Glucagon-like peptide-1 receptor

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GLP1R
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGLP1R, glucagon-like peptide 1 receptor, GLP-1, GLP-1-R, GLP-1R, glucagon like peptide 1 receptor
External IDsOMIM: 138032; MGI: 99571; HomoloGene: 1558; GeneCards: GLP1R; OMA:GLP1R - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2740

14652

Ensembl

ENSG00000112164

ENSMUSG00000024027

UniProt

P43220

O35659

RefSeq (mRNA)

NM_002062

NM_021332

RefSeq (protein)

NP_002053

NP_067307

Location (UCSC)Chr 6: 39.05 – 39.09 MbChr 17: 31.12 – 31.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6.[5][6] It is a member of the glucagon 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]

Ligands

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GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.[14]

Agonists

See also: GLP-1 receptor agonist and Category:GLP-1 receptor agonists

Antagonists:

Allosteric modulators:

Structure

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Structure of GLP1R-G protein complex bound to tirzepatide. Based on PDB entry 7RGP. 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 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

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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[18] where it is involved in the control of appetite.[19]

Mechanism of action

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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.[19]

Clinical significance

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000112164 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024027 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Thorens B (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. 89 (18): 8641–5. Bibcode:1992PNAS...89.8641T. doi:10.1073/pnas.89.18.8641. PMC 49976. PMID 1326760.
  6. ^ Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, et al. (October 1993). "Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor". Endocrinology. 133 (4): 1907–10. doi:10.1210/endo.133.4.8404634. PMID 8404634.
  7. ^ Brubaker PL, Drucker DJ (2002). "Structure-function of the glucagon receptor family of G protein-coupled receptors, coupled to: the glucagon, GIP, GLP-1, and GLP-2 receptors" (PDF). Receptors & Channels. 8 (3–4): 179–88. doi:10.1080/10606820213687. PMID 12529935.
  8. ^ Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S (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. 285 (1): 723–30. doi:10.1074/jbc.M109.033829. PMC 2804221. PMID 19861722.
  9. ^ Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, et al. (June 2017). "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators". Nature. 546 (7657): 312–315. Bibcode:2017Natur.546..312S. doi:10.1038/nature22378. PMID 28514449. S2CID 2141649.
  10. ^ a b Wootten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, et al. (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. 89 (3): 335–47. doi:10.1124/mol.115.101246. PMC 4767408. PMID 26700562.
  11. ^ a b Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Koole C, Savage EE, et al. (June 2016). "The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism". Cell. 165 (7): 1632–1643. doi:10.1016/j.cell.2016.05.023. PMC 4912689. PMID 27315480.
  12. ^ Yang D, de Graaf C, Yang L, Song G, Dai A, Cai X, et al. (June 2016). "Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP1R)". The Journal of Biological Chemistry. 291 (25): 12991–3004. doi:10.1074/jbc.M116.721977. PMC 4933217. PMID 27059958.
  13. ^ Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Furness SG, Miller LJ, et al. (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. 118: 68–87. doi:10.1016/j.bcp.2016.08.015. PMC 5063953. PMID 27569426.
  14. ^ a b c d e f Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
  15. ^ Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP (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. 292 (17): 7131–7144. doi:10.1074/jbc.M117.779496. PMC 5409479. PMID 28283573.
  16. ^ Biggs EK, Liang L, Naylor J, Madalli S, Collier R, Coghlan MP, et al. (March 2018). "Development and characterisation of a novel glucagon like peptide-1 receptor antibody". Diabetologia. 61 (3): 711–721. doi:10.1007/s00125-017-4491-0. PMC 5890879. PMID 29119245.
  17. ^ 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. PMID 31447084. S2CID 201749908.
  18. ^ Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S (October 2015). "Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain". Molecular Metabolism. 4 (10): 718–31. doi:10.1016/j.molmet.2015.07.008. PMC 4588458. PMID 26500843.
  19. ^ a b Kinzig KP, D'Alessio DA, Seeley RJ (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. 22 (23): 10470–6. doi:10.1523/JNEUROSCI.22-23-10470.2002. PMC 6758755. PMID 12451146.

Further reading

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