{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:21:33Z","timestamp":1791336093604,"version":"4.3.1"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2006,11,10]]},"abstract":"<jats:p>\n                    \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    - and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -adrenergic receptors (\u03b2ARs) are known to differentially regulate cardiomyocyte contraction and growth. We tested the hypothesis that these differences are attributable to spatial compartmentation of the second messenger cAMP. Using a fluorescent resonance energy transfer (FRET)-based approach, we directly monitored the spatial and temporal distribution of cAMP in adult cardiomyocytes. We developed a new cAMP-FRET sensor (termed HCN2-camps) based on a single cAMP binding domain of the hyperpolarization activated cyclic nucleotide-gated potassium channel 2 (HCN2). Its cytosolic distribution, high dynamic range, and sensitivity make HCN2-camps particularly well suited to monitor subcellular localization of cardiomyocyte cAMP. We generated HCN2-camps transgenic mice and performed single-cell FRET imaging on freshly isolated cardiomyocytes. Whole-cell superfusion with isoproterenol showed a moderate elevation of cAMP. Application of various phosphodiesterase (PDE) inhibitors revealed stringent control of cAMP through PDE4&gt;PDE2&gt;PDE3. The \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    AR-mediated cAMP signals were entirely dependent on PDE4 activity, whereas \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR-mediated cAMP was under control of multiple PDE isoforms. \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    AR subtype\u2013specific stimulation yielded \u22482-fold greater cAMP responses compared with selective \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -subtype stimulation, even on treatment with the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) (\u0394FRET, 17.3\u00b11.3% [\u03b2\n                    <jats:sub>1<\/jats:sub>\n                    AR] versus 8.8\u00b10.4% [\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR]). Treatment with pertussis toxin to inactivate G\n                    <jats:sub>i<\/jats:sub>\n                    did not affect cAMP production. Localized \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    AR stimulation generated a cAMP gradient propagating throughout the cell, whereas local \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR stimulation did not elicit marked cAMP diffusion. Our data reveal that in adult cardiac myocytes, \u03b2\n                    <jats:sub>1<\/jats:sub>\n                    ARs induce far-reaching cAMP signals, whereas \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    AR-induced cAMP remains locally confined.\n                  <\/jats:p>","DOI":"10.1161\/01.res.0000250046.69918.d5","type":"journal-article","created":{"date-parts":[[2006,10,13]],"date-time":"2006-10-13T06:40:54Z","timestamp":1160721654000},"page":"1084-1091","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":323,"title":["Cyclic AMP Imaging in Adult Cardiac Myocytes Reveals Far-Reaching \u03b2\n                    <sub>1<\/sub>\n                    -Adrenergic but Locally Confined \u03b2\n                    <sub>2<\/sub>\n                    -Adrenergic Receptor\u2013Mediated Signaling"],"prefix":"10.1161","volume":"99","author":[{"given":"Viacheslav O.","family":"Nikolaev","sequence":"first","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology (V.O.N., M.B., E.S., M.J.L.), University of Wuerzburg; and Rudolf-Virchow-Center (S.E.), Deutsche Forschungsgemeinschaft\u2013Research Center for Experimental Biomedicine, University of Wuerzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Bu\u0308nemann","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology (V.O.N., M.B., E.S., M.J.L.), University of Wuerzburg; and Rudolf-Virchow-Center (S.E.), Deutsche Forschungsgemeinschaft\u2013Research Center for Experimental Biomedicine, University of Wuerzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Schmitteckert","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology (V.O.N., M.B., E.S., M.J.L.), University of Wuerzburg; and Rudolf-Virchow-Center (S.E.), Deutsche Forschungsgemeinschaft\u2013Research Center for Experimental Biomedicine, University of Wuerzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin J.","family":"Lohse","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology (V.O.N., M.B., E.S., M.J.L.), University of Wuerzburg; and Rudolf-Virchow-Center (S.E.), Deutsche Forschungsgemeinschaft\u2013Research Center for Experimental Biomedicine, University of Wuerzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Engelhardt","sequence":"additional","affiliation":[{"name":"From the Institute of Pharmacology and Toxicology (V.O.N., M.B., E.S., M.J.L.), University of Wuerzburg; and Rudolf-Virchow-Center (S.E.), Deutsche Forschungsgemeinschaft\u2013Research Center for Experimental Biomedicine, University of Wuerzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0031-6997(24)01425-X","volume":"51","year":"1999","unstructured":"Brodde OE, Michel MC. Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev. 1999; 51: 651\u2013690.","journal-title":"Pharmacol Rev"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.84.1.43"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.85.11.1092"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000017187.61348.95"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.279.2.C495"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.12.7059"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8160017"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.100.22.2210"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.4.1607"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00720-4"},{"key":"e_1_3_3_11_2","first-page":"H2726","volume":"272","year":"1997","unstructured":"Aprigliano O, Rybin VO, Pak E, Robinson RB, Steinberg SF. \u03b21- and \u03b22-adrenergic receptors exhibit differing susceptibility to muscarinic accentuated antagonism. Am J Physiol. 1997; 272: H2726\u2013H2735.","journal-title":"Am J Physiol"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000218493.09370.8e"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)32287-1"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.99.18.2458"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.31.22048"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(00)76495-2"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000218273.91741.30"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1341.015"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03966"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(99)00073-3"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00057.2005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/349694a0"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/71345"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069982"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00058.2005"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00316-2"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.07.030"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C400302200"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000134629.84732.11"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1272"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000204575.94040.d1"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.69.5.1682066"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01922"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405697200"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006951200"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1997.3775"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000200178.34179.93"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.RES.0000250046.69918.d5","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T08:06:58Z","timestamp":1736582818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.RES.0000250046.69918.d5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,11,10]]},"references-count":37,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2006,11,10]]}},"alternative-id":["10.1161\/01.RES.0000250046.69918.d5"],"URL":"https:\/\/doi.org\/10.1161\/01.res.0000250046.69918.d5","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1052935.504881","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,11,10]]},"assertion":[{"value":"2006-10-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}