8.A.136. The Alpha/Beta-Arrestin (ARRB) Family
β-arrestins function in the desensitization of seven membrane spanning receptors (7MSRs, GPCRs, TC# 9.A.14), especially in the endocytosis and signaling of these receptors (Magalhaes et al. 2012). These functions reflect the ability of the beta-arrestins to bind signaling and endocytic elements, often in an agonist-dependent fashion (Lefkowitz and Whalen 2004). One system leads to MAP kinase activation via beta-arrestin-mediated scaffolding of these pathways in a receptor-dependent fashion. The beta-arrestins are also found to be involved in the regulation of novel receptor systems, such as Frizzled and TGFbeta receptors as well as certain transporters such as ion channels and carriers (i.e., SLC9A5; the sodium/hydrogen exchanger, NHE5 (TC# 2.A.36.1.16). β-arrestin-1 acts as a scaffold for ADGRG2/CFTR complex formation in apical membranes, whereas specific residues of ADGRG2 confer coupling specificity for different G protein subtypes, the specificity of which is critical for male fertility (Zhang et al. 2018).
Opioid receptors signal through two kinds of downstream partners, G-proteins and β-arrestins. Many side effects of opioid use are mediated by β-arrestins, and therefore, opioids that signal through G-proteins are preferred for treating pain. Ko et al. 2021 found that β-arrestin-based drugs can be used to treat fear and anxiety. There are distinct but overlapping functions for β-arrestin isoform. Loss of β-arrestins can cause a Warberg effect and prevent progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1 (Sabbir et al. 2021). β-arrestins that regulate agonist-mediated desensitization and integration of signaling by transmembrane receptors, may be involved in the endothelial cell response to shear stress. In fact, endothelial β-arrestins are key transducers of ciliary mechanotransduction that play a central role in shear signaling and contribute to vascular development (Park et al. 2022).
An ancient family of arrestin-fold proteins, termed alpha-arrestins, have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein; TXNIP, TC# 8.A.136.1.14), is known to regulate myocardial glucose uptake as well as other transporters (Nakayama et al. 2022).