Glucagon-like peptide-1 receptor

Ligands

GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.

Agonists

• GLP-1 – endogenous in humans
• glucagon – endogenous in humans
• oxyntomodulin
• amycretin
• exendin-4
• exenatide
• lixisenatide
• albiglutide
• beinaglutide
• dulaglutide
• efpeglenatide
• langlenatide
• liraglutide
• polyethylene glycol/PEG- loxenatide
• semaglutide
• taspoglutide
• ecnoglutide
• utreglutide
• glepaglutide
• apraglutide
• maridebart cafraglutide
• tirzepatide
• pegapamodutide
• mazdutide
• survodutide
• bamadutide
• pemvidutide
• cotadutide
• retatrutide
• lithium chloride
• cinchonine
• grutalumab
• dapiglutide
• DA1726
• GX-G6
• GZR18
• HRS9531
• PB718
• RAY1225
• VCT220
• VK2735
• BLX7006 supaglutide/efsubaglutide
• ASC30
• danuglipron
• aleniglipron
• lotiglipron
• orforglipron
• CT-996
• CT-388
• CT-868
• HEC88473
• HS-10535
• UBT251
• efinopegdutide
• efocipegtrutide
• NNC9204-1706
• TG103
• YP05002/YP-05002

Antagonists:

• [9-39]-GLP-1
• T-0632
• GLP1R0017
• avexitide / exendin 9-39

Allosteric modulators:

• Positive:

  • BETP

• Negative:

  • HTL26119

Structure

The GLP-1 receptor is a transmembrane 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 of G protein-coupled receptors, also known as secretin-like receptors. The extracellular N-terminus contains key regions involved in ligand recognition and binding. It undergoes conformational changes upon ligand binding, leading to activation of intracellular signaling cascades. The intracellular C-terminus interacts with G proteins and other signaling molecules to initiate cellular responses.

Function

Glucagon-like peptide-1 (GLP-1) is a hormone consisting of 30 amino acids. GLP-1 is released by intestinal L cells when nutrients are consumed. GLP1R is expressed on beta cells in the pancreas. Binding of GLP-1 to GLP1R has multiple effects, including enhancing insulin secretion from pancreatic beta cells in response to glucose, 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 where it is involved in the control of appetite.

Mechanism of action

Upon binding to its ligand GLP-1, the GLP-1 receptor activates intracellular signaling pathways that regulate insulin secretion, glucose metabolism, and satiety.

In pancreatic beta cells, GLP-1 receptor activation enhances glucose-stimulated insulin secretion. This occurs through the activation of adenylyl cyclase, leading to increased intracellular levels of cyclic AMP (cAMP). The rise in cAMP activates protein kinase A (PKA), which promotes insulin exocytosis and enhances beta cell survival and proliferation. GLP-1 receptor signaling in pancreatic alpha cells reduces glucagon 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.

Clinical significance

Main article: GLP-1 receptor agonist

GLP-1 receptor agonists are a class of medications that mimic the actions of the endogenous incretin hormone GLP-1, and are used in type 2 diabetes and obesity.

References

References

1. (September 1992). "Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1". Proceedings of the National Academy of Sciences of the United States of America.
2. (October 1993). "Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor". Endocrinology.
3. (2002). "Structure-function of the glucagon receptor family of G protein-coupled receptors, coupled to: the glucagon, GIP, GLP-1, and GLP-2 receptors". Receptors & Channels.
4. (January 2010). "Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor". The Journal of Biological Chemistry.
5. (June 2017). "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators". Nature.
6. (March 2016). "A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures". Molecular Pharmacology.
7. (June 2016). "The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism". Cell.
8. (June 2016). "Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP1R)". The Journal of Biological Chemistry.
9. (October 2016). "Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor". Biochemical Pharmacology.
10. "GLP-1 receptor". International Union of Basic and Clinical Pharmacology.
11. (April 2017). "Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP1R)". The Journal of Biological Chemistry.
12. (March 2018). "Development and characterisation of a novel glucagon like peptide-1 receptor antibody". Diabetologia.
13. (2019-08-09). "Identification of a novel allosteric GLP–1R antagonist HTL26119 using structure-based drug design". Bioorganic & Medicinal Chemistry Letters.
14. (October 2015). "Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain". Molecular Metabolism.
15. (December 2002). "The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness". The Journal of Neuroscience.