Key Metabolic Functions of β-Arrestins: Studies with Novel Mouse Models

Abstract

β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate cellular functions in a G protein-independent fashion. During the past few years, studies with mutant mice selectivity lacking β-arrestin-1 and/or -2 in metabolically important cell types have led to novel insights into the mechanisms through which β-arrestins regulate key metabolic processes in vivo, including whole-body glucose and energy homeostasis. The novel information gained from these studies should inform the development of novel drugs, including β-arrestin- or G protein-biased GPCR ligands, that could prove useful for the therapy of several important pathophysiological conditions, including type 2 diabetes and obesity.

Keywords: G protein-coupled receptors; diabetes; metabolism; mutant mice; obesity; β-arrestins.

Figure 1.

Canonical and non-canonical functions of β-arrestins.

Figure 2.

Canonical functions of βarr2 in mouse adipocytes and hepatocytes. A) Adipocytes. In white adipocytes from wild type mice, βarr2 is involved in terminating β3-AR signaling by interacting with activated β3-ARs and promoting receptor internalization. In white adipocytes lacking βarr2, this inhibitory regulation of β3-AR function is absent, resulting in enhanced β3-AR-mediated cellular effects [34]. B) Hepatocytes. In hepatocytes from wild type mice, βarr2 acts as a negative regulator of glucagon receptor (GCGR) signaling. In βarr2-deficient hepatocytes, GCGR signaling is no longer subject to inhibition by βarr2, leading to enhanced glucose output [49]. AC, adenyl cyclase; FFA, free fatty acids; NE, norepinephrine; PKA; protein kinase A.

Figure 3.

Non-canonical functions of β-arrestins in mouse adipocytes, pancreatic β-cells, and AgRP neurons. A) Adipocytes. In brown adipocytes from wild type mice, βarr1 binding to the PPARγ/RXRα complex is predicted to prevent activation of the myostatin (Mstn) promoter [51] In the absence of βarr1, the PPARγ/RXRα complex can activate the Mstn promoter, leading to increased plasma Mstn levels which cause peripheral insulin resistance [51]. B) β-Cells. The left side of the cartoon shows that βarr2 is required for the proper function of CAMKII in β-cells. βarr2 is predicted to form a complex with CAMKII that stimulates CAMKII activity in β-cells [21]. Activated CAMKII stimulates insulin secretion via phosphorylation of various signaling proteins involved in insulin exocytosis and has been shown to facilitate glucose-dependent calcium influx by acting on VDCCs [89]. Impaired CAMKII activity can fully account for the metabolic impairments observed with beta-βarr2-KO mice [21]. The right side of the cartoon shows that β-cell βarr1 is required for the proper function of most sulphonylurea drugs (SUs). By binding to the SUR1 subunit of the β-cell ATP-gated K⁺ channel, SU drugs cause channel closure, triggering membrane depolarization, Ca²⁺ influx through VDCCs, and eventually insulin secretion. Most SUs also stimulate the formation of a βarr1/Epac2a complex, which promotes Rap1-mediated insulin secretion [22]. C) AgRP neurons. In AgRP neurons from wild type mice, insulin induces hyperpolarization and reduced firing frequency by activating a pathway that leads to the opening of K_ATP channels. In the absence of βarr1, insulin-mediated inhibition of AgRP neurons is abolished, most likely due to reduced stability of IRS1 (IRS1 is stabilized by βarr1 in wild type neurons) [83]. AC, adenylyl cyclase; DAG, diacylglycerol; ER, endoplasmic reticulum; IP3, inositol trisphosphate; IR, insulin receptor; IRS1, insulin receptor substrate 1; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-trisphosphate; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PPARγ, peroxisome proliferator-activated receptor γ; RXRα, retinoid X receptor α, VDCC, voltage-dependent calcium channel.