Theglucagon-like peptide-1 receptor (GLP1R) is aG protein-coupled receptor (GPCR) found onbeta cells of the pancreas and onneurons of the brain. It is involved in the control ofblood sugar level by enhancing insulin secretion. In humans it is synthesised by thegeneGLP1R, which is present onchromosome 6.[5][6] It is a member of theglucagon receptor family of GPCRs.[7] GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1,[8] and one transmembrane domain (TMD)[9] that binds the N-terminal region of GLP-1.[10][11][12] In the TMD domain a fulcrum of polar residues regulates the biased signaling of the receptor[10] while the transmembrane helical boundaries[13] and extracellular surface are a trigger for biased agonism.[11]
Structure of GLP1R-G protein complex bound totirzepatide. Based on PDB entry7RGP. Tirzepatide shown in red, GLP1R shown in green,G alpha subunit shown in white,G beta-gamma complex shown in dark gray.
The GLP-1 receptor is atransmembrane protein composed of seven alpha-helical transmembrane domains (TM1-TM7), an extracellular N-terminus, and an intracellular C-terminus. It belongs to the class B family ofG protein-coupled receptors, also known as secretin-like receptors. The extracellular N-terminus contains key regions involved in ligand recognition and binding. It undergoesconformational changes upon ligand binding, leading to activation of intracellularsignaling cascades. The intracellular C-terminus interacts withG proteins and other signaling molecules to initiate cellular responses.
Glucagon-like peptide-1 (GLP-1) is a hormone consisting of 30 amino acids. GLP-1 is released by intestinalL cells when nutrients are consumed. GLP1R is expressed onbeta cells in thepancreas. Binding of GLP-1 to GLP1R has multiple effects, including enhancinginsulin secretion from pancreatic beta cells in response toglucose, increasing insulin expression, preventing beta-cell apoptosis, promoting the formation of new beta cells, reducing glucagon secretion, slowing down stomach emptying, promoting satiety, and improving glucose disposal in peripheral tissues.
GLP1R is also expressed in the brain[18] where it is involved in the control ofappetite.[19]
Upon binding to its ligand GLP-1, the GLP-1 receptor activatesintracellular signaling pathways that regulate insulin secretion, glucose metabolism, and satiety.
In pancreaticbeta cells, GLP-1 receptor activation enhances glucose-stimulatedinsulin secretion. This occurs through the activation ofadenylyl cyclase, leading to increased intracellular levels ofcyclic AMP (cAMP). The rise in cAMP activatesprotein kinase A (PKA), which promotes insulin exocytosis and enhances beta cell survival and proliferation.GLP-1 receptor signaling in pancreatic alpha cells reducesglucagon secretion, further contributing to glucose lowering.
Activation of GLP-1 receptor delays the rate at which the stomach empties, leading to increased satiety and feeling of fullness.
Activation of the GLP-1 receptor in the brain promotes feelings of satiety.[19]
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^O'Brien A, Andrews S, Baig AH, Bortolato A, Brown JH, Brown GA, et al. (2019-08-09). "Identification of a novel allosteric GLP–1R antagonist HTL26119 using structure-based drug design".Bioorganic & Medicinal Chemistry Letters.29 (20): 126611.doi:10.1016/j.bmcl.2019.08.015.PMID31447084.S2CID201749908.
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Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C (November 1993). "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.42 (11):1678–82.doi:10.2337/diabetes.42.11.1678.PMID8405712.
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Bazarsuren A, Grauschopf U, Wozny M, Reusch D, Hoffmann E, Schaefer W, et al. (May 2002). "In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor".Biophysical Chemistry.96 (2–3):305–18.doi:10.1016/S0301-4622(02)00023-6.PMID12034449.
"Glucagon Receptor Family: GLP-1".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2016-03-03. Retrieved2007-10-25.
