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bioRxiv · 10.64898/2026.02.09.704723

Unraveling β2-Adrenergic Receptor Signaling Bias Between Gαs and Gα15 in Shaping Macrophage Function

Sun, Y.-E.·Li, Q.·English, J. G.
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Abstract

Myocardial infarction and heart failure are leading global causes of mortality. Chronic {beta}-adrenergic receptor ({beta}AR) activation in cardiomyocytes promotes heart failure via Gs signaling after myocardial infarction, whereas {beta}2AR activation may also provide cardiac protection and repair through alternative pathways. Macrophages play a pivotal role in cardiac repair, and {beta}2AR has been reported to signal via the hematopoietic-specific G15 in these cells. We aimed to characterize signaling bias between Gs and G15 downstream of {beta}2AR and to elucidate their roles in macrophage polarization. Using TRUPATH triple assays, we observed that several {beta}2AR agonists activate G15 with at least an order of magnitude greater potency than Gs in this system. In addition, clinically used {beta}-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 {beta}2AR agonist clenbuterol revealed enrichment of M1 transcriptional profile and repair-related hallmarks. Knockdown of Gs showed M1 enrichment, whereas G15 knockdown was associated with negative M2 enrichment as well as M1 enrichment. Loss of either Gs or G15 negatively affected repair-associated hallmarks. In contrast, pharmacological intervention of the Gs-cAMP signaling produced opposing M1/M2 transcriptional responses, while suppressing repair-associated hallmarks. These in vitro findings explore the distinct pharmacological profiles of {beta}2AR ligands toward Gs and G15 and reveal how {beta}2AR agonism may modulate macrophage function through dual-transducer signaling.

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Sun, Y.-E., Li, Q., English, J. G.. 2026-02-11. Unraveling β2-Adrenergic Receptor Signaling Bias Between Gαs and Gα15 in Shaping Macrophage Function. https://doi.org/10.64898/2026.02.09.704723

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