5-HT<jats:sub>4<\/jats:sub> receptor-cAMP responses. Isolated human atrial myocytes from patients in SR, with paroxysmal AF (paAF) or peAF, were adenovirally transduced to express the FRET-based cAMP sensor Epac1-camps. Forty-eight hours later, cAMP responses to 5-HT (100\u00a0\u03bcM) were measured in the absence or concomitant presence of the PDE3 inhibitor cilostamide (0.3\u00a0\u03bcM) and the PDE4 inhibitor rolipram (1\u00a0\u03bcM). We successfully established real-time cAMP imaging in AF myocytes. 5-HT increased cAMP in SR, paAF, and peAF, but in line with previous findings on contractility, this increase was considerably smaller in peAF than in SR or paAF. The maximal cAMP response to forskolin (10\u00a0\u03bcM) was preserved in all groups. The diminished cAMP response to 5-HT in peAF was recovered by preincubation with cilostamide + rolipram. We uncovered a significantly diminished cAMP response to 5-HT<jats:sub>4<\/jats:sub> receptor stimulation which may explain the blunted 5-HT inotropic responses observed in peAF. Since both cAMP and force responses but not arrhythmic responses were recovered after concomitant inhibition of PDE3 + PDE4, they might be regulated in different subcellular microdomains.<\/jats:p>","DOI":"10.1007\/s00210-020-01968-1","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T11:02:59Z","timestamp":1600513379000},"page":"291-298","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Impact of phosphodiesterases PDE3 and PDE4 on 5-hydroxytryptamine receptor4-mediated increase of cAMP in human atrial fibrillation"],"prefix":"10.1007","volume":"394","author":[{"given":"Bernardo","family":"Dolce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten","family":"Christ","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nefeli","family":"Grammatika Pavlidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalin","family":"Yildirim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Reichenspurner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viacheslav O.","family":"Nikolaev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto J","family":"Kaumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3094-1568","authenticated-orcid":false,"given":"Cristina E","family":"Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,19]]},"reference":[{"key":"1968_CR1","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1093\/cvr\/cvy221","volume":"115","author":"Z Bastug-\u00d6zel","year":"2019","unstructured":"Bastug-\u00d6zel Z, Wright PT, Kraft AE, Pavlovic D, Howie J, Froese A et al (2019) Heart failure leads to altered \u03b22-adrenoceptor\/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman\/Na,K ATPase microdomain. Cardiovasc Res 115:546\u2013555. https:\/\/doi.org\/10.1093\/cvr\/cvy221","journal-title":"Cardiovasc Res"},{"key":"1968_CR2","doi-asserted-by":"publisher","first-page":"2478","DOI":"10.1111\/bph.13525","volume":"173","author":"E Berk","year":"2016","unstructured":"Berk E, Christ T, Schwarz S, Ravens U, Knaut M, Kaumann AJ (2016) In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias. Br J Pharmacol 173:2478\u20132489. https:\/\/doi.org\/10.1111\/bph.13525","journal-title":"Br J Pharmacol"},{"key":"1968_CR3","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nprot.2010.198","volume":"6","author":"S Borner","year":"2011","unstructured":"Borner S, Schwede F, Schlipp A, Berisha F, Calebiro D, Lohse MJ et al (2011) FRET measurements of intracellular cAMP concentrations and cAMP analog permeability in intact cells. Nat Protoc 6:427\u2013438. https:\/\/doi.org\/10.1038\/nprot.2010.198","journal-title":"Nat Protoc"},{"key":"1968_CR4","doi-asserted-by":"publisher","first-page":"11193","DOI":"10.1073\/pnas.1324132111","volume":"111","author":"T Christ","year":"2014","unstructured":"Christ T, Rozmaritsa N, Engel A, Berk E, Knaut M, Metzner K et al (2014) Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation. Proc Natl Acad Sci U S A 111:11193\u201311198. https:\/\/doi.org\/10.1073\/pnas.1324132111","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1968_CR5","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1146\/annurev.biochem.76.060305.150444","volume":"76","author":"M Conti","year":"2007","unstructured":"Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481\u2013511. https:\/\/doi.org\/10.1146\/annurev.biochem.76.060305.150444","journal-title":"Annu Rev Biochem"},{"key":"1968_CR6","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1016\/s0140-6736(10)60096-7","volume":"375","author":"D Dobrev","year":"2010","unstructured":"Dobrev D, Nattel S (2010) New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375:1212\u20131223. https:\/\/doi.org\/10.1016\/s0140-6736(10)60096-7","journal-title":"Lancet"},{"key":"1968_CR7","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1111\/j.1476-5381.2008.00023.x","volume":"156","author":"A Galindo-Tovar","year":"2009","unstructured":"Galindo-Tovar A, Vargas ML, Escudero E, Kaumann AJ (2009) Ontogenic changes of the control by phosphodiesterase-3 and -4 of 5-HT responses in porcine heart and relevance to human atrial 5-HT(4) receptors. Br J Pharmacol 156:237\u2013249. https:\/\/doi.org\/10.1111\/j.1476-5381.2008.00023.x","journal-title":"Br J Pharmacol"},{"key":"1968_CR8","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1152\/ajpheart.00691.2009","volume":"299","author":"U Gergs","year":"2010","unstructured":"Gergs U, Baumann M, B\u00f6ckler A, Buchwalow IB, Ebelt H, Fabritz L et al (2010) Cardiac overexpression of the human 5-HT4 receptor in mice. Am J Physiol Heart Circ Physiol 299:788\u2013798. https:\/\/doi.org\/10.1152\/ajpheart.00691.2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"1968_CR9","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s00210-013-0831-x","volume":"386","author":"U Gergs","year":"2013","unstructured":"Gergs U, B\u00f6ckler A, Ebelt H, Hauptmann S, Keller N, Otto V et al (2013) Human 5-HT receptor stimulation in atria of transgenic mice. Naunyn Schmiedeberg's Arch Pharmacol 386:357\u2013367. https:\/\/doi.org\/10.1007\/s00210-013-0831-x","journal-title":"Naunyn Schmiedeberg's Arch Pharmacol"},{"key":"1968_CR10","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/0165-6147(94)90058-2","volume":"15","author":"AJ Kaumann","year":"1994","unstructured":"Kaumann AJ (1994) Do human atrial 5-HT4 receptors mediate arrhythmias? Trends Pharmacol Sci 15:451\u2013455. https:\/\/doi.org\/10.1016\/0165-6147(94)90058-2","journal-title":"Trends Pharmacol Sci"},{"key":"1968_CR11","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1111\/j.1476-5381.1990.tb14108.x","volume":"100","author":"AJ Kaumann","year":"1990","unstructured":"Kaumann AJ, Sanders L, Brown AM, Murray KJ, Brown MJ (1990) A 5-hydroxytryptamine receptor in human atrium. Br J Pharmacol 100:879\u2013885. https:\/\/doi.org\/10.1111\/j.1476-5381.1990.tb14108.x","journal-title":"Br J Pharmacol"},{"key":"1968_CR12","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1016\/j.jacc.2012.01.060","volume":"59","author":"CE Molina","year":"2012","unstructured":"Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee IO et al (2012) Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 59:2182\u20132190. https:\/\/doi.org\/10.1016\/j.jacc.2012.01.060","journal-title":"J Am Coll Cardiol"},{"key":"1968_CR13","doi-asserted-by":"publisher","first-page":"345","DOI":"10.2165\/00003495-199448030-00003","volume":"48","author":"S Nattel","year":"1994","unstructured":"Nattel S, Hadjis T, Talajic M (1994) The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations. Drugs 48:345\u2013371. https:\/\/doi.org\/10.2165\/00003495-199448030-00003","journal-title":"Drugs"},{"key":"1968_CR14","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1152\/physiol.00057.2005","volume":"21","author":"VO Nikolaev","year":"2006","unstructured":"Nikolaev VO, Lohse MJ (2006) Monitoring of cAMP synthesis and degradation in living cells. Physiology (Bethesda) 21:86\u201392. https:\/\/doi.org\/10.1152\/physiol.00057.2005","journal-title":"Physiology (Bethesda)"},{"key":"1968_CR15","doi-asserted-by":"publisher","first-page":"37215","DOI":"10.1074\/jbc.c400302200","volume":"279","author":"VO Nikolaev","year":"2004","unstructured":"Nikolaev VO, Bunemann M, Hein L, Hannawacker A, Lohse MJ (2004) Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 279:37215\u201337258. https:\/\/doi.org\/10.1074\/jbc.c400302200","journal-title":"J Biol Chem"},{"key":"1968_CR16","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.yjmcc.2006.08.007","volume":"42","author":"D Pau","year":"2007","unstructured":"Pau D, Workman AJ, Kane KA, Rankin AC (2007) Electrophysiological and arrhythmogenic effects of 5-hydroxytryptamine on human atrial cells are reduced in atrial fibrillation. J Mol Cell Cardiol 42:54\u201362. https:\/\/doi.org\/10.1016\/j.yjmcc.2006.08.007","journal-title":"J Mol Cell Cardiol"},{"key":"1968_CR17","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1161\/01.res.0000218493.09370.8e","volume":"98","author":"F Rochais","year":"2006","unstructured":"Rochais F, Abi-Gerges A, Horner K, Lefebvre F, Cooper DM, Conti M et al (2006) A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res 98:1081\u20131088. https:\/\/doi.org\/10.1161\/01.res.0000218493.09370.8e","journal-title":"Circ Res"},{"key":"1968_CR18","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1007\/bf00170877","volume":"349","author":"L Sanders","year":"1994","unstructured":"Sanders L, Kaumann AJ (1994) 5-hydroxytryptamine causes rate-dependent arrhythmias through 5-HT4 receptors in human atrium: facilitation by chronic \u03b2-adrenoceptor blockade. Naunyn Schmiedeberg's Arch Pharmacol 349:331\u2013337. https:\/\/doi.org\/10.1007\/bf00170877","journal-title":"Naunyn Schmiedeberg's Arch Pharmacol"},{"key":"1968_CR19","doi-asserted-by":"publisher","first-page":"2526","DOI":"10.1161\/01.cir.92.9.2526","volume":"92","author":"L Sanders","year":"1995","unstructured":"Sanders L, Lynham JA, Bond B, del Monte F, Harding SE, Kaumann AJ (1995) Sensitization of human atrial 5-HT4 receptors by chronic beta-blocker treatment. Circulation 92:2526\u20132539. https:\/\/doi.org\/10.1161\/01.cir.92.9.2526","journal-title":"Circulation"},{"key":"1968_CR20","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1161\/01.cir.103.5.691","volume":"103","author":"U Schotten","year":"2001","unstructured":"Schotten U, Ausma J, Stellbrink C, Sabatschus I, Vogel M, Frechen D et al (2001) Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation 103:691\u2013698. https:\/\/doi.org\/10.1161\/01.cir.103.5.691","journal-title":"Circulation"},{"key":"1968_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3791\/4081","volume":"66","author":"JU Sprenger","year":"2012","unstructured":"Sprenger JU, Perera RK, G\u00f6tz KR, Nikolaev VO (2012) FRET microscopy for real-time monitoring of signaling events in live cells using unimolecular biosensors. J Vis Exp 66:1\u20137. https:\/\/doi.org\/10.3791\/4081","journal-title":"J Vis Exp"},{"key":"1968_CR22","doi-asserted-by":"publisher","first-page":"15031","DOI":"10.1038\/ncomms15031","volume":"8","author":"NC Surdo","year":"2017","unstructured":"Surdo NC, Berrera M, Koschinski A, Brescia M, Machado MR, Carr C et al (2017) FRET biosensor uncovers cAMP nano-domains at \u03b2-adrenergic targets that dictate precise tuning of cardiac contractility. Nat Commun 8:15031. https:\/\/doi.org\/10.1038\/ncomms15031","journal-title":"Nat Commun"}],"container-title":["Naunyn-Schmiedeberg's Archives of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-020-01968-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00210-020-01968-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-020-01968-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,19]],"date-time":"2021-09-19T00:33:31Z","timestamp":1632011611000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00210-020-01968-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,19]]},"references-count":22,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["1968"],"URL":"https:\/\/doi.org\/10.1007\/s00210-020-01968-1","relation":{},"ISSN":["0028-1298","1432-1912"],"issn-type":[{"value":"0028-1298","type":"print"},{"value":"1432-1912","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,19]]},"assertion":[{"value":"8 June 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}