{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:01:22Z","timestamp":1790312482590,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,6,18]]},"abstract":"\n Background<\/jats:title>\n \n Chronic sympathetic stimulation drives desensitization and downregulation of \u03b21 adrenergic receptor (\u03b2\n 1<\/jats:sub>\n AR) in heart failure. We aim to explore the differential downregulation subcellular pools of \u03b2\n 1<\/jats:sub>\n AR signaling in the heart.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL\/6J mice. We applied confocal and proximity ligation assay to examine \u03b2\n 1<\/jats:sub>\n AR association with L\u2010type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and F\u00f6rster resonance energy transfer\u2010based biosensors to probe subcellular \u03b2\n 1<\/jats:sub>\n AR\u2010PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced \u03b2\n 1<\/jats:sub>\n AR protein levels, receptor association with L\u2010type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta\/cell, 29.65 saline versus 14.17 isoproterenol,\n P<\/jats:italic>\n <0.05), and receptor\u2010induced PKA signaling at the plasma membrane (F\u00f6rster resonance energy transfer, 28.9% saline versus 1.9% isoproterenol,\n P<\/jats:italic>\n <0.05) and ryanodine receptor 2 complex (F\u00f6rster resonance energy transfer, 30.2% saline versus 10.6% isoproterenol,\n P<\/jats:italic>\n <0.05). However, the \u03b2\n 1<\/jats:sub>\n AR association with SERCA2a was enhanced (puncta\/cell, 51.4 saline versus 87.5 isoproterenol,\n P<\/jats:italic>\n <0.05), and the receptor signal was minimally affected. The isoproterenol\u2010infused hearts displayed decreased PDE4D (phosphodiesterase 4D) and PDE3A and increased PDE2A, PDE4A, and PDE4B protein levels. We observed a reduced role of PDE4 and enhanced roles of PDE2 and PDE3 on the \u03b2\n 1<\/jats:sub>\n AR\u2010PKA activity at the ryanodine receptor 2 complexes and myocyte shortening. Despite the enhanced \u03b2\n 1<\/jats:sub>\n AR association with SERCA2a, the endogenous norepinephrine\u2010induced signaling was reduced at the SERCA2a complexes. Inhibiting monoamine oxidase A rescued the norepinephrine\u2010induced PKA signaling at the SERCA2a and myocyte shortening.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This study reveals distinct mechanisms for the downregulation of subcellular \u03b2\n 1<\/jats:sub>\n AR signaling in the heart under chronic adrenergic stimulation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.123.033733","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T05:17:45Z","timestamp":1718083065000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Differential Downregulation of \u03b2\n 1<\/sub>\n \u2010Adrenergic Receptor Signaling in the Heart"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2766-8755","authenticated-orcid":false,"given":"Bing","family":"Xu","sequence":"first","affiliation":[{"name":"VA Northern California Health Care System","place":["Mather, USA"]},{"name":"University of California at Davis","place":["Davis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9310-8349","authenticated-orcid":false,"given":"Sherif","family":"Bahriz","sequence":"additional","affiliation":[{"name":"University of California at Davis","place":["Davis, USA"]},{"name":"Mansoura University","place":["Mansoura, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6576-0287","authenticated-orcid":false,"given":"Victoria R.","family":"Salemme","sequence":"additional","affiliation":[{"name":"University of California at Davis","place":["Davis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"University of California at Davis","place":["Davis, USA"]},{"name":"Southern University of Science and Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-2225","authenticated-orcid":false,"given":"Chaoqun","family":"Zhu","sequence":"additional","affiliation":[{"name":"University of California at Davis","place":["Davis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meimi","family":"Zhao","sequence":"additional","affiliation":[{"name":"University of California at Davis","place":["Davis, USA"]},{"name":"China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1786-9143","authenticated-orcid":false,"given":"Yang K.","family":"Xiang","sequence":"additional","affiliation":[{"name":"VA Northern California Health Care System","place":["Mather, USA"]},{"name":"University of California at Davis","place":["Davis, 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