Teaching old receptors new tricks: biasing seven-transmembrane receptors

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Abstract
Seven-transmembrane receptors (7TMRs), also known as G protein-couple receptors, are the largest class of transmembrane receptors and a common target for therapeutics. Initially thought to signal only through heterotrimeric G proteins, it is now recognized that they also signal through the multifunctional adapter proteins β-arrestin 1 and β-arrestin 2. β-arrestin-mediated signalling can have distinct functional consequences from G protein-mediated signalling. G protein-mediated signalling is usually accomplished via the generation of second messengers that signal to downstream partners. By contrast, β-arrestin-mediated signalling usually results in the formation of signalling complexes scaffolded by β-arrestins that lead to activation of kinases and other downstream targets. Biased agonists are capable of signalling through only a restricted subset of all of the pathways usually available to the receptor. β-arrestin-biased agonists act as agonists for β-arrestin-mediated signalling and as weak partial agonists or antagonists of G protein-mediated signalling. In many systems, receptor activation by β-arrestin-biased agonists results in functionally distinct responses from activation by non-biased agonists. For example, a β-arrestin-biased agonist of the parathyroid hormone receptor is capable of stimulating trabecular bone growth in mice without increasing bone resorption, whereas an unbiased full agonist stimulates both bone growth and resorption. Cell-based assays used to facilitate the discovery of β-arrestin-biased agonists may be based on redistribution of labelled receptor or β-arrestin; proximity between receptor and β-arrestin; conformation of receptor or β-arrestin; or activation of downstream signalling pathways known to be regulated selectively by β-arrestins. Most of these assays have been adapted for high-throughput screening. As we learn more about β-arrestin-mediated signalling at other 7TMRs, new targets for the development of β-arrestin-biased agonists will undoubtedly arise. Thus, it is important that we continue to focus on studying the physiological impact of β-arrestin-mediated signaling in cell-based and animal studies.

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