GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats

Velden, Wijnand J C van der; Smit, Florent Xavier; Christiansen, C.; Møller, Thor C.; Hjortø, Gertrud Malene; Larsen, Olav; Schiellerup, Sine; Bräuner‐Osborne, Hans; Holst, Jens J.; Hartmann, Bolette; Frimurer, Thomas M.; Rosenkilde, Mette M.

doi:10.1021/acsptsci.0c00193

Cited by 25 publications

(24 citation statements)

References 82 publications

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“…The β-arrestin 1/2 recruitment assay was performed as described ( 17 ). Briefly, the bioluminescence resonance energy transfer assay was conducted by washing the cells with 2 ml PBS followed by resuspension in 2 ml PBS + 1% glucose (0.5 M).…”

Section: Methodsmentioning

confidence: 99%

“…The β-arrestin 1/2 recruitment assay was performed as previously described (17). Briefly, the BRET assay was conducted by washing the cells with 2 ml PBS followed by a resuspension in 2 ml PBS + 1% glucose J o u r n a l P r e -p r o o f 19 (0.5M).…”

Section: Bioluminescence Resonance Energy Transfer (Bret) β-Arrestin 1/2 Recruitment Assaymentioning

confidence: 99%

“…Another common phenomenon for class B1 receptors is their maintained but low potent β-arrestin recruitment as opposed to their high potency in G protein coupling ( 17 , 18 ). β-Arrestins bind sterically to the receptor, thereby hampering the receptor–G protein interaction and the subsequent (agonist-mediated) G protein signaling.…”

mentioning

confidence: 99%

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Molecular and in vivo phenotyping of missense variants of the human glucagon receptor

Velden

Lindquist

Madsen

et al. 2022

Journal of Biological Chemistry

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Naturally occurring missense variants of G protein–coupled receptors with loss of function have been linked to metabolic disease in case studies and in animal experiments. The glucagon receptor, one such G protein–coupled receptor, is involved in maintaining blood glucose and amino acid homeostasis; however, loss-of-function mutations of this receptor have not been systematically characterized. Here, we observed fewer glucagon receptor missense variants than expected, as well as lower allele diversity and fewer variants with trait associations as compared with other class B1 receptors. We performed molecular pharmacological phenotyping of 38 missense variants located in the receptor extracellular domain, at the glucagon interface, or with previously suggested clinical implications. These variants were characterized in terms of cAMP accumulation to assess glucagon-induced Gα s coupling, and of recruitment of β-arrestin-1/2. Fifteen variants were impaired in at least one of these downstream functions, with six variants affected in both cAMP accumulation and β-arrestin-1/2 recruitment. For the eight variants with decreased Gα s signaling (D63 ECD N, P86 ECD S, V96 ECD E, G125 ECD C, R225 3.30 H, R308 5.40 W, V368 6.59 M, and R378 7.35 C) binding experiments revealed preserved glucagon affinity, although with significantly reduced binding capacity. Finally, using the UK Biobank, we found that variants with wildtype-like Gα s signaling did not associate with metabolic phenotypes, whereas carriers of cAMP accumulation-impairing variants displayed a tendency toward increased risk of obesity and increased body mass and blood pressure. These observations are in line with the essential role of the glucagon system in metabolism and support that Gα s is the main signaling pathway effecting the physiological roles of the glucagon receptor.

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Section: Methodsmentioning

confidence: 99%

Section: Bioluminescence Resonance Energy Transfer (Bret) β-Arrestin 1/2 Recruitment Assaymentioning

confidence: 99%

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Molecular and in vivo phenotyping of missense variants of the human glucagon receptor

Velden

Lindquist

Madsen

et al. 2022

Journal of Biological Chemistry

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“…In other words, RMSF is a metric that reflects the atom mobility of each residue. In a study by van der Velden et al, the authors were able to find a correlation between the RMSF of the extracellular domain (ECD) and the (un)biased signaling profile for the GLP-1 receptor [ 23 ]. Therefore, the GLP-1 receptor showed markedly lower RMSF when bound to the endogenous GLP-1 peptide, which elicits an unbiased signaling response.…”

Section: Detection Of Allosteric Network In Gpcr Signalingmentioning

confidence: 99%

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Morales-Pastor¹,

Nerín-Fonz²,

Aranda-García³

et al. 2022

IJMS

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Signaling bias is a promising characteristic of G protein-coupled receptors (GPCRs) as it provides the opportunity to develop more efficacious and safer drugs. This is because biased ligands can avoid the activation of pathways linked to side effects whilst still producing the desired therapeutic effect. In this respect, a deeper understanding of receptor dynamics and implicated allosteric communication networks in signaling bias can accelerate the research on novel biased drug candidates. In this review, we aim to provide an overview of computational methods and techniques for studying allosteric communication and signaling bias in GPCRs. This includes (i) the detection of allosteric communication networks and (ii) the application of network theory for extracting relevant information pipelines and highly communicated sites in GPCRs. We focus on the most recent research and highlight structural insights obtained based on the framework of allosteric communication networks and network theory for GPCR signaling bias.

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“…The selection medium was refreshed every 4–5 days until approximately 60% confluence was reached. The expression of the receptor in each clone was assessed using the DiscoverX cAMP accumulation assay [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Induced Human Regulatory T Cells Express the Glucagon-like Peptide-1 Receptor

Rode

Buus

Mraz

et al. 2022

Cells

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The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans.

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GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats

Cited by 25 publications

References 82 publications

Molecular and in vivo phenotyping of missense variants of the human glucagon receptor

Molecular and in vivo phenotyping of missense variants of the human glucagon receptor

In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias

Induced Human Regulatory T Cells Express the Glucagon-like Peptide-1 Receptor

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