RT Journal Article SR Electronic T1 β-Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP PHARMREV-AR-2021-000302 DO 10.1124/pharmrev.121.000302 A1 Jürgen Wess A1 Antwi-Boasiako Oteng A1 Osvaldo Rivera-Gonzalez A1 Eugenia V. Gurevich A1 Vsevolod V. Gurevich YR 2023 UL http://pharmrev.aspetjournals.org/content/early/2023/04/07/pharmrev.121.000302.abstract AB The two beta-arrestins, beta-arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiological functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both beta-arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how beta-arrestins bind to activated GPCRs and downstream effector proteins. Studies with beta-arrestin mutant mice have identified numerous physiological and pathophysiological processes regulated by beta-arrestin-1 and/or -2. Following a brief summary of recent structural studies, this review will primarily focus on beta-arrestin-regulated physiological functions, with particular focus on the central nervous system and the roles of beta-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review will also highlight potential therapeutic implications of these studies and discuss strategies that could prove useful for targeting specific beta-arrestin-regulated signaling pathways for therapeutic purposes. Significance Statement The two beta-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with beta-arrestin mutant mice and cultured cells, complemented by novel insights into beta-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific beta-arrestin functions.