The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors

Abstract

The ␤-arrestins (␤arrs) are versatile, multifunctional adapter proteins that are best known for their ability to desensitize G protein-coupled receptors (GPCRs), but also regulate a diverse array of cellular functions. To signal in such a complex fashion, ␤arrs adopt multiple conformations and are regulated at multiple levels to differentially activate downstream pathways. Recent structural studies have demonstrated that ␤arrs have a conserved structure and activation mechanism, with plasticity of their structural fold, allowing them to adopt a wide array of conformations. Novel roles for ␤arrs continue to be identified, demonstrating the importance of these dynamic regulators of cellular signaling. ␤-Arrestins (␤arrs)2 are ubiquitously expressed proteins that were first described for their role in desensitizing G proteincoupled receptors (GPCRs) (1). We now appreciate that these proteins are multifunctional adapter proteins that regulate a vast array of cellular functions. ␤arrs were identified through their sequence homology to visual arrestin (arrestin-1), so named because of its ability to "arrest" rhodopsin signaling in the retina (2). There are two ␤arr isoforms, ␤-arrestin1 and ␤-arrestin2 (also denoted as arrestin-2 and arrestin-3, respectively). Both are expressed ubiquitously and share 78% sequence homology (3). ␤arrs are highly conserved across species, with ϳ50% sequence homology between vertebrates and invertebrates. The other arrestins are expressed in the eye: arrestin-1 (visual arrestin) and arrestin-4 (cone arrestin) (4). There are other proteins, termed ␣-arrestins or arrestin domain-containing proteins, that share the arrestin structural fold and are involved in receptor endocytosis, although the full breadth of their functions is still emerging (5). Similar to arrestin's function in the visual system, ␤arrs were first identified for their capacity to desensitize ␤2 adrenergic receptor (␤2AR) G protein signaling following agonist stimulation (1). Through a number of investigations, it became apparent that the two ␤arr isoforms shared the capability to interact with activated GPCRs, but that they differed in terms of their expression patterns, their specificity for different GPCRs, and their functional effects (6). We now appreciate that the ␤arrs regulate a diverse array of cellular processes including MAPK signaling, receptor transactivation, receptor trafficking, and transcriptional regulation in addition to the canonical roles of GPCR desensitization and internalization (7,8). These studies have revealed the current spectrum of ␤arr-mediated cell processes downstream of GPCRs (Fig. 1). Distinct and Overlapping Roles for the ␤arrs␤arr1 and ␤arr2 knockouts are phenotypically normal and produce viable progeny, but these mice display abnormal responses to physiologic stresses (9, 10). This suggests a compensatory ability for each isoform. Nevertheless, important differences between ␤arr isoforms are present (11). Although both accumulate in the cytoplasm following overexpression, ␤arr1, but not...

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