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• W3185156700 endingPage "334" @default.
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• W3185156700 abstract "The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitization and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cAMP. Here, we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analog, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and β-arrestins, endocytic and postendocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency, but exendin-4-C16 showed ∼2.5-fold bias toward G protein recruitment and a ∼60% reduction in β-arrestin-2 recruitment efficacy compared with exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting toward recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach and a ∼70% increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology. SIGNIFICANCE STATEMENT: Acylation is a common strategy to enhance the pharmacokinetics of peptide-based drugs. This work shows how acylation can also affect various other pharmacological parameters, including biased agonism, receptor trafficking, and interactions with the plasma membrane, which may be therapeutically important." @default.
• W3185156700 created "2021-08-02" @default.
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• W3185156700 date "2021-07-27" @default.
• W3185156700 modified "2023-10-11" @default.
• W3185156700 title "Acylation of the Incretin Peptide Exendin-4 Directly Impacts Glucagon-Like Peptide-1 Receptor Signaling and Trafficking" @default.
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• W3185156700 cites W159020113 @default.
• W3185156700 cites W1963136808 @default.
• W3185156700 cites W1976676978 @default.
• W3185156700 cites W1987856394 @default.
• W3185156700 cites W1995694102 @default.
• W3185156700 cites W1996106696 @default.
• W3185156700 cites W1997514666 @default.
• W3185156700 cites W2006036698 @default.
• W3185156700 cites W2006523830 @default.
• W3185156700 cites W2012838605 @default.
• W3185156700 cites W2013591171 @default.
• W3185156700 cites W2023779179 @default.
• W3185156700 cites W2033468763 @default.
• W3185156700 cites W2036683613 @default.
• W3185156700 cites W2049253479 @default.
• W3185156700 cites W2082908456 @default.
• W3185156700 cites W2101613382 @default.
• W3185156700 cites W2119126373 @default.
• W3185156700 cites W2125678640 @default.
• W3185156700 cites W2129215906 @default.
• W3185156700 cites W2133533488 @default.
• W3185156700 cites W2139923324 @default.
• W3185156700 cites W2144799280 @default.
• W3185156700 cites W2153134360 @default.
• W3185156700 cites W2162140339 @default.
• W3185156700 cites W2162422341 @default.
• W3185156700 cites W2184364461 @default.
• W3185156700 cites W2186153196 @default.
• W3185156700 cites W2226712470 @default.
• W3185156700 cites W2303462194 @default.
• W3185156700 cites W2319292032 @default.
• W3185156700 cites W2395914593 @default.
• W3185156700 cites W2464207063 @default.
• W3185156700 cites W2513698079 @default.
• W3185156700 cites W2519031788 @default.
• W3185156700 cites W2524451022 @default.
• W3185156700 cites W2568027424 @default.
• W3185156700 cites W2593841038 @default.
• W3185156700 cites W2606932135 @default.
• W3185156700 cites W2622865236 @default.
• W3185156700 cites W2718966341 @default.
• W3185156700 cites W2743448525 @default.
• W3185156700 cites W2767430428 @default.
• W3185156700 cites W2790939152 @default.
• W3185156700 cites W2791419854 @default.
• W3185156700 cites W2791680789 @default.
• W3185156700 cites W2800843957 @default.
• W3185156700 cites W2800926943 @default.
• W3185156700 cites W2890949658 @default.
• W3185156700 cites W2923923573 @default.
• W3185156700 cites W2924479779 @default.
• W3185156700 cites W2924586952 @default.
• W3185156700 cites W2946861851 @default.
• W3185156700 cites W2969232909 @default.
• W3185156700 cites W2969637142 @default.
• W3185156700 cites W2973135310 @default.
• W3185156700 cites W2996306092 @default.
• W3185156700 cites W3000083217 @default.
• W3185156700 cites W3002178166 @default.
• W3185156700 cites W3009892545 @default.
• W3185156700 cites W3012148265 @default.
• W3185156700 cites W3016119493 @default.
• W3185156700 cites W3022812876 @default.
• W3185156700 cites W3026891472 @default.
• W3185156700 cites W3041386761 @default.
• W3185156700 cites W3045729180 @default.
• W3185156700 cites W3100966455 @default.
• W3185156700 cites W3127014820 @default.
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• W3185156700 doi "https://doi.org/10.1124/molpharm.121.000270" @default.
• W3185156700 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8626645" @default.
• W3185156700 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34315812" @default.
• W3185156700 hasPublicationYear "2021" @default.
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