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Related Experiment Videos

Functional differences between full and partial agonists: evidence for ligand-specific receptor conformations.

R Seifert1, K Wenzel-Seifert, U Gether

  • 1Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California, USA.

The Journal of Pharmacology and Experimental Therapeutics
|May 18, 2001
PubMed
Summary
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Agonist efficacy at beta(2)-adrenoceptor (beta(2)AR) differs between stabilizing the G-protein complex and activating GTPase activity. Partial agonists may slow G-protein turnover by stabilizing the ternary complex.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • G-protein-coupled receptors (GPCRs) initiate signaling cascades upon agonist binding.
  • Agonist efficacy is linked to stabilizing the active GPCR state.
  • The G-protein activation cycle involves GDP/GTP exchange and complex dissociation.

Purpose of the Study:

  • To investigate how beta(2)-adrenoceptor (beta(2)AR) agonist efficacy relates to stabilizing the GPCR/G-protein ternary complex and steady-state GTPase activity.
  • To differentiate the GPCR states involved in G-protein activation versus ternary complex stabilization.

Main Methods:

  • Examined beta(2)AR agonists with varying efficacies (partial to full agonists).
  • Utilized wild-type and constitutively active mutant beta(2)AR (beta(2)AR(CAM)) fused to G(salpha).

Related Experiment Videos

  • Assessed ternary complex stabilization (high-affinity, GTP-sensitive binding) and steady-state GTPase activity.

    • Main Results:

    • No correlation was found between GTPase activation efficacy and ternary complex stabilization for beta(2)AR(CAM) agonists.
    • Results suggest distinct GPCR conformations are optimal for GDP release/GTP binding versus ternary complex stabilization.
    • Partial agonists strongly stabilizing the ternary complex may decrease G-protein turnover rate.

    Conclusions:

    • Agonist efficacy is not solely determined by ternary complex stabilization.
    • Distinct GPCR active states may govern different steps in the G-protein cycle.
    • Understanding these distinct states offers insights into partial agonist mechanisms.