Glucagon-like peptide-1 receptor

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]

GLP1R
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3C59, 3C5T, 3IOL, 4ZGM
Identifiers
Aliases	GLP1R, glucagon-like peptide 1 receptor, GLP-1, GLP-1-R, GLP-1R, glucagon like peptide 1 receptor
External IDs	OMIM: 138032; MGI: 99571; HomoloGene: 1558; GeneCards: GLP1R; OMA:GLP1R - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.2 Start 39,048,781 bp[1] End 39,091,303 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 A3.3|17 15.8 cM Start 31,120,791 bp[2] End 31,159,765 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in islet of Langerhans sperm vena cava body of pancreas oocyte periodontal fiber secondary oocyte cardia Medulla Oblongata Pons Top expressed in islet of Langerhans supraoptic nucleus left lung lobe right lung lobe lumbar subsegment of spinal cord pontine nuclei lateral septal nucleus duodenum epithelium of stomach ganglion of vagus nerve More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled peptide receptor activity G protein-coupled receptor activity signal transducer activity protein binding glucagon receptor activity transmembrane signaling receptor activity glucagon-like peptide 1 receptor activity peptide hormone binding Cellular component integral component of membrane membrane plasma membrane intracellular anatomical structure integral component of plasma membrane Biological process regulation of heart contraction regulation of insulin secretion positive regulation of cytosolic calcium ion concentration cellular response to glucagon stimulus activation of adenylate cyclase activity cell surface receptor signaling pathway positive regulation of blood pressure learning or memory cAMP-mediated signaling signal transduction adenylate cyclase-activating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway response to psychosocial stress Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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: 31.12 – 31.16 Mb PubMed search [3] [4]
Wikidata
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Ligands

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

Agonists:

• 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]
• PEG- Loxenatide
• semaglutide
• taspoglutide
• Ecnoglutide
• Utreglutide
• Glepaglutide
• Apraglutide
• Maridebart Cafraglutide/AMG133
• Tirzepatide
• pegapamodutide
• Mazdutide
• Survodutide
• Bamadutide
• Pemvidutide
• Cotadutide
• Retatrutide
• lithium chloride
• Grutalumab
• DA1726
• GX-G6
• GZR18
• HRS9531
• BGMO504
• PB718
• RAY1225
• VCT220
• VK2735
• BLX7006
• Supaglutide/Efsubaglutide: approved in China for treatment of Diabetes mellitus.
• ASC30
• Danuglipron
• Aleniglipron(GSBR-1290)
• Lotiglipron
• Orforglipron
• CT-996
• CT-388
• HS-10535
• UBT251 : GLP-1, GIP & Glucagon receptor triple agonist.
• Efinopegdutide : HM12525A/MK-6024/JNJ-64565111/ LAPS-GLP-1R/GCGR agonist
• Efocipegtrutide/HM15211

Antagonists:

• [9-39]-GLP-1
• T-0632^[16]
• GLP1R0017^[17]
• Avexitide/ exendin 9-39

Allosteric modulators

• Positive:
  • BETP

• Negative:
  • HTL26119^[18]

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 G proteins and other signaling molecules to initiate cellular responses.

Structure of GLP-1R-G protein complex bound to tirzepatide. Based on PDB entry 7RGP(cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide). Tirzepatide shown in red, GLP-1R shown in green, G alpha subunit shown in white, G beta-gamma complex shown in dark gray.

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

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]

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

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 dipeptidyl peptidase-4 (DPP-4) enzymes (The clinical use of GLP-1 is hampered by its short half-life in the circulation (1-2 min), because of its proteolytic degradation by the enzymes DPP-4 and neutral endopeptidase). One strategy used for overcoming this problem is by synthesising new GLP-1 receptor agonists with a prolonged circulating half-life that will display a reduced degradation by DPP-4 enzymes. Another strategy is to inihibit DPP-4 enzymes.

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

Schematic representation of the structures of semaglutide and liraglutide, compared to GLP-1

Commercially known as Ozempic, semaglutide is one of a class of drugs called glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It is primarily used for the treatment of type 2 diabetes. Semaglutide has an experimented half-life of 165–184 hours compared with Liraglutide (13 hours) and GLP-1 (2 minutes).

Semaglutide has also shown effectiveness in treating obesity. In doses higher than those used for diabetes management, it can help reduce appetite and body weight. The precise mechanism of action is not fully understood, but it is believed to involve multiple factors. Semaglutide decreases appetite by acting on the brain. It also slows down stomach emptying, which further reduces appetite.

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 tolerance.

Clinical trials reported the efficacy of semaglutide in improving glycemic control, in terms of reductions in HbA1c (a measure of long-term blood sugar control) as well as fasting and postprandial (after-meal) glucose levels.

Possible side effects

Common side effects include nausea, vomiting, diarrhea, and constipation. These 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 consider potential side effects and risks before starting treatment.

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 (htt) 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 and islet structure, reduced mutated human huntingtin aggregates in the brain and pancreas, and also improved 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

• Glucagon-like peptide-1
• Dipeptidyl peptidase-4