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

Prasenjit Prasad Saha, Valentin Gogonea, Wendy Sweet, Maradumane L. Mohan, Khuraijam Dhanachandra Singh, James T. Anderson, Deepthi Mallela, Conner Witherow, Niladri Kar, Kate Stenson, Terri Harford, Michael A. Fischbach, J. Mark Brown, Sadashiva S. Karnik, Christine S. Moravec, Joseph A. DiDonato, Sathyamangla Venkata Naga Prasad and Stanley L. Hazen ()
Additional contact information
Prasenjit Prasad Saha: Cleveland Clinic
Valentin Gogonea: Cleveland Clinic
Wendy Sweet: Cleveland Clinic
Maradumane L. Mohan: Cleveland Clinic
Khuraijam Dhanachandra Singh: Cleveland Clinic
James T. Anderson: Cleveland Clinic
Deepthi Mallela: Cleveland Clinic
Conner Witherow: Cleveland Clinic
Niladri Kar: Cleveland Clinic
Kate Stenson: Cleveland Clinic
Terri Harford: Cleveland Clinic
Michael A. Fischbach: Stanford University
J. Mark Brown: Cleveland Clinic
Sadashiva S. Karnik: Cleveland Clinic
Christine S. Moravec: Cleveland Clinic
Joseph A. DiDonato: Cleveland Clinic
Sathyamangla Venkata Naga Prasad: Cleveland Clinic
Stanley L. Hazen: Cleveland Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50855-3

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