Glucagon-like peptide 1 receptor

Last updated
GLP1R
Protein GLP1R PDB 3C59.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GLP1R , entrez:2740, glucagon-like peptide 1 receptor, GLP-1, GLP-1-R, GLP-1R, glucagon like peptide 1 receptor
External IDs MGI: 99571 HomoloGene: 1558 GeneCards: GLP1R
Gene location (Human)
Ideogram human chromosome 6.svg
Chr. Chromosome 6 (human) [1]
Human chromosome 6 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 6p21.2Start39,048,798 bp [1]
End39,087,743 bp [1]
RNA expression pattern
PBB GE GLP1R 208390 s at fs.png

PBB GE GLP1R 208391 s at fs.png

PBB GE GLP1R 208401 s at fs.png
More reference expression data
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 Mb Chr 17: 30.9 – 30.94 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] It is a member of the glucagon receptor family of G protein-coupled receptors. [7] GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, [8] and one transmembrane (TMD) domain [9] that binds the N-terminal region of GLP-1. [10] [11] [12] In the TMD domain there is fulcrum of polar residues that regulates the biased signaling of the receptor [10] while the transmembrane helical boundaries [13] and extracellular surface are a trigger for biased agonism. [11]

Receptor (biochemistry) protein molecule receiving signals for a cell

In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers, which bind to a receptor, they cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway. In this sense, a receptor is a protein-molecule that recognizes and responds to endogenous chemical signals. For example, an acetylcholine receptor recognizes and responds to its endogenous ligand, acetylcholine. However, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters, and ion channels.

Beta cells are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with type I or type II diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

Blood sugar level

The blood sugar level, blood sugar concentration, or blood glucose level is the amount of glucose present in the blood of humans and other animals. Glucose is a simple sugar and approximately 4 grams of glucose are present in the blood of a 70-kilogram (150 lb) human at all times. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. Glucose is stored in skeletal muscle and liver cells in the form of glycogen; in fasted individuals, blood glucose is maintained at a constant level at the expense of glycogen stores in the liver and skeletal muscle.

Contents

Human receptor ligands

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

Glucagon-like peptide-1 chemical compound

Glucagon-like peptide-1 (GLP-1) is a 31 amino acid long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 composes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

Receptor agonists:

Liraglutide pharmaceutical drug

Liraglutide, sold under the brand name Victoza among others, is a medication used to treat diabetes mellitus type 2 and obesity. In diabetes it is a less preferred agent. Its effect on long term health outcomes like heart disease and life expectancy are unclear. In obesity if after 12 weeks less than 5% of body weight is lost it is recommended the medication be stopped. It is give by injection under the skin.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist for the treatment of diabetes type II.

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. [17] Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes mellitus. [18] Exendin-4 is the peptide used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using genetically engineered amino acids. [15]

Pancreas glandular organ in the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach.

Adenylyl cyclase enzyme

Adenylyl cyclase is an enzyme with key regulatory roles in essentially all cells. It is the most polyphyletic known enzyme: six distinct classes have been described, all catalyzing the same reaction but representing unrelated gene families with no known sequence or structural homology. The best known class of adenylyl cyclases is class III or AC-III. AC-III occurs widely in eukaryotes and has important roles in many human tissues.

Insulin Hormone in vertebrates

Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of carbohydrates, especially glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

GLP1R is also expressed in the brain [19] where it is involved in the control of appetite. [20] Furthermore, mice that over express GLP1R display improved memory and learning. [21]

Appetite is the desire to eat food, sometimes due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Appetite has a relationship with every individual's behavior. Appetitive behaviour also known as approach behaviour, and consummatory behaviours, are the only processes that involve energy intake, whereas all other behaviours affect the release of energy. When stressed, appetite levels may increase and result in an increase of food intake. Decreased desire to eat is termed anorexia, while polyphagia is increased eating. Dysregulation of appetite contributes to anorexia nervosa, bulimia nervosa, cachexia, overeating, and binge eating disorder.

Stretch responsive vagal neurons in the stomach and intestines also express GLP1R. [22] GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation. [22]

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. [23]

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. [24]

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. [23]

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. [23]

See also

Related Research Articles

Pancreatic islets regions of the pancreas

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1 to 2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

Glucokinase protein-coding gene in the species Homo sapiens

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

Incretin A group of gastrointestinal hormones

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism.

Gastric inhibitory polypeptide chemical compound

Gastric inhibitory polypeptide (GIP) or gastroinhibitory peptide, also known as the glucose-dependent insulinotropic peptide, is an inhibiting hormone of the secretin family of hormones. While it is weak inhibitor of gastric acid secretion, its main role is to stimulate insulin secretion.

Exenatide pharmaceutical drug

Exenatide, sold under the brand name Byetta and Bydureon among others, is a medication used to treat diabetes mellitus type 2. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a less preferred treatment option after metformin and sulfonylureas. It is given by injection under the skin within an hour before the first and last meal of the day. A once-weekly injection version is also avaliable.

Glucagon receptor protein-coding gene in the species Homo sapiens

The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. In humans, the glucagon receptor is encoded by the GCGR gene.

Enteroendocrine cell

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas.

Gastric inhibitory polypeptide receptor protein-coding gene in the species Homo sapiens

The gastric inhibitory polypeptide receptor (GIP-R), also known as the glucose-dependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene. GIP-R is a member of the 7-transmembrane protein family, a class of G protein–coupled receptors. GIP-R is found on beta-cells in the pancreas.

Glucagon-like peptide-2 receptor protein-coding gene in the species Homo sapiens

Glucagon-like peptide-2 receptor (GLP-2R) is a protein that in human is encoded by the GLP2R gene located on chromosome 17.

Albiglutide is a glucagon-like peptide-1 agonist drug marketed by GlaxoSmithKline (GSK) for treatment of type 2 diabetes. As of 2017 it is unclear if it affects a person's risk of death. GSK has announced that it intends to withdraw the drug from the worldwide market by July 2018 for economic reasons.

Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists or incretin mimetics, are agonists of the GLP-1 receptor. This class of medications is used for the treatment of type 2 diabetes. One of their advantages over older insulin secretagogues, such as sulfonylureas or meglitinides, is that they have a lower risk of causing hypoglycemia.

FOXO1 protein-coding gene in the species Homo sapiens

Forkhead box protein O1 (FOXO1) also known as forkhead in rhabdomyosarcoma is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

Dulaglutide is a glucagon-like peptide-1 receptor agonist consisting of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4. It is used for the treatment of type 2 diabetes and can be used once weekly. GLP-1 is a hormone that is involved in the normalization of level of glucose in blood (glycemia). The FDA approved dulaglutide for use in the United States in September 2014. The drug is manufactured by Eli Lilly under the brand name Trulicity.

Semaglutide chemical compound

Semaglutide is a pharmaceutical drug developed by Danish company Novo Nordisk. Originally developed for the treatment of type 2 diabetes in 2012, it was found in 2017 that it can be used for the treatment of obesity.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024027 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Thorens B (September 1992). "Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1". Proc. Natl. Acad. Sci. U.S.A. 89 (18): 8641–5. doi:10.1073/pnas.89.18.8641. PMC   49976  Lock-green.svg. PMID   1326760.
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  7. ↑ 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.
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  9. ↑ 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: 312–315. doi:10.1038/nature22378.
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  11. 1 2 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  Lock-green.svg. PMID   27315480.
  12. ↑ 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. PMID   27059958.
  13. ↑ 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  Lock-green.svg. PMID   27569426.
  14. 1 2 3 4 5 6 7 8 Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
  15. 1 2 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: 7131–7144. doi:10.1074/jbc.M117.779496. PMC   5409479  Lock-green.svg. PMID   28283573.
  16. ↑ 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. PMID   29119245.
  17. ↑ Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (May 1987). "Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line". Proc. Natl. Acad. Sci. U.S.A. 84 (10): 3434–8. doi:10.1073/pnas.84.10.3434. PMC   304885  Lock-green.svg. PMID   3033647.
  18. ↑ 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. PMID   15155141.
  19. ↑ Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S (4 August 2015). "Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain". Mol Met. 4 (10): 718–731. doi:10.1016/j.molmet.2015.07.008. PMC   4588458  Lock-green.svg. PMID   26500843.
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  21. ↑ 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.
  22. 1 2 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  Lock-green.svg. PMID   27238020.
  23. 1 2 3 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  Lock-green.svg. PMID   18984744.
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