Therapeutic potential of β-arrestin- and G protein-biased agonists

Abstract

Members of the seven-transmembrane receptor (7TMR), or G protein-coupled receptor (GPCR), superfamily represent some of the most successful targets of modern drug therapy, with proven efficacy in the treatment of a broad range of human conditions and disease processes. It is now appreciated that β-arrestins, once viewed simply as negative regulators of traditional 7TMR-stimulated G protein signaling, act as multifunctional adapter proteins that regulate 7TMR desensitization and trafficking and promote distinct intracellular signals in their own right. Moreover, several 7TMR biased agonists, which selectively activate these divergent signaling pathways, have been identified. Here we highlight the diversity of G protein- and β-arrestin-mediated functions and the therapeutic potential of selective targeting of these in disease states.

Figure 1

7TMR signaling and regulation by the GRKs and β-arrestins. (a) Agonist-stimulated, 7TMR-mediated G protein activation. (b) Subsequent desensitization of 7TMR-mediated G protein signaling and activation of β-arrestin-mediated signals. (c) β-Arrestin-mediated 7TMR receptor internalization involving clathrin and AP-2.

Figure 2

Differential 7TMR-stimulated G protein- and β-arrestin-mediated signaling. (a) Traditional agonist with linear efficacy. (b) Traditional antagonist, blocking all aspects of 7TMR signaling. (c) G protein-biased ligand, promoting 7TMR G protein signaling in the absence of β-arrestin-mediated desensitization, internalization and signaling. (d) β-Arrestin-biased ligand, promoting β-arrestin-mediated signaling and internalization in the absence of G protein activation.