G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7-TMRs), are the largest protein receptor superfamily in the body. These receptors and their ligands direct a diverse array of physiological responses, and hence have broad relevance to numerous diseases. As a result, they have generated considerable interest in the pharmaceutical industry as drug targets. Recently, GPCRs have been demonstrated to elicit signals through interaction with the scaffolding proteins, β-arrestins-1 and 2, independent of heterotrimeric G-protein coupling. This review discusses several known G-protein-independent, β-arrestin-dependent pathways and their potential physiological and pharmacological significance. The emergence of G-protein-independent signalling changes the way in which GPCR signalling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics.
British Journal of Pharmacology (2008) 153, S298–S309; doi:10.1038/sj.bjp.0707508; published online 26 November 2007