Acylation of the incretin peptide exendin-4 directly impacts glucagon-like peptide-1 receptor signaling and traffickings

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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 Cterminally acylated analog, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and b-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 b-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.

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Lucey, M., Ashik, T., Marzook, A., Wang, Y., Goulding, J., Oishi, A., … Jones, B. (2021). Acylation of the incretin peptide exendin-4 directly impacts glucagon-like peptide-1 receptor signaling and traffickings. Molecular Pharmacology, 100(4), 319–334. https://doi.org/10.1124/molpharm.121.000270

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