Abstract
The two β-arrestins, β-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 physiologic 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 β-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 β-arrestins bind to activated GPCRs and downstream effector proteins. Studies with β-arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by β-arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on β-arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of β-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific β-arrestin-regulated signaling pathways for therapeutic purposes.
Significance Statement The two β-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 β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions.
Footnotes
- Received January 17, 2021.
- Revision received March 23, 2023.
- Accepted April 3, 2023.
This work was supported by funding through the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Program (J.W., A.-B.O., and O.R.-G.), as well as National Institutes of Health National Institute of General Medical Sciences [Grant GM122491] and National Eye Institute [Grant EY011500], and Cornelius Vanderbilt Endowed Chair (E.V.G. and V.V.G.).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- U.S. Government work not protected by U.S. copyright.
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- Abstract
- I. Introduction
- II. Arrestin Structure and Function
- III. Tools for Studying Arrestin Function and Physiology
- IV. Role of β-Arrestins in Modulating Key Functions of the Central Nervous System
- V. Modulation of Cardiovascular Functions by β-Arrestins
- VI. Cancer and β-Arrestins
- VII. Regulation of Metabolic Functions by β-Arrestins
- VIII. Targeting β-Arrestins for Therapeutic Purposes
- IX. Conclusion
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