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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
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GTP release-selective agonists prolong opioid analgesic efficacy
Edward L Stahl1, Matthew A Swanson2,3, Vuong Q Dang4
1Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. EStahl@usf.edu.
Nature
|December 17, 2025
Summary
G-protein-coupled receptors (GPCRs) can promote GTP release, not just binding. Certain agonists selectively trigger GTP release, potentially separating pain relief from side effects.
Area of Science:
- Pharmacology
- Molecular Biology
- Neuroscience
Background:
- G-protein-coupled receptors (GPCRs) function as guanine nucleotide exchange factors (GEFs).
- GPCRs facilitate heterotrimeric G protein activation by GDP/GTP exchange.
- This GEF activity is not limited to promoting GTP binding.
Purpose of the Study:
- To investigate state-selective agonist affinities for GPCRs.
- To determine if agonists can preferentially promote GTP release over GTP binding.
- To explore the in vivo physiological consequences of such selective agonists.
Main Methods:
- Assessed state-selective affinities of mu opioid receptor agonists.
- Identified agonists with preference for promoting GTP release.
- Administered release-preferring agonists in mice to evaluate antinociceptive and physiological effects.
Main Results:
- Identified mu opioid receptor agonists with state-selective affinity for promoting GTP release.
- Two agonists demonstrated a marked preference for promoting GTP release.
- In mice, release-preferring agonists enhanced and prolonged antinociception without increasing respiratory or cardiac side effects.
Conclusions:
- Agonist active-state selectivity may dictate the direction of GPCR GEF function.
- This selectivity could influence receptor-effector engagement kinetics and specificity.
- Potential for disentangling multifaceted drug-induced physiological responses, such as separating analgesia from adverse effects.
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