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).  β-arrestins are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation (Maharana et al. 2024).

Plasma membrane transporters play pivotal roles in the import of nutrients, including sugars, amino acids, nucleobases, carboxylic acids, and metal ions, that surround fungal cells. The selective removal of these transporters by endocytosis is one of the most important regulatory mechanisms that ensures a rapid adaptation of cells to the changing environment (e.g., nutrient fluctuations or different stresses). At the heart of this mechanism lies a network of proteins that includes the arrestin-related trafficking adaptors (ARTs) which link the ubiquitin ligase Rsp5 to nutrient transporters and endocytic factors (Barata-Antunes et al. 2021). Transporter conformational changes, as well as dynamic interactions between its cytosolic termini/loops and with lipids of the plasma membrane, are also critical during the endocytic process. Barata-Antunes et al. 2021 reviewed the current knowledge and recent findings on the molecular mechanisms involved in nutrient transporter endocytosis, both in the budding yeast Saccharomyces cerevisiae and in some species of the filamentous fungus Aspergillus.