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 geneGLP1R, 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]
GLP1R is known to be expressed in pancreaticbeta 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]
↑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. PMID28514449.
↑ 10.010.110.210.310.410.510.610.7Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
↑Holst JJ (May 2004). "Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors". Expert Opin Emerg Drugs. 9 (1): 155–66. doi:10.1517/eoed.9.1.155.32952. PMID15155141.
van Eyll B, Lankat-Buttgereit B, Bode HP, et al. (1994). "Signal transduction of the GLP-1-receptor cloned from a human insulinoma". FEBS Lett. 348 (1): 7–13. doi:10.1016/0014-5793(94)00553-2. PMID7517895.
Gromada J, Rorsman P, Dissing S, Wulff BS (1995). "Stimulation of cloned human glucagon-like peptide 1 receptor expressed in HEK 293 cells induces cAMP-dependent activation of calcium-induced calcium release". FEBS Lett. 373 (2): 182–6. doi:10.1016/0014-5793(95)01070-U. PMID7589461.
Wei Y, Mojsov S (1995). "Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences". FEBS Lett. 358 (3): 219–24. doi:10.1016/0014-5793(94)01430-9. PMID7843404.
Lankat-Buttgereit B, Göke R, Stöckmann F, et al. (1994). "Detection of the human glucagon-like peptide 1(7-36) amide receptor on insulinoma-derived cell membranes". Digestion. 55 (1): 29–33. doi:10.1159/000201119. PMID8112494.
Graziano MP, Hey PJ, Borkowski D, et al. (1993). "Cloning and functional expression of a human glucagon-like peptide-1 receptor". Biochem. Biophys. Res. Commun. 196 (1): 141–6. doi:10.1006/bbrc.1993.2226. PMID8216285.
Stoffel M, Espinosa R, Le Beau MM, Bell GI (1993). "Human glucagon-like peptide-1 receptor gene. Localization to chromosome band 6p21 by fluorescence in situ hybridization and linkage of a highly polymorphic simple tandem repeat DNA polymorphism to other markers on chromosome 6". Diabetes. 42 (8): 1215–8. doi:10.2337/diabetes.42.8.1215. PMID8392011.
Dillon JS, Tanizawa Y, Wheeler MB, et al. (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. PMID8404634.
Thorens B, Porret A, Bühler L, et al. (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.
Lankat-Buttgereit B, Göke B (1997). "Cloning and characterization of the 5' flanking sequences (promoter region) of the human GLP-1 receptor gene". Peptides. 18 (5): 617–24. doi:10.1016/S0196-9781(97)00001-6. PMID9213353.
Xiao Q, Jeng W, Wheeler MB (2001). "Characterization of glucagon-like peptide-1 receptor-binding determinants". J. Mol. Endocrinol. 25 (3): 321–35. doi:10.1677/jme.0.0250321. PMID11116211.
Bazarsuren A, Grauschopf U, Wozny M, et al. (2003). "In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor". Biophys. Chem. 96 (2–3): 305–18. doi:10.1016/S0301-4622(02)00023-6. PMID12034449.
Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature. 425 (6960): 805–11. doi:10.1038/nature02055. PMID14574404.
Tokuyama Y, Matsui K, Egashira T, et al. (2005). "Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population". Diabetes Res. Clin. Pract. 66 (1): 63–9. doi:10.1016/j.diabres.2004.02.004. PMID15364163.
Jorgensen R, Martini L, Schwartz TW, Elling CE (2005). "Characterization of glucagon-like peptide-1 receptor beta-arrestin 2 interaction: a high-affinity receptor phenotype". Mol. Endocrinol. 19 (3): 812–23. doi:10.1210/me.2004-0312. PMID15528268.
Mahon MJ, Shimada M (2005). "Calmodulin interacts with the cytoplasmic tails of the parathyroid hormone 1 receptor and a sub-set of class b G-protein coupled receptors". FEBS Lett. 579 (3): 803–7. doi:10.1016/j.febslet.2004.12.056. PMID15670850.
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. PMID28514449.
External links
"Glucagon Receptor Family: GLP-1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.