Conceptual and experimental issues in biased agonism.

Area of Science:

• Pharmacology
• Biochemistry
• Molecular Biology

Background:

• G protein-coupled receptors (GPCRs) mediate diverse cellular responses.
• Signaling bias, or functional selectivity, describes ligands that preferentially activate specific signaling pathways.
• Understanding agonism is crucial for interpreting GPCR ligand activity.

Purpose of the Study:

• To review the theoretical and experimental basis for assessing agonism in biased GPCR signaling.
• To reconcile classical receptor theory with chemical thermodynamics in measuring agonism.
• To emphasize the importance of dissecting efficacy from affinity for understanding biased agonism.

Main Methods:

• Theoretical analysis of classical receptor theory and chemical thermodynamics.
• Review of experimental approaches for assessing ligand efficacy and signaling bias.
• Examination of concentration-dependent functional data.

Main Results:

• Classical receptor theory's efficacy measure and chemical thermodynamics' allosteric effect are coincident measures of agonism.
• Classical theory is a mathematical tool for efficacy extraction, not a mechanistic descriptor of ligand-receptor signaling.
• Dissecting efficacy from affinity is essential for understanding agonism and biased agonism.

Conclusions:

• Biased agonism arises from the preferential formation of specific GPCR-transducer complexes.
• Identifying ligands with true efficacy bias is fundamental for exploring GPCR conformational space.
• Understanding efficacy bias is critical for advancing GPCR-targeted drug discovery.