Inverse agonism: more than reverting constitutively active receptor signaling

Seven-transmembrane receptors constitute one of the major families of proteins encoded by the genome. This type of receptor is one of the most important targets of the pharmaceutical industry, and many of the drugs with significant therapeutic action have been shown to be inverse agonists. Concepts regarding the mechanisms by which ligands activate and inactivate receptors are thought to be far more complex that a simple on–off switch. For both drug design and pharmacology principles, it is important to understand the mechanisms by which these drugs achieve their effects. Recent studies have demonstrated intriguing actions of inverse agonists. They have been shown not only to block constitutive responses of receptors but also to activate and regulate seven-transmembrane receptor signaling and trafficking. The activation of pathways by inverse agonists was shown to occur mainly via G-protein-independent mechanisms. These findings emphasize the importance of inverse agonism as a principle of receptor regulation. In this paper, we will review the evidence supporting inverse agonist promoted signaling and trafficking.Key words: G-protein-coupled receptor, seven-transmembrane receptor, inverse agonist, platelet-activating factor receptor, β2-adrenergic receptor.