Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of β2-adrenergic receptors

• Published in: Nature communications Vol. 15; no. 1; pp. 6696 - 14
• Main Authors: Saha, Prasenjit Prasad, Gogonea, Valentin, Sweet, Wendy, Mohan, Maradumane L., Singh, Khuraijam Dhanachandra, Anderson, James T., Mallela, Deepthi, Witherow, Conner, Kar, Niladri, Stenson, Kate, Harford, Terri, Fischbach, Michael A., Brown, J. Mark, Karnik, Sadashiva S., Moravec, Christine S., DiDonato, Joseph A., Naga Prasad, Sathyamangla Venkata, Hazen, Stanley L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 49/47; 631/326/2565/2134; 631/337; 631/80/86; 64/60; 96/106; Adrenergic receptors; Allosteric properties; Allosteric Regulation; Animals; Cardiac muscle; Cardiomyocytes; Cardiovascular diseases; Congestive heart failure; G protein-coupled receptors; Gastrointestinal Microbiome; Glutamine - metabolism; Heart diseases; Heart Failure - metabolism; Heart Failure - microbiology; Heart function; HEK293 Cells; Humanities and Social Sciences; Humans; Intestinal microflora; Male; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Microbiota; Microorganisms; Modulation; Modulators; Molecular Docking Simulation; multidisciplinary; Mutagenesis, Site-Directed; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Receptor mechanisms; Receptors (physiology); Receptors, Adrenergic, beta-1 - genetics; Receptors, Adrenergic, beta-1 - metabolism; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - metabolism; Science; Science (multidisciplinary); Site-directed mutagenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50855-3

Allosteric modulation is a central mechanism for metabolic regulation but has yet to be described for a gut microbiota-host interaction. Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, has previously been clinically associated with and mechanistically linked to cardiovascular disease (CVD) and heart failure (HF). Here, using cells expressing β1- versus β2-adrenergic receptors (β1AR and β2AR), PAGln is shown to act as a negative allosteric modulator (NAM) of β2AR, but not β1AR. In functional studies, PAGln is further shown to promote NAM effects in both isolated male mouse cardiomyocytes and failing human heart left ventricle muscle (contracting trabeculae). Finally, using in silico docking studies coupled with site-directed mutagenesis and functional analyses, we identified sites on β2AR (residues E122 and V206) that when mutated still confer responsiveness to canonical β2AR agonists but no longer show PAGln-elicited NAM activity. The present studies reveal the gut microbiota-obligate metabolite PAGln as an endogenous NAM of a host GPCR. Allosteric modulation is crucial in metabolic regulation but unexplored in gut microbehost interactions. Here the authors show gut microbe-derived phenylacetylglutamine acts as a negative allosteric modulator of β2-adrenergic receptors, impacting heart function.