Beta-arrestin-biased ligands at seven-transmembrane receptors.
Seven-transmembrane receptors (7TMRs), the most common molecular targets of modern drug therapy, are critically regulated by beta-arrestins, which both inhibit classic G-protein signaling and initiate distinct beta-arrestin signaling. The interplay of G-protein and beta-arrestin signals largely determines the cellular consequences of 7TMR-targeted drugs. Until recently, a drug's efficacy for beta-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 beta-arrestin functions and thus elicit novel biological effects from even well-studied 7TMRs. Here, we discuss the current state of beta-arrestin-biased ligand research and the prospects for beta-arrestin bias as a therapeutic target. Consideration of ligand bias might have profound influences on the way scientists approach 7TMR-targeted drug discovery.
Violin
Jonathan D
JD
Department of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Lefkowitz
Robert J
RJ
D000494:Allosteric Regulation; D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000071557:beta-Arrestins
D019390:Arrestins; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C450520:seven-transmembrane G-protein-coupled receptor