β-Arrestin-biased ligands at seven-transmembrane receptors

Seven-transmembrane receptors (7TMRs), the most common molecular targets of modern drug therapy, are critically regulated by β-arrestins, which both inhibit classic G-protein signaling and initiate distinct β-arrestin signaling. The interplay of G-protein and β-arrestin signals largely determines the cellular consequences of 7TMR-targeted drugs. Until recently, a drug's efficacy for β-arrestin recruitment was believed to be proportional to its efficacy for G-protein activities. This paradigm restricts 7TMR drug effects to a linear spectrum of responses, ranging from inhibition of all responses to stimulation of all responses. However, it is now clear that 'biased ligands' can selectively activate G-protein or β-arrestin functions and thus elicit novel biological effects from even well-studied 7TMRs. Here, we discuss the current state of β-arrestin-biased ligand research and the prospects for β-arrestin bias as a therapeutic target. Consideration of ligand bias might have profound influences on the way scientists approach 7TMR-targeted drug discovery.