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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
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Mu Opioid Receptor Positive Allosteric Modulator BMS-986122 Confers Agonist-Dependent G Protein Subtype Signaling

Grant M Grieble1, Brian I Knapp1, Jean M Bidlack1

  • 1Department of Pharmacology & Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, United States.

Biochemistry
|May 16, 2025
PubMed

Insights

Positive allosteric modulators (PAMs) like BMS-986122 enhance mu opioid receptor (MOR) signaling differently depending on the specific G protein subtype. This differential effect, especially with partial agonists, offers new avenues for developing safer analgesics.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • The mu opioid receptor (MOR) mediates the effects of medically used opioids, influencing analgesia and respiratory depression.
  • Understanding how opioid chemical structures affect MOR functional activation of G protein subtypes is key to developing safer analgesics.
  • Positive allosteric modulators (PAMs) like BMS-986122 are emerging tools that enhance MOR agonist activity.

Purpose of the Study:

  • To investigate how the MOR-selective PAM BMS-986122 uniquely affects opioid pharmacology when MOR signals through specific inhibitory Gα subunits.
  • To explore the influence of different Gα subunits on BMS-986122 binding affinity and its modulation of opioid efficacy.
  • To identify key amino acid residues in Gαi/o subunits responsible for differential signaling outcomes.

Main Methods:

  • Utilized a nanoBRET-based functional assay in live HEK 293T cells to measure MOR signaling.
  • Assessed the impact of BMS-986122 on opioid activity across different Gα subunits (Gαi/o/z).
  • Employed site-directed mutagenesis on Gαi/o subunits to pinpoint critical amino acid residues.

Main Results:

  • BMS-986122 demonstrated differential enhancement of opioid activity depending on the specific Gα subunit engaged by the MOR, with partial agonists showing the most pronounced differences.
  • The binding affinity of BMS-986122 to the MOR was significantly modulated by the co-binding Gα subunit.
  • Mutagenesis studies identified specific amino acid differences in Gαi/o subunits that underlie these differential signaling effects.

Conclusions:

  • BMS-986122 exhibits biased allosteric modulation, enhancing MOR signaling in a Gα subunit-dependent manner.
  • This Gα subunit-specific modulation by PAMs provides insights into biased opioid signaling.
  • Findings may guide the rational design of novel biased agonists or allosteric modulators for safer opioid therapeutics.

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