Glucagon-like peptide-1 receptor

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The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas. 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.[1][2] It is a member of the glucagon receptor family of G protein-coupled receptors.[3] GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1,[4] and one transmembrane (TMD) domain[5] that binds the N-terminal region of GLP-1.[6][7][8] In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor [6] while the transmembrane helical boundaries[9] and extracellular surface are a trigger for biased agonism.[7]

Human receptor ligands

GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.[10]

Receptor agonists:

Receptor antagonists:

Receptor positive allosteric modulators:

Function and therapeutic potential

GLP1R is known to be expressed in pancreatic beta cells. Activated GLP1R stimulates the adenylyl cyclase pathway which results in increased insulin synthesis and release of insulin.[13] Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes mellitus.[14] Exendin-4 is one of the peptides used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using genetically engineered amino acids.[11]

GLP1R is also expressed in the brain[15] where it is involved in the control of appetite.[16] Furthermore, mice that over express GLP1R display improved memory and learning.[17]

Stretch responsive vagal neurons in the stomach and intestines also express GLP1R.[18] GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation.[18]

Huntington's disease

The diabetic, pancreatic, and neuroprotection implications of GLP1R are also thought to be potential therapies for treating the diabetes and energy metabolism abnormalities associated with Huntington's disease affecting the brain and periphery. Exendin-4, an FDA-approved antidiabetic glucagon-like peptide 1 (GLP-1) receptor agonist, has been tested in mice with the mutated human huntingtin protein showing neurodegenerative changes, motor dysfunction, poor energy metabolism, and high blood glucose levels. Exendin-4 (Ex-4) treatment reduced the accumulation of mhtt protein aggregates, improved motor function, extended the survival time, improved glucose regulation, and decreased brain and pancreas pathology.[19]

Exendin-4 increases beta cell mass in the pancreatic islets to improve the release of insulin to ultimately increase glucose uptake. The mechanism regarding this insulin increase involves Ex-4 and GLP-1. When the islets in the pancreas are exposed to GLP-1, there is an increased expression of the anti-apoptotic gene bcl-2 and decreased expression of pro-apoptotic genes bax and caspase-3, which leads to greater cell survival. GLP-1 binding to its G protein-coupled receptor activates various different pathways including the growth factor receptor and is coupled to pathways stimulating mitogenesis. Some of these pathways include Rap, Erk1/2, MAPK, B-RAF, PI3-K, cAMP, PKA, and TORC2 that are activated to initiate exocytosis, proinsulin gene expression and translation, increase insulin biosynthesis, and genetically increase beta cell proliferation and neogenesis. The GLP-1R is a G protein-coupled receptor that is dependent on glucose and GLP-1 is a peptide hormone that acts directly on the beta cell to stimulate insulin secretion by activating signal transduction when glucose is present. When glucose is not present, this receptor no longer couples to stimulate insulin secretion in order to prevent hypoglycemia.[20]

Relating glucose metabolism and insulin sensitivity back to Huntington's disease, increased insulin release and beta cell proliferation by a GLP-1 agonist, Ex-4, helps combat the damage done by mutant htt in peripheral tissues. Htt aggregation decreases beta cell mass and thus impairs insulin release and increases blood glucose levels. Disruption of glycemic homeostasis then affects nutrient availability to neurons and alters neuron function contributing to neurodegeneration and motor problems seen in Huntington's disease. The health of the nervous system is related to metabolic health, thus a diabetes medication as a Huntington's disease treatment is a potential treatment. Ex-4 easily crosses the blood-brain barrier and GLP-1 and Ex-4 have been shown to act on neurons in the brain by exerting neuroprotective actions.[19]

In studies with Huntington's disease mice, daily treatments of Ex-4 significantly reduced glucose levels compared to those mice treated with saline. It also increased insulin sensitivity by about 50%, improved insulin-stimulated glucose uptake, and protect pancreatic beta cell function. Huntington's disease has also been linked to imbalances in leptin and ghrelin levels. Ex-4 restored ghrelin levels and also lowered leptin levels allowing Huntington's disease mice to eat more and counteract symptomatic weight loss. This treatment restored beta cell cells and islet structure, reduce mhtt aggregates in the brain and pancreas, and also improve motor function seen by the increased activity level of the mice. Improvements were found in the areas of the body that expressed GLP-1R. In addition to its other effects on the Huntington's disease mouse model, daily treatment of Ex-4, the GLP-1R agonist, significantly delayed the onset of mortality and extended the lifespan by approximately one month.[19]

See also


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  2. Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE III (October 1993). "Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor". Endocrinology. 133 (4): 1907–10. doi:10.1210/en.133.4.1907. PMID 8404634.
  3. Brubaker PL, Drucker DJ (2002). "Structure-function of the glucagon receptor family of the G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors" (PDF). Recept. Channels. 8 (3–4): 179–88. doi:10.1080/10606820213687. PMID 12529935. Retrieved 2008-07-14.
  4. Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S (June 2010). "Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor". Journal of Biological Chemistry. 285 (1): 723–730. doi:10.1074/jbc.M109.033829. PMC 2804221. PMID 19861722.
  5. Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S, Liu K, Cai X, Dai A, Lin G, Liu D, Wu F, Wu Y, Zhao S, Ye L, Han GW, Lau J, Wu B, Hanson MA, Liu ZJ, Wang MW, Stevens RC (2017). "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators)". Nature. 546 (7657): 312–315. doi:10.1038/nature22378. PMID 28514449.
  6. 6.0 6.1 Wooten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopolous A, Sexton PM (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): 335–347. doi:10.1124/mol.115.101246. PMC 4767408. PMID 26700562.
  7. 7.0 7.1 Wooten D, Reynolds CA, Smith KJ, Mobarec JC, Koole C, Savage EE, Pabreja K, Simms J, Sridhar R, Furness SG, Liu M, Thompson PE, Miller LJ, Christopolous A, Sexton PM (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.
  8. Yang D, de Graaf C, Yang L, Song G, Dai A, Cai X, Feng Y, Reedtz-Runge S, Hanson MA, Yang H, Jiang H, Stevens RC, Wang MW (June 2016). "Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)". Journal of Biological Chemistry. 291 (25): 12991–3004. doi:10.1074/jbc.M116.721977. PMC 4933217. PMID 27059958.
  9. Wooten D, Reynolds CA, Smith KJ, Mobarec JC, Furness SG, Miller LJ, Christopolous A, Sexton PM (August 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.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
  11. 11.0 11.1 Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP (March 2017). "Genetically-Encoded Photocrosslinkers Determine the Biological Binding Site of Exendin-4 in the N-Terminal Domain of the Intact Human Glucagon-Like Peptide-1 Receptor (GLP-1R)". Journal of Biological Chemistry. 292 (17): 7131–7144. doi:10.1074/jbc.M117.779496. PMC 5409479. PMID 28283573.
  12. Biggs EK, Liang L, Naylor J, Madalli S, Collier R, Coghlan MP, Baker DJ, Hornigold DC, Ravn P, Reimann F, Gribble FM (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.
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  16. Kinzig KP, D'Alessio DA, Seeley RJ (1 December 2002). "The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness". J. Neurosci. 22 (23): 10470–6. PMID 12451146.
  17. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN (September 2003). "Glucagon-like peptide-1 receptor is involved in learning and neuroprotection". Nat. Med. 9 (9): 1173–9. doi:10.1038/nm919. PMID 12925848.
  18. 18.0 18.1 Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD (June 2016). "Sensory Neurons that Detect Stretch and Nutrients in the Digestive System". Cell. 166 (1): 209–21. doi:10.1016/j.cell.2016.05.011. PMC 4930427. PMID 27238020.
  19. 19.0 19.1 19.2 Martin B, Golden E, Carlson OD, Pistell P, Zhou J, Kim W, Frank BP, Thomas S, Chadwick WA, Greig NH, Bates GP, Sathasivam K, Bernier M, Maudsley S, Mattson MP, Egan JM (February 2009). "Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease". Diabetes. 58 (2): 318–28. doi:10.2337/db08-0799. PMC 2628604. PMID 18984744.
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Further reading

External links