What is GLP-1 receptor?
Also called: GLP-1R, Glucagon-like peptide-1 receptor, GLP1R
The class B G protein-coupled receptor activated by glucagon-like peptide-1; it signals mainly through Gαs and cAMP and is the target of semaglutide and other incretin analogues.
By the APL Research Team · Updated
The GLP-1 receptor (GLP-1R) is the cell-surface receptor for glucagon-like peptide-1, a hormone cut from proglucagon and secreted by intestinal L cells. It was cloned in 1992 from a rat pancreatic islet library: a 463-residue protein with seven transmembrane helices that bound GLP-1 with high affinity, activated adenylate cyclase, and ignored glucagon, GIP, VIP and secretin [1]. Its closest relatives are the receptors for secretin, calcitonin and parathyroid hormone, which together make up class B (the secretin family) of G protein-coupled receptors [1].
Structure and signalling
Class B receptors bind their peptide ligands in two places. In the 2017 cryo-EM structure of the activated receptor, GLP-1 is clasped between the large N-terminal extracellular domain and the transmembrane core, and binding bends transmembrane helix 6 outward to make room for the stimulatory G protein, Gαs [2]. Gαs activation raises cAMP, which in β-cells acts through protein kinase A and Epac2. Physiological roles attributed to the receptor include glucose-dependent insulin secretion, slower gastric emptying and reduced food intake [3]. The activated receptor also recruits β-arrestins and internalises, and ligands differ in how strongly they drive each branch: tirzepatide, for example, favours cAMP over β-arrestin recruitment at GLP-1R in cell assays [4].
Where it is expressed
A validated monoclonal antibody, with results confirmed by in situ binding of radiolabelled GLP-1, mapped the receptor in human and monkey tissue [5]:
| Tissue | Cells expressing GLP-1R |
|---|---|
| Pancreas | Mainly β-cells; weaker in acinar cells; absent from ducts |
| Kidney and lung | Smooth muscle of arteries and arterioles only |
| Heart | Myocytes of the sinoatrial node |
| Gut | Highest in duodenal Brunner's glands; also gastric parietal cells, smooth muscle and myenteric neurons |
| Liver, thyroid | Not detected |
Ligands used in research
| Ligand | Type | Research note |
|---|---|---|
| GLP-1(7-36)amide | Endogenous agonist | Cleaved by dipeptidyl peptidase-4 in human plasma in vitro, half-life 20.4 min at 37 °C [6] |
| GLP-1(9-36)amide | DPP-4 metabolite | Identified by HPLC and mass spectrometry as a major circulating form [6] |
| Exendin-4 | Agonist | From the venom of the lizard Heloderma suspectum; raises cAMP at the human receptor [7] |
| Exendin(9-39) | Antagonist | Blocks GLP-1-induced cAMP production [7] |
| Semaglutide | Acylated analogue | Aib8 and Arg34 substitutions plus a fatty acid on Lys26 for albumin binding [8] |
| Retatrutide | Triple agonist | Also activates GIP and glucagon receptors [9] |
Exendin(9-39) is the standard tool for showing that an effect runs through GLP-1R; the GIP receptor and glucagon receptor are the usual counter-screens because they share the class B architecture.
Points of confusion
- "GLP-1" versus "GLP-1R agonist". The native hormone is itself an agonist, but in the literature the phrase usually means a stabilised analogue. See receptor agonist for how potency and bias are compared.
- Species matter. The human receptor is about 90% identical to the rat receptor and bound GLP-1 with a Kd of 0.5 nM in transfected fibroblasts, where GLP-1 raised cAMP with an EC50 of 93 pM [7]; rodent data do not transfer automatically.
- Native GLP-1 is short-lived. Its rapid DPP-4 cleavage is why semaglutide carries Aib at position 8, alongside a fatty acid that extends half-life through albumin binding [6, 8].
How peptide half-life is measured and extended is covered in the peptide half-life guide, and assay layout for potency comparisons in the concentration–response design guide.
References
- 1.Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A. 1992. PubMed 1326760
- 2.Zhang Y, Sun B, Feng D, et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature. 2017. PubMed 28538729
- 3.Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019. PubMed 31767182
- 4.Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020. PubMed 32730231
- 5.Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014. PubMed 24467746
- 6.Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995. PubMed 7883856
- 7.Thorens B, Porret A, Bühler L, et al. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor. Diabetes. 1993. PubMed 8405712
- 8.Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015. PubMed 26308095
- 9.Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022. PubMed 35985340