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

Author

Listed:
  • Prasenjit Prasad Saha

    (Cleveland Clinic
    Cleveland Clinic)

  • Valentin Gogonea

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland State University)

  • Wendy Sweet

    (Cleveland Clinic)

  • Maradumane L. Mohan

    (Cleveland Clinic)

  • Khuraijam Dhanachandra Singh

    (Cleveland Clinic)

  • James T. Anderson

    (Cleveland Clinic
    Cleveland Clinic)

  • Deepthi Mallela

    (Cleveland Clinic
    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
    Cleveland Clinic)

  • Sadashiva S. Karnik

    (Cleveland Clinic)

  • Christine S. Moravec

    (Cleveland Clinic)

  • Joseph A. DiDonato

    (Cleveland Clinic
    Cleveland Clinic)

  • Sathyamangla Venkata Naga Prasad

    (Cleveland Clinic)

  • Stanley L. Hazen

    (Cleveland Clinic
    Cleveland Clinic
    Cleveland Clinic)

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.

Suggested Citation

  • 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, 2024. "Gut microbe-generated phenylacetylglutamine is an endogenous allosteric modulator of β2-adrenergic receptors," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50855-3
    DOI: 10.1038/s41467-024-50855-3
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