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8.A.136. The 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 beta-arrestins can cause a Warberg effect and prevent progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1 (Sabbir et al. 2021).

References associated with 8.A.136 family:

Carroll, S.H., E. Zhang, B.F. Wang, K.B. LeClair, A. Rahman, D.E. Cohen, J. Plutzky, P. Patwari, and R.T. Lee. (2017). Adipocyte arrestin domain-containing 3 protein (Arrdc3) regulates uncoupling protein 1 (Ucp1) expression in white adipose independently of canonical changes in β-adrenergic receptor signaling. PLoS One 12: e0173823. 28291835
Chen, W., N. Li, T. Chen, Y. Han, C. Li, Y. Wang, W. He, L. Zhang, T. Wan, and X. Cao. (2005). The lysosome-associated apoptosis-inducing protein containing the pleckstrin homology (PH) and FYVE domains (LAPF), representative of a novel family of PH and FYVE domain-containing proteins, induces caspase-independent apoptosis via the lysosomal-mitochondrial pathway. J. Biol. Chem. 280: 40985-40995. 16188880
Gupta, M.K., M.L. Mohan, and S.V. Naga Prasad. (2018). G Protein-Coupled Receptor Resensitization Paradigms. Int Rev Cell Mol Biol 339: 63-91. 29776605
Han, S.O., R.P. Kommaddi, and S.K. Shenoy. (2013). Distinct roles for β-arrestin2 and arrestin-domain-containing proteins in β2 adrenergic receptor trafficking. EMBO Rep 14: 164-171. 23208550
Kazan, J.M., G. Desrochers, C.E. Martin, H. Jeong, D. Kharitidi, P.M. Apaja, A. Roldan, N. St Denis, A.C. Gingras, G.L. Lukacs, and A. Pause. (2021). Endofin is required for HD-PTP and ESCRT-0 interdependent endosomal sorting of ubiquitinated transmembrane cargoes. iScience 24: 103274. 34761192
Ko, M.J., T. Chiang, A.A. Mukadam, G.E. Mulia, A.M. Gutridge, A. Lin, J.A. Chester, and R.M. van Rijn. (2021). β-Arrestin-dependent ERK signaling reduces anxiety-like and conditioned fear-related behaviors in mice. Sci Signal 14:. 34344831
Lefkowitz, R.J. and E.J. Whalen. (2004). β-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 16: 162-168. 15196559
Magalhaes, A.C., H. Dunn, and S.S. Ferguson. (2012). Regulation of GPCR activity, trafficking and localization by GPCR-interacting proteins. Br J Pharmacol 165: 1717-1736. 21699508
Nabhan, J.F., H. Pan, and Q. Lu. (2010). Arrestin domain-containing protein 3 recruits the NEDD4 E3 ligase to mediate ubiquitination of the beta2-adrenergic receptor. EMBO Rep 11: 605-611. 20559325
Patwari, P., V. Emilsson, E.E. Schadt, W.A. Chutkow, S. Lee, A. Marsili, Y. Zhang, R. Dobrin, D.E. Cohen, P.R. Larsen, A.M. Zavacki, L.G. Fong, S.G. Young, and R.T. Lee. (2011). The arrestin domain-containing 3 protein regulates body mass and energy expenditure. Cell Metab 14: 671-683. 21982743
Sabbir, M.G., A. Inoue, C.G. Taylor, and P. Zahradka. (2021). Loss of β-Arrestins or six Gα proteins in HEK293 cells caused Warburg effect and prevented progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1. J Steroid Biochem Mol Biol 214: 105995. 34506922
Seet, L.F. and W. Hong. (2001). Endofin, an endosomal FYVE domain protein. J. Biol. Chem. 276: 42445-42454. 11546807
Seet, L.F., N. Liu, B.J. Hanson, and W. Hong. (2004). Endofin recruits TOM1 to endosomes. J. Biol. Chem. 279: 4670-4679. 14613930
Shi, E., X. Zhou, D. Li, Y. Zhang, J. Yuan, and J. Zou. (2019). β-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation. Cell Mol Biol (Noisy-le-grand) 65: 132-137. 31880531
Tan, K.W., V. Nähse, C. Campsteijn, A. Brech, K.O. Schink, and H. Stenmark. (2021). JIP4 is recruited by the phosphoinositide-binding protein Phafin2 to promote recycling tubules on macropinosomes. J Cell Sci 134:. 34109410
Zhang, D.L., Y.J. Sun, M.L. Ma, Y.J. Wang, H. Lin, R.R. Li, Z.L. Liang, Y. Gao, Z. Yang, D.F. He, A. Lin, H. Mo, Y.J. Lu, M.J. Li, W. Kong, K.Y. Chung, F. Yi, J.Y. Li, Y.Y. Qin, J. Li, A.R.B. Thomsen, A.W. Kahsai, Z.J. Chen, Z.G. Xu, M. Liu, D. Li, X. Yu, and J.P. Sun. (2018). Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. Elife 7:. 29393851