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BibTex format

@article{Lucey:2021:10.1124/molpharm.121.000270,
author = {Lucey, M and Ashik, T and Marzook, A and Wang, Y and Goulding, J and Oishi, A and Broichhagen, J and Hodson, D and Minnion, J and Elani, Y and Jockers, R and Briddon, S and Bloom, S and Tomas, A and Jones, B},
doi = {10.1124/molpharm.121.000270},
journal = {Molecular Pharmacology},
pages = {319--334},
title = {Acylation of the incretin peptide exendin-4 directly impacts GLP-1 receptor signalling and trafficking},
url = {http://dx.doi.org/10.1124/molpharm.121.000270},
volume = {100},
year = {2021}
}

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TY  - JOUR
AB  - 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 desensitisation 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 cyclic adenosine monophosphate (cAMP). Here we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analogue, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and β-arrestins, endocytic and post-endocytic 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 towards G protein recruitment and a ~60% reduction in β-arrestin-2 recruitment efficacy compared to exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting towards 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.
AU  - Lucey,M
AU  - Ashik,T
AU  - Marzook,A
AU  - Wang,Y
AU  - Goulding,J
AU  - Oishi,A
AU  - Broichhagen,J
AU  - Hodson,D
AU  - Minnion,J
AU  - Elani,Y
AU  - Jockers,R
AU  - Briddon,S
AU  - Bloom,S
AU  - Tomas,A
AU  - Jones,B
DO  - 10.1124/molpharm.121.000270
EP  - 334
PY  - 2021///
SN  - 0026-895X
SP  - 319
TI  - Acylation of the incretin peptide exendin-4 directly impacts GLP-1 receptor signalling and trafficking
T2  - Molecular Pharmacology
UR  - http://dx.doi.org/10.1124/molpharm.121.000270
UR  - http://hdl.handle.net/10044/1/90656
VL  - 100
ER  -

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Professor Sir Steve Bloom FMedSci, FRS

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