Glucagon-like peptide-1 receptor

{{cs1 config|name-list-style=vanc}} {{Short description|Receptor activated by peptide hormone GLP-1}} {{Infobox_gene}} 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.<ref name="pmid1326760">{{cite journal | vauthors = Thorens B | title = Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 18 | pages = 8641–5 | date = September 1992 | pmid = 1326760 | pmc = 49976 | doi = 10.1073/pnas.89.18.8641 | bibcode = 1992PNAS...89.8641T | doi-access = free }}</ref><ref name="pmid8404634">{{cite journal | vauthors = Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE | display-authors = 6 | title = Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor | journal = Endocrinology | volume = 133 | issue = 4 | pages = 1907–10 | date = October 1993 | pmid = 8404634 | doi = 10.1210/endo.133.4.8404634 }}</ref> It is a member of the glucagon receptor family of GPCRs.<ref name="pmid12529935">{{cite journal | vauthors = Brubaker PL, Drucker DJ | title = Structure-function of the glucagon receptor family of G protein-coupled receptors, coupled to: the glucagon, GIP, GLP-1, and GLP-2 receptors | journal = Receptors & Channels | volume = 8 | issue = 3–4 | pages = 179–88 | year = 2002 | pmid = 12529935 | doi = 10.1080/10606820213687 | url = http://www.glucagon.com/pdfs/Receptors%20and%20Channels.pdf }}</ref> GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1,<ref name="pmid27059958">{{cite journal | vauthors = Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S | title = Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor | journal = The Journal of Biological Chemistry | volume = 285 | issue = 1 | pages = 723–30 | date = January 2010 | pmid = 19861722 | pmc = 2804221 | doi = 10.1074/jbc.M109.033829 | doi-access = free }}</ref> and one transmembrane domain (TMD)<ref name="doi10.1038/nature22378">{{cite journal | vauthors = 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 | display-authors = 6 | title = Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators | journal = Nature | volume = 546 | issue = 7657 | pages = 312–315 | date = June 2017 | pmid = 28514449 | doi = 10.1038/nature22378 | bibcode = 2017Natur.546..312S | s2cid = 2141649 }}</ref> that binds the N-terminal region of GLP-1.<ref name="pmid26700562">{{cite journal | vauthors = Wootten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopoulos A, Sexton PM | display-authors = 6 | title = 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 | journal = Molecular Pharmacology | volume = 89 | issue = 3 | pages = 335–47 | date = March 2016 | pmid = 26700562 | pmc = 4767408 | doi = 10.1124/mol.115.101246 }}</ref><ref name="pmid27315480">{{cite journal | vauthors = Wootten 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, Christopoulos A, Sexton PM | display-authors = 6 | title = The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism | journal = Cell | volume = 165 | issue = 7 | pages = 1632–1643 | date = June 2016 | pmid = 27315480 | pmc = 4912689 | doi = 10.1016/j.cell.2016.05.023 }}</ref><ref name="pmid19861722">{{cite journal | vauthors = 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 | display-authors = 6 | title = Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP1R) | journal = The Journal of Biological Chemistry | volume = 291 | issue = 25 | pages = 12991–3004 | date = June 2016 | pmid = 27059958 | pmc = 4933217 | doi = 10.1074/jbc.M116.721977 | doi-access = free }}</ref> In the TMD domain a fulcrum of polar residues regulates the biased signaling of the receptor <ref name="pmid26700562"/> while the transmembrane helical boundaries<ref name="pmid27569426">{{cite journal | vauthors = Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Furness SG, Miller LJ, Christopoulos A, Sexton PM | display-authors = 6 | title = 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 | journal = Biochemical Pharmacology | volume = 118 | pages = 68–87 | date = October 2016 | pmid = 27569426 | pmc = 5063953 | doi = 10.1016/j.bcp.2016.08.015 }}</ref> and extracellular surface are a trigger for biased agonism.<ref name="pmid27315480"/>

== Ligands == GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.<ref name="IUPHAR 2015 GLP-1">{{cite web |title=GLP-1 receptor|url=http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=249 |work= IUPHAR/BPS Guide to PHARMACOLOGY |publisher=International Union of Basic and Clinical Pharmacology |access-date= 13 September 2015 |vauthors=Maguire JJ, Davenport AP}}</ref>

Agonists {{See also|GLP-1 receptor agonist|Category:GLP-1 receptor agonists}}

{{div col|colwidth=20em}} *GLP-1 – endogenous in humans<ref name="IUPHAR 2015 GLP-1"/> *glucagon – endogenous in humans<ref name="IUPHAR 2015 GLP-1"/> *oxyntomodulin *amycretin/ zenagamtide *UBT251 *exendin-4<ref name="IUPHAR 2015 GLP-1"/><ref name="pmid28283573">{{cite journal | vauthors = Koole C, Reynolds CA, Mobarec JC, Hick C, Sexton PM, Sakmar TP | title = Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP1R) | journal = The Journal of Biological Chemistry | volume = 292 | issue = 17 | pages = 7131–7144 | date = April 2017 | pmid = 28283573 | pmc = 5409479 | doi = 10.1074/jbc.M117.779496 | doi-access = free }}</ref> *exenatide *lixisenatide<ref name="IUPHAR 2015 GLP-1"/> *albiglutide *beinaglutide *dulaglutide *efpeglenatide *langlenatide *liraglutide<ref name="IUPHAR 2015 GLP-1"/> *polyethylene glycol/PEG- loxenatide *semaglutide *taspoglutide *ecnoglutide *utreglutide *glepaglutide *apraglutide *maridebart cafraglutide *tirzepatide *pegapamodutide *mazdutide *survodutide *bamadutide *pemvidutide *cotadutide *retatrutide *Lithium chloride *Cinchonine *grutalumab *dapiglutide *DA1726 *GX-G6 *GZR18 *HRS9531/ KAI-9531/ Ribupatide *PB718 *RAY1225 *VCT220 *VK2735 *BLX7006 *supaglutide/efsubaglutide *ASC30 *HRS7535 *Danuglipron *Aleniglipron *Lotiglipron *Orforglipron *Conveglipron *CT-996 *CT-388 *CT-868 *HEC88473 *HS-10535 *UBT251 *efinopegdutide *efocipegtrutide *NNC9204-1706 *TG103 *YP05002/YP-05002 {{Div col end}}

Antagonists: *[9-39]-GLP-1 * T-0632 * GLP1R0017<ref>{{cite journal | vauthors =Biggs EK, Liang L, Naylor J, Madalli S, Collier R, Coghlan MP, Baker DJ, Hornigold DC, Ravn P, Reimann F, Gribble FM | display-authors = 6 | title = Development and characterisation of a novel glucagon like peptide-1 receptor antibody | journal = Diabetologia | volume = 61 | issue = 3 | pages = 711–721 | date = March 2018 | pmid = 29119245 | pmc = 5890879 | doi = 10.1007/s00125-017-4491-0 }}</ref> * avexitide / exendin 9-39

Allosteric modulators: * Positive:

** BETP * Negative:

** HTL26119<ref>{{Cite journal | vauthors = O'Brien A, Andrews S, Baig AH, Bortolato A, Brown JH, Brown GA, etal |date=2019-08-09|title=Identification of a novel allosteric GLP–1R antagonist HTL26119 using structure-based drug design | journal= Bioorganic & Medicinal Chemistry Letters |volume= 29|issue=20|page= 126611|doi=10.1016/j.bmcl.2019.08.015 |pmid=31447084|s2cid=201749908 }}</ref>

== Structure == [[File:GLP-1R complex.png|thumb|Structure of GLP1R-G protein complex bound to tirzepatide. Based on PDB entry [https://www.rcsb.org/structure/7RGP 7RGP]. Tirzepatide shown in red, GLP1R shown in green, G alpha subunit shown in white, G beta-gamma complex shown in dark gray.]]

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 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.

== Function == Glucagon-like peptide-1 (GLP-1) is a hormone consisting of 30 amino acids. GLP-1 is released by intestinal L cells when nutrients are consumed. GLP1R is expressed on beta cells in the pancreas. Binding of GLP-1 to GLP1R 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.

GLP1R is also expressed in the brain<ref name= "pmid26500843">{{cite journal | vauthors = Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S | title = Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain | journal = Molecular Metabolism | volume = 4 | issue = 10 | pages = 718–31 | date = October 2015 | pmid = 26500843 | pmc = 4588458 | doi = 10.1016/j.molmet.2015.07.008 }}</ref> where it is involved in the control of appetite.<ref name="pmid12451146">{{cite journal | vauthors = Kinzig KP, D'Alessio DA, Seeley RJ | title = The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness | journal = The Journal of Neuroscience | volume = 22 | issue = 23 | pages = 10470–6 | date = December 2002 | pmid = 12451146 | doi = 10.1523/JNEUROSCI.22-23-10470.2002 | pmc = 6758755 | author-link3 = Randy Seeley | doi-access = free }}</ref>

== 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.

Activation of GLP-1 receptor delays the rate at which the stomach empties, leading to increased satiety and feeling of fullness.

Activation of the GLP-1 receptor in the brain promotes feelings of satiety.<ref name="pmid12451146"/>

== Clinical significance == {{Main|GLP-1 receptor agonist}} GLP-1 receptor agonists are a class of medications that mimic the actions of the endogenous incretin hormone GLP-1, and are used in type 2 diabetes and obesity.

== References == {{Reflist|32em}}

== Further reading == {{Refbegin|32em}} * {{cite journal | vauthors = van Eyll B, Lankat-Buttgereit B, Bode HP, Göke R, Göke B | title = Signal transduction of the GLP-1-receptor cloned from a human insulinoma | journal = FEBS Letters | volume = 348 | issue = 1 | pages = 7–13 | date = July 1994 | pmid = 7517895 | doi = 10.1016/0014-5793(94)00553-2 | s2cid = 9085188 | doi-access = free | bibcode = 1994FEBSL.348....7V }} * {{cite journal | vauthors = Liu C, Sun S, Xie J, Li H, Li T, Wu Q, Zhang Y, Bai X, Wang J, Wang X, Li Z, Wang W | title = GLP-1R Agonist Exendin-4 Protects Against Hemorrhagic Transformation Induced by rtPA After Ischemic Stroke via the Wnt/β-Catenin Signaling Pathway | journal = Mol Neurobiol | year = 2022 | volume = 59 | issue = 6 | pages = 3649–3664 | pmid = 35359227 | doi = 10.1007/s12035-022-02811-9 | pmc = 9148281 }} * {{cite journal | vauthors = Gromada J, Rorsman P, Dissing S, Wulff BS | title = Stimulation of cloned human glucagon-like peptide 1 receptor expressed in HEK 293 cells induces cAMP-dependent activation of calcium-induced calcium release | journal = FEBS Letters | volume = 373 | issue = 2 | pages = 182–6 | date = October 1995 | pmid = 7589461 | doi = 10.1016/0014-5793(95)01070-U | s2cid = 28488846 | doi-access = free | bibcode = 1995FEBSL.373..182G }} * {{cite journal | vauthors = Wei Y, Mojsov S | title = Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences | journal = FEBS Letters | volume = 358 | issue = 3 | pages = 219–24 | date = January 1995 | pmid = 7843404 | doi = 10.1016/0014-5793(94)01430-9 | s2cid = 44371465 | doi-access = free | bibcode = 1995FEBSL.358..219W }} * {{cite journal | vauthors = Lankat-Buttgereit B, Göke R, Stöckmann F, Jiang J, Fehmann HC, Göke B | title = Detection of the human glucagon-like peptide 1(7-36) amide receptor on insulinoma-derived cell membranes | journal = Digestion | volume = 55 | issue = 1 | pages = 29–33 | year = 1994 | pmid = 8112494 | doi = 10.1159/000201119 }} * {{cite journal | vauthors = Graziano MP, Hey PJ, Borkowski D, Chicchi GG, Strader CD | title = Cloning and functional expression of a human glucagon-like peptide-1 receptor | journal = Biochemical and Biophysical Research Communications | volume = 196 | issue = 1 | pages = 141–6 | date = October 1993 | pmid = 8216285 | doi = 10.1006/bbrc.1993.2226 | bibcode = 1993BBRC..196..141G }} * {{cite journal | vauthors = Stoffel M, Espinosa R, Le Beau MM, Bell GI | title = 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 | journal = Diabetes | volume = 42 | issue = 8 | pages = 1215–8 | date = August 1993 | pmid = 8392011 | doi = 10.2337/diabetes.42.8.1215 }} * {{cite journal | vauthors = Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE | display-authors = 6 | title = Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor | journal = Endocrinology | volume = 133 | issue = 4 | pages = 1907–10 | date = October 1993 | pmid = 8404634 | doi = 10.1210/endo.133.4.8404634 }} * {{cite journal | vauthors = Thorens B, Porret A, Bühler L, Deng SP, Morel P, Widmann C | title = 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 | journal = Diabetes | volume = 42 | issue = 11 | pages = 1678–82 | date = November 1993 | pmid = 8405712 | doi = 10.2337/diabetes.42.11.1678 }} * {{cite journal | vauthors = Lankat-Buttgereit B, Göke B | title = Cloning and characterization of the 5' flanking sequences (promoter region) of the human GLP-1 receptor gene | journal = Peptides | volume = 18 | issue = 5 | pages = 617–24 | year = 1997 | pmid = 9213353 | doi = 10.1016/S0196-9781(97)00001-6 | s2cid = 29733898 }} * {{cite journal | vauthors = Frimurer TM, Bywater RP | title = Structure of the integral membrane domain of the GLP1 receptor | journal = Proteins | volume = 35 | issue = 4 | pages = 375–86 | date = June 1999 | pmid = 10382665 | doi = 10.1002/(SICI)1097-0134(19990601)35:4<375::AID-PROT1>3.0.CO;2-2 | doi-access = free }} * {{cite journal | vauthors = Huypens P, Ling Z, Pipeleers D, Schuit F | title = Glucagon receptors on human islet cells contribute to glucose competence of insulin release | journal = Diabetologia | volume = 43 | issue = 8 | pages = 1012–9 | date = August 2000 | pmid = 10990079 | doi = 10.1007/s001250051484 | doi-access = free }} * {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }} * {{cite journal | vauthors = Xiao Q, Jeng W, Wheeler MB | title = Characterization of glucagon-like peptide-1 receptor-binding determinants | journal = Journal of Molecular Endocrinology | volume = 25 | issue = 3 | pages = 321–35 | date = December 2000 | pmid = 11116211 | doi = 10.1677/jme.0.0250321 | doi-access = free }} * {{cite journal | vauthors = Bazarsuren A, Grauschopf U, Wozny M, Reusch D, Hoffmann E, Schaefer W, Panzner S, Rudolph R | display-authors = 6 | title = In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor | journal = Biophysical Chemistry | volume = 96 | issue = 2–3 | pages = 305–18 | date = May 2002 | pmid = 12034449 | doi = 10.1016/S0301-4622(02)00023-6 }} * {{cite journal | vauthors = Tokuyama Y, Matsui K, Egashira T, Nozaki O, Ishizuka T, Kanatsuka A | title = Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population | journal = Diabetes Research and Clinical Practice | volume = 66 | issue = 1 | pages = 63–9 | date = October 2004 | pmid = 15364163 | doi = 10.1016/j.diabres.2004.02.004 | doi-access = free }} * {{cite journal | vauthors = Jorgensen R, Martini L, Schwartz TW, Elling CE | title = Characterization of glucagon-like peptide-1 receptor beta-arrestin 2 interaction: a high-affinity receptor phenotype | journal = Molecular Endocrinology | volume = 19 | issue = 3 | pages = 812–23 | date = March 2005 | pmid = 15528268 | doi = 10.1210/me.2004-0312 | doi-access = free }} * {{cite journal | vauthors = Mahon MJ, Shimada M | title = Calmodulin interacts with the cytoplasmic tails of the parathyroid hormone 1 receptor and a sub-set of class b G-protein coupled receptors | journal = FEBS Letters | volume = 579 | issue = 3 | pages = 803–7 | date = January 2005 | pmid = 15670850 | doi = 10.1016/j.febslet.2004.12.056 | s2cid = 6471940 | doi-access = | bibcode = 2005FEBSL.579..803M }} * {{cite journal | vauthors = Graaf C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, Ahn JM, Liao J, Fletcher MM, Yang D, Brown AJ, Zhou C, Deng J, Wang MW | display-authors = 6 | title = Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes | journal = Pharmacological Reviews | volume = 68 | issue = 4 | pages = 954–1013 | date = October 2016 | pmid = 27630114 | pmc = 5050443 | doi = 10.1124/pr.115.011395 }} * {{cite journal | vauthors = 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 | display-authors = 6 | title = Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators | journal = Nature | volume = 546 | issue = 7657 | pages = 312–315 | date = June 2017 | pmid = 28514449 | doi = 10.1038/nature22378 | s2cid = 2141649 | bibcode = 2017Natur.546..312S }} * {{cite journal | vauthors = Brunton S | title = GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? | journal = International Journal of Clinical Practice | volume = 68 | issue = 5 | pages = 557–567 | date = May 2014 | pmid = 24499291 | doi = 10.1111/ijcp.12361 | pmc = 4238422 }} * {{cite journal | vauthors = Donnelly D | title = The structure and function of the glucagon-like peptide-1 receptor and its ligands | journal = British Journal of Pharmacology | volume = 166 | issue = 1 | pages = 27–41 | date = May 2012 | pmid = 21950636 | doi = 10.1111/j.1476-5381.2011.01687.x | pmc = 3415635 }} {{Refend}}

== External links == * {{cite web |url= http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2288 |title= Glucagon Receptor Family: GLP-1 |work= IUPHAR Database of Receptors and Ion Channels |publisher= International Union of Basic and Clinical Pharmacology |access-date= 2007-10-25 |archive-date= 2016-03-03 |archive-url= https://web.archive.org/web/20160303203617/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2288 }} *{{MeSH name|glucagon-like+peptide+receptor}} * {{PDBe-KB2|P43220|Glucagon-like peptide 1 receptor}}

Category:G protein-coupled receptors