Glucagon-like peptide-1 receptor
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Location (UCSC) | Chr 6: 39.05 – 39.09 Mb | Chr 17: 31.12 – 31.16 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
The glucagon-like peptide-1 receptor (GLP1R) is a
Ligands
GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.[14]
- GLP-1 – endogenous in humans[14]
- glucagon – endogenous in humans[14]
- oxyntomodulin
- exendin-4,[14][15]
- exenatide
- lixisenatide[14]
- albiglutide
- beinaglutide
- dulaglutide
- efpeglenatide
- langlenatide
- liraglutide[14]
- semaglutide
- taspoglutide
- pegapamodutide
- lithium chloride
- Positive:
- BETP[14]
- Benaglutide / Beinaglutide ( Renhui Biotechnology, China )
- Tilpotide / Tirzepatide
- GCGR co- agonist and a long- acting synthetic oxyntomodulinanalog )
- Ecnoglutide ( XW003, XianWeida Biotechnology )
- Survodutide / BI456906 ( Boehringer Ingelheim )
- Utreglutide
- Glepaglutide
- GLP-2analog )
- GCGRco- agonist )
- GCGRco- agonist )
- Cotadutide
- GCGR co- agonist and Oxyntomodulin analog; NeuroBo Pharmaceuticals)
- GX-G6 ( Genexine / I-MAB / CSPC )
- GZR18
- HRS9531
- GIPRTriple agonist )
- BGM0504
- MWN101
- PB-718
- RAY1225
- VCT220
- Grutalumab
- PEG- Loxenatide ( PEX- 168 )
- GIPR.
- GIPR. Developed by Viking Therapeutics
- Negative:
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 N-terminus of the receptor is responsible for binding glucagon-like peptide-1 (GLP-1) ligands, while the intracellular C-terminus interacts with intracellular signaling proteins to initiate downstream signaling pathways.
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
Function
Glucagon-like peptide-1 (GLP-1) is a hormone consisting of 30 amino acids. It is released by intestinal L cells when nutrients are consumed. GLP-1 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. Due to these diverse effects, there has been significant interest in developing long-lasting agonists of the GLP-1 receptor (GLP-1R) for the treatment of type 2 diabetes (T2D).
GLP1R is also expressed in the brain[18] where it is involved in the control of appetite.[19] Furthermore, mice that over express GLP1R display improved memory and learning.[20]
Stretch responsive vagal neurons in the stomach and intestines also express GLP1R.[21] GLP1R neurons particularly and densely innervate stomach muscle and can communicate with additional organ systems changing breathing and heart rate due to activation.[21]
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. By inhibiting glucagon release, GLP-1 receptor activation helps to maintain glucose homeostasis. Another important function of the GLP-1 receptor is the regulation of gastric emptying. Activation of the receptor delays the rate at which the stomach empties, leading to increased satiety and reduced food intake. This effect contributes to weight management and appetite control.
'Appetite regulation and satiety': GLP-1 receptor signaling influences the central nervous system, particularly regions involved in appetite regulation. Activation of the GLP-1 receptor promotes feelings of satiety, leading to a reduction in food intake and improved weight management.
Gastric emptying': GLP-1 receptor activation slows down the rate at which the stomach empties its contents into the small intestine. This delay in gastric emptying contributes to the feeling of fullness and aids in controlling postprandial blood glucose levels.
Clinical significance
This article needs more primary sources. (January 2024) |
Glucose Control: GLP-1 and its agonists enhance glucose control by promoting insulin secretion from pancreatic beta cells in a glucose-dependent manner. This means that they stimulate insulin release when blood glucose levels are elevated, helping to maintain normal blood sugar levels. By mimicking the physiological actions of GLP-1, GLP-1 receptor agonists effectively lower blood glucose levels, particularly after meals.
Weight Management: GLP-1 and its agonists have demonstrated the ability to promote weight loss or weight stabilization. These agents help reduce appetite, delay gastric emptying, and enhance satiety, leading to reduced food intake. The weight loss effect is particularly beneficial for individuals with type 2 diabetes who often struggle with obesity or overweight conditions.
Cardiovascular Protection: GLP-1 receptor agonists have shown potential cardiovascular benefits beyond glucose control. Some studies suggest that these agents may reduce the risk of cardiovascular events, such as heart attacks, strokes, and cardiovascular-related mortality. The cardiovascular protective effects may be related to their favorable effects on blood pressure, lipid profiles, inflammation, and endothelial function.
Beta Cell Preservation: GLP-1 and its agonists have been found to exert protective effects on pancreatic beta cells, which are responsible for producing insulin. They can enhance beta cell survival, promote beta cell proliferation, and inhibit beta cell apoptosis, thus preserving beta cell function over time.
Combination Therapy: GLP-1 receptor agonists are often used as part of combination therapy in the treatment of type 2 diabetes. They can be prescribed alongside other oral antidiabetic medications, such as metformin or sulfonylureas, to provide additional glycemic control and improve overall treatment outcomes.
Different GLP-1 receptor agonists go through inactivation by
The debate about which treatment in combatting T2D still wages. Some studies suggest GLP1 Receptor Agonists (GLP1RAs) which have shown significant results compared to treatment with DPP-4 inhibitors. Some studies provided an insight into the reduction in limb incidents when treated with GLP1RAs. Other studies showed that GLP1RAs provide superior glycaemic control and weight loss when compared with DPP-4 inhibitors in patients with T2D.
Semaglutide
Commercially known as
Concerning obesity, semaglutide has also shown effectiveness in treating obesity. In higher doses than those used for diabetes management, it can help reduce body weight. The precise mechanism by which semaglutide induces weight loss is not fully understood, but it is believed to involve various factors. Semaglutide decreases appetite by acting on the brain's centers responsible for appetite regulation, leading to a feeling of fullness and reduced food intake. It also slows down the emptying of the stomach, which can contribute to a decreased caloric intake. These combined effects on appetite and digestion help individuals lose weight.
The medication is administered as a once-weekly subcutaneous injection. The starting dose is usually low and gradually increased over several weeks to help minimize potential gastrointestinal side effects, such as nausea. The optimal dose for an individual is determined by their healthcare provider based on factors such as blood sugar levels, response to treatment, and tolerability.
Clinical trials have demonstrated the efficacy of Ozempic in improving glycemic control. The medication has shown significant reductions in HbA1c (a measure of long-term blood sugar control) as well as fasting and postprandial (after-meal) glucose levels.
possible Side effects of semaglutide:
Like any medication, Ozempic may cause side effects. Common side effects include nausea, vomiting, diarrhea, and constipation. These side effects are usually temporary and tend to diminish over time. Rare but more serious side effects may include pancreatitis, gallbladder disease, and allergic reactions. It is essential to discuss potential side effects and risks with a healthcare provider before starting Ozempic.
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 mutated human huntingtin protein aggregates, improved motor function, extended the survival time, improved glucose regulation, and decreased brain and pancreas pathology.[22]
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
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.[22]
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 mutated human huntingtin 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.[22]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000112164 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024027 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ a b c d e f g h Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
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- ^ PMID 27238020.
- ^ PMID 18984744.
- ^ Drucker DJ. "Resurrecting the Beta Cell in Type 2 Diabetes: Beta-cell Function, Preservation, and Neogenesis". PowerPoint slides. Medscape.
Further reading
- van Eyll B, Lankat-Buttgereit B, Bode HP, Göke R, Göke B (July 1994). "Signal transduction of the GLP-1-receptor cloned from a human insulinoma". FEBS Letters. 348 (1): 7–13. S2CID 9085188.
- Liu C, Sun S, Xie J, Li H, Li T, Wu Q, Zhang Y, Bai X, Wang J, Wang X, Li Z, Wang W (2022). "GLP-1R Agonist Exendin-4 Protects Against Hemorrhagic Transformation Induced by rtPA After Ischemic Stroke via the Wnt/β-Catenin Signaling Pathway". Mol Neurobiol. 59 (6): 3649–3664. PMID 35359227.
- Gromada J, Rorsman P, Dissing S, Wulff BS (October 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 Letters. 373 (2): 182–6. S2CID 28488846.
- Wei Y, Mojsov S (January 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 Letters. 358 (3): 219–24. S2CID 44371465.
- Lankat-Buttgereit B, Göke R, Stöckmann F, Jiang J, Fehmann HC, Göke B (1994). "Detection of the human glucagon-like peptide 1(7-36) amide receptor on insulinoma-derived cell membranes". Digestion. 55 (1): 29–33. PMID 8112494.
- Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD (October 1993). "Cloning and functional expression of a human glucagon-like peptide-1 receptor". Biochemical and Biophysical Research Communications. 196 (1): 141–6. PMID 8216285.
- Stoffel M, Espinosa R, Le Beau MM, Bell GI (August 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. PMID 8392011.
- 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. PMID 8404634.
- Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C (November 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. PMID 8405712.
- 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. S2CID 29733898.
- Frimurer TM, Bywater RP (June 1999). "Structure of the integral membrane domain of the GLP1 receptor". Proteins. 35 (4): 375–86. PMID 10382665.
- Huypens P, Ling Z, Pipeleers D, Schuit F (August 2000). "Glucagon receptors on human islet cells contribute to glucose competence of insulin release". Diabetologia. 43 (8): 1012–9. PMID 10990079.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. PMID 11076863.
- Xiao Q, Jeng W, Wheeler MB (December 2000). "Characterization of glucagon-like peptide-1 receptor-binding determinants". Journal of Molecular Endocrinology. 25 (3): 321–35. PMID 11116211.
- Bazarsuren A, Grauschopf U, Wozny M, Reusch D, Hoffmann E, Schaefer W, et al. (May 2002). "In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor". Biophysical Chemistry. 96 (2–3): 305–18. PMID 12034449.
- Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A (October 2004). "Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population". Diabetes Research and Clinical Practice. 66 (1): 63–9. PMID 15364163.
- Jorgensen R, Martini L, Schwartz TW, Elling CE (March 2005). "Characterization of glucagon-like peptide-1 receptor beta-arrestin 2 interaction: a high-affinity receptor phenotype". Molecular Endocrinology. 19 (3): 812–23. PMID 15528268.
- Mahon MJ, Shimada M (January 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 Letters. 579 (3): 803–7. S2CID 6471940.
- Graaf C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, et al. (October 2016). "Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes". Pharmacological Reviews. 68 (4): 954–1013. PMID 27630114.
- 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. S2CID 2141649.
- Brunton S (May 2014). "GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other?". International Journal of Clinical Practice. 68 (5): 557–567. PMID 24499291.
- Donnelly D (May 2012). "The structure and function of the glucagon-like peptide-1 receptor and its ligands". British Journal of Pharmacology. 166 (1): 27–41. PMID 21950636.
- Christou GA, Katsiki N, Blundell J, Fruhbeck G, Kiortsis DN (June 2019). "Semaglutide as a promising antiobesity drug". Obesity Reviews. 20 (6): 805–815. S2CID 73422503.
External links
- "Glucagon Receptor Family: GLP-1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-10-25.
- glucagon-like+peptide+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P43220 (Glucagon-like peptide 1 receptor) at the PDBe-KB.