{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:01:43Z","timestamp":1790348503145,"version":"4.1.0"},"posted":{"date-parts":[[2026,2,11]]},"group-title":"Pharmacology and Toxicology","reference-count":92,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Myocardial infarction and heart failure are leading global causes of mortality. Chronic \u03b2-adrenergic receptor (\u03b2AR) activation in cardiomyocytes promotes heart failure via G\u03b1s signaling after myocardial infarction, whereas \u03b22AR activation may also provide cardiac protection and repair through alternative pathways. Macrophages play a pivotal role in cardiac repair, and \u03b22AR has been reported to signal via the hematopoietic-specific G\u03b115 in these cells. We aimed to characterize signaling bias between G\u03b1s and G\u03b115 downstream of \u03b22AR and to elucidate their roles in macrophage polarization. Using TRUPATH triple assays, we observed that several \u03b22AR agonists activate G\u03b115 with at least an order of magnitude greater potency than G\u03b1s in this system. In addition, clinically used \u03b2-blockers may exhibit differential inhibition on these two pathways. Macrophages are briefly classified into M1 and M2 polarization according to their activating stimuli and functional properties. Transcriptomic profiling of THP-1-derived macrophage-like cells treated with the \u03b22AR agonist clenbuterol revealed enrichment of M1 transcriptional profile and repair-related hallmarks. Knockdown of G\u03b1s showed M1 enrichment, whereas G\u03b115 knockdown was associated with negative M2 enrichment as well as M1 enrichment. Loss of either G\u03b1s or G\u03b115 negatively affected repair-associated hallmarks. In contrast, pharmacological intervention of the G\u03b1s-cAMP signaling produced opposing M1\/M2 transcriptional responses, while suppressing repair-associated hallmarks. These\n                  <jats:italic>in vitro<\/jats:italic>\n                  findings explore the distinct pharmacological profiles of \u03b22AR ligands toward G\u03b1s and G\u03b115 and reveal how \u03b22AR agonism may modulate macrophage function through dual-transducer signaling.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance statement<\/jats:title>\n                  <jats:p>\u03b22AR agonism engaged G\u03b115 signaling in the TRUPATH triple assay, with several agonists showing higher apparent potency for G\u03b115 than G\u03b1s and \u03b2-blockers showing distinct inhibitory profiles across G\u03b1s and G\u03b115. In macrophage-like cells, \u03b22AR was associated with an M1 transcriptional profile. Notably, G\u03b115 may contribute to M2-associated transcriptional profile under \u03b22AR activation, whereas the G\u03b1s-cAMP showed an opposing M1 transcriptional pattern. These findings suggest that G\u03b115 signaling may represent a noncanonical pathway contributing to \u03b22AR-induced transcriptional responses in macrophages.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.09.704723","type":"posted-content","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:06:16Z","timestamp":1770815176000},"source":"Crossref","is-referenced-by-count":0,"title":["Pharmacological and Transcriptomic Exploration of \u03b22-Adrenergic Receptor-G\u03b115 Signaling in THP-1-Derived Macrophages"],"prefix":"10.64898","author":[{"given":"Yuan-En","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"High-Throughput Genomics and Cancer Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin G","family":"English","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, 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