β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells

Sonoda, Noriyuki; Imamura, Teruhiko; Yoshizaki, Takeshi; Babendure, Jennie L.; Lu, Juu Chin; Olefsky, Jerrold M.

doi:10.1073/pnas.0710402105

Cited by 195 publications

(225 citation statements)

References 39 publications

(58 reference statements)

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“…These studies demonstrated that mice deficient in either ␤-arrestin isoform appear normal but that, in the presence of various pathological challenges, these mice display phenotypes associated with related disorders, suggesting a link between ␤-arrestin malfunction and a predisposition toward many complex diseases. Combined with previous studies (11,27,28), our work establishes that ␤-arrestin-1 and ␤-arrestin-2 critically regulate whole-body metabolic reactions and energy balance in a distinct but coordinate manner. A deficiency in either ␤-arrestin isoform contributes to the pathogenesis of metabolic disorders, including obesity, insulin resistance, and diabetes.…”

Section: Discussionsupporting

confidence: 75%

“…We found significant differences between the genotypes, indicating that the regulation of adipogenesis and the inflammatory response by ␤-arrestin-1 may be an underlying mechanism. Previous studies have shown that ␤-arrestin-1 mediates glucagon-like peptide-1 signaling, which induces insulin secretion in cultured ␤-cells (27). We have demonstrated here that insulin sensitivity is maintained in HFD-fed ␤arr1-tg mice compared with HFD-fed wild-type littermate control mice.…”

Section: Discussionsupporting

confidence: 52%

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β-Arrestin-1 Protein Represses Diet-induced Obesity

Zhuang

Zhang

et al. 2011

Journal of Biological Chemistry

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Diet-related obesity is a major metabolic disorder. Excessive fat mass is associated with type 2 diabetes, hepatic steatosis, and arteriosclerosis. Dysregulation of lipid metabolism and adipose tissue function contributes to diet-induced obesity. Here, we report that ␤-arrestin-1 knock-out mice are susceptible to dietinduced obesity. Knock-out of the gene encoding ␤-arrestin-1 caused increased fat mass accumulation and decreased wholebody insulin sensitivity in mice fed a high-fat diet. In ␤-arrestin-1 knock-out mice, we observed disrupted food intake and energy expenditure and increased macrophage infiltration in white adipose tissue. At the molecular level, ␤-arrestin-1 deficiency affected the expression of many lipid metabolic genes and inflammatory genes in adipose tissue. Consistently, transgenic overexpression of ␤-arrestin-1 repressed diet-induced obesity and improved glucose tolerance and systemic insulin sensitivity. Thus, our findings reveal that ␤-arrestin-1 plays a role in metabolism regulation.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 52%

β-Arrestin-1 Protein Represses Diet-induced Obesity

Zhuang

Zhang

et al. 2011

Journal of Biological Chemistry

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“…However, this is not the case for coupling to ERK1/2 phosphorylation. The GLP-1R has been shown to signal downstream of coupling to Gs, Gi/o, and Gq proteins as well as β-arrestins (33,37), with at least part of the intracellular calcium signal being Gi dependent (38) and at least part of the pERK response dependent on β-arrestin (37). It is likely that the disruption to dimerization seen in the current study differentially alters the coupling efficiency of the receptor to these different effectors.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

Harikumar

Wootten

Pinon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The glucagon-like peptide-1 receptor (GLP-1R) is a family B G proteincoupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent highaffinity binding to GLP-1(7-36)NH 2 but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.allosteric modulation | biased signaling | G protein-coupled receptors | family B GPCRs G protein-coupled receptors (GPCRs) are the largest superfamily of cell surface proteins and play crucial roles in virtually every physiological process. Their widespread abundance, yet selective distribution, and ability to couple to a variety of signaling and effector systems make them extremely attractive targets for drug development (1). Recently, there has been increasing interest in the stoichiometry of receptors involved in GPCR signaling complexes and how this may impact on receptor function and drug discovery (2-4).With the exception of family C GPCRs, where obligate dimerization can occur (4), the role of oligomerization in GPCR function has remained controversial (2-8), and this has been the subject of a number of recent reviews (9-11). Although there is an increasing body of evidence supporting dimerization of GPCRs as a widespread feature of GPCR biology, including numerous studies on family A GPCRs, whether these are stable, transient, constitutive, or ligand dependent, and how they impact on receptor function and drug discovery are less clear, and general rules for oligomeric behavior are not evident (9-16). Even where effects on signaling are studied, these are generally linked to a single pathway and the role of dimerization in the control of receptor engagement and preference for distinct intracellular signaling intermediates (i.e., signal bias) is virtually unstudied.For family B GPCRs, which encompass many ther...

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“…The emphasis of a favorable cellular signal, such as b-arrestin-2 activation for parathyroid agonists in osteoporosis (Ferrari et al, 2005;Gesty-Palmer et al, 2006) and b-arrestin-1 activation for glucagon-like peptide 1 (GLP-1) effect in diabetes (Sonoda et al, 2008). 2.…”

Section: Therapeutic Applications Of Signaling Biasmentioning

confidence: 99%

The Effective Application of Biased Signaling to New Drug Discovery

Kenakin

2015

Mol Pharmacol

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The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions.

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β-Arrestin-1 mediates glucagon-like peptide-1 signaling to insulin secretion in cultured pancreatic β cells

Cited by 195 publications

References 39 publications

β-Arrestin-1 Protein Represses Diet-induced Obesity

β-Arrestin-1 Protein Represses Diet-induced Obesity

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

The Effective Application of Biased Signaling to New Drug Discovery

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