Therapeutic Potential of Targeting ß-Arrestin

Abstract

ß-arrestins are multifunctional proteins that modulate heptahelical 7 transmembrane receptors, also known as G protein-coupled receptors (GPCRs), a superfamily of receptors that regulate most physiological processes. ß-arrestin modulation of GPCR function includes termination of G protein-dependent signaling, initiation of ß-arrestin-dependent signaling, receptor trafficking to degradative or recycling pathways, receptor transactivation, transcriptional regulation, and localization of second messenger regulators. The pleiotropic influence ß-arrestins exert on these receptors regulates a breadth of physiological functions, and additionally, ß-arrestins are involved in the pathophysiology of numerous and wide-ranging diseases, making them prime therapeutic targets. In this review, we briefly describe the mechanisms by which ß-arrestins regulate GPCR signaling, including the functional cellular mechanisms modulated by ß-arrestins and relate this to observed pathophysiological responses associated with ß-arrestins. We focus on the role for ß-arrestins in transducing cell signaling; a pathway that is complementary to the classical G protein-coupling pathway. The existence of these GPCR dual signaling pathways offers an immense therapeutic opportunity through selective targeting of one signaling pathway over the other. Finally, we will consider several mechanisms by which the potential of dual signaling pathway regulation can be harnessed and the implications for improved disease treatments.

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“…Moreover, they can act alone (ago-PAM) or in conjunction with the endogenous ligands (PAM or NAM) [141,142]. Importantly, some biased ligands have been reported to increase the window between side effects and therapeutic benefits, therefore opening great opportunities in drug discovery [143,144]. Of course, these advances and novel opportunities also apply to the targeting of FSHR.…”

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“…Therefore, identi cation of the regulators involved in microglia activation may create new avenues for drug design in the treatment of PD. β-Arrestins (ARRBs) are originally identi ed to mediate the desensitization and intracellular tra cking of G protein-coupled receptors (GPCRs) [16][17][18][19][20][21]. There are two ARRB isoforms, ARRB1 and ARRB2; they share 78% amino acid identity.…”

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“…It is now recognised that β-arrestins are also capable of triggering signalling cascades independent of G-protein signalling and β 2 -adrenoceptors can signal not only via activation of G-proteins, but also via β-arrestins [105]. Some manifestations of the signalling capacities of β-arrestins have also been appreciated and, in effect, numerous substrates including ERK, cJun N-terminal kinase, p38 MAPK, phosphoinositide-3-kinase, Akt, and RhoA have been identified for β-arrestin-dependent signalling in the cytoplasm [106] Therefore, interfering with β-arrestin-driven processes could offer novel strategies for therapeutic intervention [107]. Conveniently, ligands could be biased or "functionally selective" toward either a G-protein or β-arrestin-mediated pathway (figure 4) [107,108].…”

“…Some manifestations of the signalling capacities of β-arrestins have also been appreciated and, in effect, numerous substrates including ERK, cJun N-terminal kinase, p38 MAPK, phosphoinositide-3-kinase, Akt, and RhoA have been identified for β-arrestin-dependent signalling in the cytoplasm [106] Therefore, interfering with β-arrestin-driven processes could offer novel strategies for therapeutic intervention [107]. Conveniently, ligands could be biased or "functionally selective" toward either a G-protein or β-arrestin-mediated pathway (figure 4) [107,108]. Agonists that show a higher potency to specific signalling pathways over others are known as "biased agonists" and have a better therapeutic index [109].…”