Functional selectivity

Functional selectivity (also known as ligand bias or agonist trafficking) is a concept in pharmacology that describes the ability of different ligands to stabilize different conformations of a receptor, leading to a unique intracellular response for each ligand-receptor complex.

Overview

Functional selectivity is a phenomenon observed in G protein-coupled receptors (GPCRs), which are a large and diverse group of membrane proteins that respond to various external signals. GPCRs are involved in many diseases and are the target of approximately 40% of all modern medicinal drugs.

In the traditional view of receptor activation, a ligand either activates a receptor (as an agonist) or prevents its activation (as an antagonist). However, functional selectivity proposes that different ligands can stabilize different conformations of the same receptor, leading to a unique intracellular response for each ligand-receptor complex.

Mechanism

The mechanism of functional selectivity involves the binding of a ligand to a receptor, which induces a conformational change in the receptor. This change allows the receptor to interact with different intracellular signaling proteins, leading to a unique response for each ligand-receptor complex.

For example, a ligand may bind to a GPCR and induce a conformation that preferentially activates the G protein pathway, leading to a specific cellular response. Another ligand may bind to the same GPCR and induce a different conformation that preferentially activates the beta-arrestin pathway, leading to a different cellular response.

Implications

Functional selectivity has significant implications for drug discovery and development. It suggests that it may be possible to develop drugs that selectively target specific signaling pathways, leading to more effective treatments with fewer side effects.

For example, a drug that selectively activates the G protein pathway may be more effective in treating a certain disease, while a drug that selectively activates the beta-arrestin pathway may be more effective in treating a different disease.

See also

• Pharmacodynamics
• Signal transduction
• Receptor theory

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