Oxyntomodulin Differentially Affects Glucagon-Like Peptide-1 Receptor β-Arrestin Recruitment and Signaling through Gα

Jørgensen, Rasmus; Kubale, Valentina; Vrecl, Milka; Schwartz, Thue W.; Elling, Christian

doi:10.1124/jpet.107.120006

Cited by 118 publications

(127 citation statements)

References 40 publications

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“…Only molindone mediated a significant increase in the BRET signal with both the hD2 S and hD2 L receptors although the increase in the BRET signal was limited. Taken together these observations are perhaps somewhat surprising given the studies of a number of other receptors for which biased agonism towards β-arrestin2 recruitment has been observed (Azzi et al, 2003;Violin and Lefkowitz, 2007;Wisler et al, 2007;Jorgensen et al, 2007).We cannot rule out that the anti-psychotics stabilize a conformation of the hD2 S and hD2 L receptors that indeed is able to recruit β-arrestin2 but somehow inadequate for BRET to occur. This possibility is unlikely, however, because the long flexible linker used to separate hD2 S /hD2 L and Rluc8 would be expected to allow for detection of BRET independent on the actual receptor conformation.…”

Section: Discussionmentioning

confidence: 66%

“…To increase the sensitivity of the BRET assay and to confirm that clozapine was unable to recruit β-arrestin2 to hD2 S , we took advantage of a previously described double mutant in β-arrestin2(R393E,R395E) that has been reported to exhibit prolonged interaction with both class A and class B GPCRs (Vrecl et al, 2004;Jorgensen et al, 2007). Using β-arrestin2(R393E,R395E)-mVenus in our BRET experiments, we observed an approximately twofold increase in the BRET ratio induced by the full agonists.…”

Section: Agonist Induced Recruitment Of β-Arrestin2 To Hd2 S Charactementioning

confidence: 99%

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Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

et al. 2008

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Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through β-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human β-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying β-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating β-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced β-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most antipsychotics are incapable of stimulating β-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.

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Section: Discussionmentioning

confidence: 66%

Section: Agonist Induced Recruitment Of β-Arrestin2 To Hd2 S Charactementioning

confidence: 99%

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

et al. 2008

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“…The characteristics of this autoantibody not only help to explain the mechanisms underlying AHH but also support the existence of biased agonism in GPCR signaling. At about the same time, several other examples of biased agonism in GPCR systems were reported including oxyntomodulin for the GLP-1 receptor [24], aripiprazole for the D2 receptor [25], carvedilol for the β2 receptor [26].…”

Section: Two-state Versus Multi-state Modelmentioning

confidence: 99%

Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]

Makita

Iiri

2014

Endocr J

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Abstract. The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.

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“…Subsequently, PKA and EPAC increase protein phosphorylation and intracellular Ca 2+ concentration (Kieffer et al, 1999), causing increased synthesis and secretion of insulin by β-cells. Activated GLP1R is phosphorylated by GPCR kinase (GRK) and is internalized to the cytosol by binding to β-arrestin (Jorgensen et al, 2007). Receptor-bound β-arrestin induces Erk phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

Moon

Kim

Park

et al. 2011

Molecules and Cells

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion from pancreatic β-cells in a glucose-dependent manner. However, factors other than glucose that regulate the β-cell response to GLP-1 remain poorly understood. In this study, we examined the possible involvement of insulin and receptor tyrosine kinase signaling in regulation of the GLP-1 responsiveness of β-cells. Pretreatment of β-cells with HNMPA, an insulin receptor inhibitor, and AG1478, an epidermal growth factor receptor inhibitor, further increased the cAMP level and Erk phosphorylation in the presence of exendin-4 (exe-4), a GLP-1 agonist. When β-cells were exposed to a high concentration of glucose (25 mM), which stimulates insulin secretion, exe-4-induced cAMP formation declined gradually as exposure time was increased. This decreased cAMP formation was not observed in the presence of HNMPA. HNMPA was able to further increase the exe-4-induced insulin secretion when β-cells were exposed to high glucose for 18 h. Treatment of β-cells with insulin significantly decreased exe-4-induced cAMP formation in a dose-dependent manner. Lowering the phospho-Akt level by HNMPA or LY294002, a PI3K inhibitor, further augmented exe-4-induced cAMP formation and Erk phosphorylation. These results suggest that insulin contributes to fine-tuning of the β-cell response to GLP-1.

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Oxyntomodulin Differentially Affects Glucagon-Like Peptide-1 Receptor β-Arrestin Recruitment and Signaling through Gα

Cited by 118 publications

References 40 publications

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

Recruitment of β-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling

Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]

Insulin Contributes to Fine-Tuning of the Pancreatic Beta-Cell Response to Glucagon-Like Peptide-1

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