Glucagon-like peptide 1 receptor: Difference between revisions

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{{Infobox_gene}}
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The '''glucagon-like peptide 1 receptor''' ('''GLP1R''') is a [[Receptor (biochemistry)|receptor protein]] found on [[beta cell]]s 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]].<ref name="pmid1326760">{{cite journal | author = Thorens B | title = Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 18 | pages = 8641–5 |date=September 1992 | pmid = 1326760 | pmc = 49976 | doi = 10.1073/pnas.89.18.8641 }}</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 III)) | 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/en.133.4.1907 }}</ref> It is a member of the [[glucagon receptor family]] of [[G protein-coupled receptor]]s.<ref name="pmid12529935">{{cite journal |vauthors=Brubaker PL, Drucker DJ | title = Structure-function of the glucagon receptor family of the G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors | journal = Recept. Channels | volume = 8 | issue = 3-4 | pages = 179–88 | year = 2002 | pmid = 12529935| url = http://www.glucagon.com/pdfs/Receptors%20and%20Channels.pdf |format=PDF| accessdate = 2008-07-14 | doi = 10.1080/10606820213687}}</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 = Journal of Biological Chemistry |volume = 285 |issue = 1 |pages = 723–730 |date=June 2010 |pmid = 19861722 |pmc=2804221|doi=10.1074/jbc.M109.033829}}</ref> and one transmembrane (TMD) domain<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 |title = Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators) |journal = Nature |doi= 10.1038/nature22378}}</ref> that binds the N-terminal region of GLP-1.<ref name="pmid26700562">{{cite journal |vauthors=Wooten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopolous A, Sexton PM |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 = 335–347 |date=March 2016 |pmid = 26700562 |doi=10.1124/mol.115.101246 }}</ref><ref name="pmid27315480">{{cite journal |vauthors=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 |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 |doi=10.1016/j.cell.2016.05.023 |pmc=4912689}}</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 |title = Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R) |journal = Journal of Biological Chemistry |volume = 291 |issue = 25 |pages = 12991–3004 |date=June 2016 |pmid = 27059958 |doi=10.1074/jbc.M116.721977 }}</ref> In the TMD domain there is fulcrum of polar residues that regulates the biased signaling of the receptor <ref name="pmid26700562"/> while the transmembrane helical boundaries<ref name="pmid27569426">{{cite journal |vauthors=Wooten D, Reynolds CA, Smith KJ, Mobarec JC, Furness SG, Miller LJ, Christopolous A, Sexton PM |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 |issue =  |pages = 68–87 |date=August 2016 |pmid = 27569426 |doi=10.1016/j.bcp.2016.08.015 |pmc=5063953}}</ref> and extracellular surface are a trigger for biased agonism.<ref name="pmid27315480"/>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==Human receptor ligands==
{{GNF_Protein_box
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 | accessdate= 13 September 2015 |vauthors=Maguire JJ, Davenport AP }}</ref>
| image =
| image_source =
| PDB =  
| Name = Glucagon-like peptide 1 receptor
| HGNCid = 4324
| Symbol = GLP1R
| AltSymbols =; MGC138331
| OMIM = 138032
| ECnumber = 
| Homologene = 1558
| MGIid = 99571
| GeneAtlas_image1 = PBB_GE_GLP1R_208401_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_GLP1R_208390_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_GLP1R_208391_s_at_tn.png
| Function = {{GNF_GO|id=GO:0004930 |text = G-protein coupled receptor activity}} {{GNF_GO|id=GO:0004967 |text = glucagon receptor activity}} {{GNF_GO|id=GO:0008528 |text = peptide receptor activity, G-protein coupled}}
| Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007190 |text = adenylate cyclase activation}} {{GNF_GO|id=GO:0007204 |text = elevation of cytosolic calcium ion concentration}} {{GNF_GO|id=GO:0007611 |text = learning and/or memory}} {{GNF_GO|id=GO:0008016 |text = regulation of heart contraction}} {{GNF_GO|id=GO:0019933 |text = cAMP-mediated signaling}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2740
    | Hs_Ensembl = ENSG00000112164
    | Hs_RefseqProtein = NP_002053
    | Hs_RefseqmRNA = NM_002062
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 6
    | Hs_GenLoc_start = 39124552
    | Hs_GenLoc_end = 39163497
    | Hs_Uniprot = P43220
    | Mm_EntrezGene = 14652
    | Mm_Ensembl = ENSMUSG00000024027
    | Mm_RefseqmRNA = XM_001000702
    | Mm_RefseqProtein = XP_001000702
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 30628889
    | Mm_GenLoc_end = 30663545
    | Mm_Uniprot = Q104P0
  }}
}}


{{CMG}}
[[Receptor agonist]]s:
*[[GLP-1]] - endogenous in humans<ref name="IUPHAR 2015 GLP-1" />
*[[glucagon]] - endogenous in humans<ref name="IUPHAR 2015 GLP-1" />
*[[liraglutide]]<ref name="IUPHAR 2015 GLP-1" />
*[[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 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 = Journal of Biological Chemistry |date=March 2017 |pmid = 28283573 |doi=10.1074/jbc.M117.779496 }}</ref>
*[[lixisenatide]]<ref name="IUPHAR 2015 GLP-1" />


==Overview==
[[Receptor antagonist]]s:
The gene for  the [[glucagon-like peptide 1 receptor]] ('''GLP-1''') receptor is on [[chromosome 6]] and is known to be expressed in [[pancreas|pancreatic]] [[beta cells]].<ref name="pmid12529935">{{cite journal | author = Brubaker PL, Drucker DJ | title = Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors | journal = Recept. Channels | volume = 8 | issue = 3-4 | pages = 179-88 | year = 2002 | pmid = 12529935 | doi = | issn = | url = http://www.glucagon.com/Receptors%20and%20Channels.pdf | accessdate = 2007-08-24}}</ref>
*"T-0632"<ref name="IUPHAR 2015 GLP-1" />
 
Receptor [[positive allosteric modulator]]s:
*"BETP"<ref name="IUPHAR 2015 GLP-1" />
 
== Function and therapeutic potential ==
 
GLP1R is known to be expressed in [[pancreas|pancreatic]] [[beta cells]].  Activated GLP1R stimulates the [[adenylyl cyclase]] pathway which results in increased [[insulin]] synthesis and release of insulin.<ref name="pmid3033647">{{cite journal |vauthors=Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF | title = Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 84 | issue = 10 | pages = 3434–8 |date=May 1987 | pmid = 3033647 | pmc = 304885 | doi = 10.1073/pnas.84.10.3434 }}</ref>  Consequently, GLP1R has been a target for developing drugs usually referred to as [[Glucagon-like peptide-1 agonist|GLP1R agonists]] to treat [[diabetes]].<ref name="pmid15155141">{{cite journal | author = Holst JJ | title = Treatment of type 2 diabetes mellitus with agonists of the GLP-1 receptor or DPP-IV inhibitors | journal = Expert Opin Emerg Drugs | volume = 9 | issue = 1 | pages = 155–66 |date=May 2004 | pmid = 15155141 | doi = 10.1517/eoed.9.1.155.32952}}</ref> Exendin-4 is the peptide used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using generically engineered amino acids.<ref name="pmid28283573"/>
 
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 = Mol Met | volume = 4 | issue = 10 | pages = 718–731 | date=4 August 2015| pmid = 26500843  | url = http://www.sciencedirect.com/science/article/pii/S2212877815001428 }}</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 = J. Neurosci. | volume = 22 | issue = 23 | pages = 10470–6 | date=1 December 2002| pmid = 12451146  | url = http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12451146 }}</ref> Furthermore, mice which over express GLP1R display improved memory and learning.<ref name="pmid12925848">{{cite journal |vauthors=During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN | title = Glucagon-like peptide-1 receptor is involved in learning and neuroprotection | journal = Nat. Med. | volume = 9 | issue = 9 | pages = 1173–9 |date=September 2003 | pmid = 12925848 | doi = 10.1038/nm919 }}</ref>
 
[http://www.genome.jp/kegg-bin/show_pathway?ko04911+K04581 '''Insulin release pathways''']
 
=== 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.<ref name="Martin_2009">{{cite journal |vauthors=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 | title = Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington's disease | journal = Diabetes | volume = 58 | issue = 2 | pages = 318–28 |date=February 2009 | pmid = 18984744 | pmc = 2628604 | doi = 10.2337/db08-0799 }}</ref>
 
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 [[Bcl-2-associated X protein|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 [[RAP1A|Rap]], [[Extracellular signal-regulated kinases|Erk1/2]], [[MAPK]], [[B-RAF]], [[PI3-K]], [[Cyclic adenosine monophosphate|cAMP]], [[Protein kinase A|PKA]], and [[CRTC2|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.<ref>{{cite web | author = Drucker DJ | title = Resurrecting the Beta Cell in Type 2 Diabetes: Beta-cell Function, Preservation, and Neogenesis | url=http://www.medscape.org/viewarticle/544820_2 | work = PowerPoint slides | publisher = Medscape }}</ref>
 
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 [[Huntingtin|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.<ref name="Martin_2009"/>
 
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.<ref name="Martin_2009"/>


==See also==
==See also==
* [[Glucagon-like peptide-1]]
* [[Glucagon-like peptide-1]]
* [[Dipeptidyl peptidase-4]]


==References==
==References==
<references/>
{{Reflist|2}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{Refbegin | 2}}
{{PBB_Further_reading
*{{cite journal   |vauthors=van Eyll B, Lankat-Buttgereit B, Bode HP, etal |title=Signal transduction of the GLP-1-receptor cloned from a human insulinoma |journal=FEBS Lett. |volume=348 |issue= 1 |pages= 7–13 |year= 1994 |pmid= 7517895 |doi=10.1016/0014-5793(94)00553-2 }}
| citations =
*{{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 Lett. |volume=373 |issue= 2 |pages= 182–6 |year= 1995 |pmid= 7589461 |doi=10.1016/0014-5793(95)01070-U }}
*{{cite journal | author=van Eyll B, Lankat-Buttgereit B, Bode HP, ''et al.'' |title=Signal transduction of the GLP-1-receptor cloned from a human insulinoma. |journal=FEBS Lett. |volume=348 |issue= 1 |pages= 7-13 |year= 1994 |pmid= 7517895 |doi=  }}
*{{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 Lett. |volume=358 |issue= 3 |pages= 219–24 |year= 1995 |pmid= 7843404 |doi=10.1016/0014-5793(94)01430-9 }}
*{{cite journal  | author=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 Lett. |volume=373 |issue= 2 |pages= 182-6 |year= 1995 |pmid= 7589461 |doi=  }}
*{{cite journal   |vauthors=Lankat-Buttgereit B, Göke R, Stöckmann F, etal |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  | author=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 Lett. |volume=358 |issue= 3 |pages= 219-24 |year= 1995 |pmid= 7843404 |doi=  }}
*{{cite journal   |vauthors=Graziano MP, Hey PJ, Borkowski D, etal |title=Cloning and functional expression of a human glucagon-like peptide-1 receptor |journal=Biochem. Biophys. Res. Commun. |volume=196 |issue= 1 |pages= 141–6 |year= 1993 |pmid= 8216285 |doi= 10.1006/bbrc.1993.2226 }}
*{{cite journal | author=Lankat-Buttgereit B, Göke R, Stöckmann F, ''et al.'' |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=  }}
*{{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 |year= 1993 |pmid= 8392011 |doi=10.2337/diabetes.42.8.1215 }}
*{{cite journal | author=Graziano MP, Hey PJ, Borkowski D, ''et al.'' |title=Cloning and functional expression of a human glucagon-like peptide-1 receptor. |journal=Biochem. Biophys. Res. Commun. |volume=196 |issue= 1 |pages= 141-6 |year= 1993 |pmid= 8216285 |doi= 10.1006/bbrc.1993.2226 }}
*{{cite journal   |vauthors=Dillon JS, Tanizawa Y, Wheeler MB, etal |title=Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor |journal=Endocrinology |volume=133 |issue= 4 |pages= 1907–10 |year= 1993 |pmid= 8404634 |doi=10.1210/en.133.4.1907 }}
*{{cite journal  | author=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 |year= 1993 |pmid= 8392011 |doi=  }}
*{{cite journal   |vauthors=Thorens B, Porret A, Bühler L, etal |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 |year= 1993 |pmid= 8405712 |doi=10.2337/diabetes.42.11.1678 }}
*{{cite journal | author=Dillon JS, Tanizawa Y, Wheeler MB, ''et al.'' |title=Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. |journal=Endocrinology |volume=133 |issue= 4 |pages= 1907-10 |year= 1993 |pmid= 8404634 |doi=  }}
*{{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 }}
*{{cite journal | author=Thorens B, Porret A, Bühler L, ''et al.'' |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 |year= 1993 |pmid= 8405712 |doi=  }}
*{{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 |year= 1999 |pmid= 10382665 |doi=10.1002/(SICI)1097-0134(19990601)35:4<375::AID-PROT1>3.0.CO;2-2  }}
*{{cite journal  | author=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=  }}
*{{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 |year= 2001 |pmid= 10990079 |doi=10.1007/s001250051484 }}
*{{cite journal  | author=Frimurer TM, Bywater RP |title=Structure of the integral membrane domain of the GLP1 receptor. |journal=Proteins |volume=35 |issue= 4 |pages= 375-86 |year= 1999 |pmid= 10382665 |doi= }}
*{{cite journal  |vauthors=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=10.1101/gr.143000  | pmc=310948 }}
*{{cite journal  | author=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 |year= 2001 |pmid= 10990079 |doi=  }}
*{{cite journal  |vauthors=Xiao Q, Jeng W, Wheeler MB |title=Characterization of glucagon-like peptide-1 receptor-binding determinants |journal=J. Mol. Endocrinol. |volume=25 |issue= 3 |pages= 321–35 |year= 2001 |pmid= 11116211 |doi=10.1677/jme.0.0250321 }}
*{{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi=  }}
*{{cite journal   |vauthors=Bazarsuren A, Grauschopf U, Wozny M, etal |title=In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor |journal=Biophys. Chem. |volume=96 |issue= 2-3 |pages= 305–18 |year= 2003 |pmid= 12034449 |doi=10.1016/S0301-4622(02)00023-6 }}
*{{cite journal  | author=Xiao Q, Jeng W, Wheeler MB |title=Characterization of glucagon-like peptide-1 receptor-binding determinants. |journal=J. Mol. Endocrinol. |volume=25 |issue= 3 |pages= 321-35 |year= 2001 |pmid= 11116211 |doi=  }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 }}
*{{cite journal | author=Bazarsuren A, Grauschopf U, Wozny M, ''et al.'' |title=In vitro folding, functional characterization, and disulfide pattern of the extracellular domain of human GLP-1 receptor. |journal=Biophys. Chem. |volume=96 |issue= 2-3 |pages= 305-18 |year= 2003 |pmid= 12034449 |doi=  }}
*{{cite journal   |vauthors=Mungall AJ, Palmer SA, Sims SK, etal |title=The DNA sequence and analysis of human chromosome 6 |journal=Nature |volume=425 |issue= 6960 |pages= 805–11 |year= 2003 |pmid= 14574404 |doi= 10.1038/nature02055 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal   |vauthors=Tokuyama Y, Matsui K, Egashira T, etal |title=Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population |journal=Diabetes Res. Clin. Pract. |volume=66 |issue= 1 |pages= 63–9 |year= 2005 |pmid= 15364163 |doi= 10.1016/j.diabres.2004.02.004 }}
*{{cite journal | author=Mungall AJ, Palmer SA, Sims SK, ''et al.'' |title=The DNA sequence and analysis of human chromosome 6. |journal=Nature |volume=425 |issue= 6960 |pages= 805-11 |year= 2003 |pmid= 14574404 |doi= 10.1038/nature02055 }}
*{{cite journal   |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 }}
*{{cite journal | author=Tokuyama Y, Matsui K, Egashira T, ''et al.'' |title=Five missense mutations in glucagon-like peptide 1 receptor gene in Japanese population. |journal=Diabetes Res. Clin. Pract. |volume=66 |issue= 1 |pages= 63-9 |year= 2005 |pmid= 15364163 |doi= 10.1016/j.diabres.2004.02.004 }}
*{{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=Mol. Endocrinol. |volume=19 |issue= 3 |pages= 812–23 |year= 2005 |pmid= 15528268 |doi= 10.1210/me.2004-0312 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{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 Lett. |volume=579 |issue= 3 |pages= 803–7 |year= 2005 |pmid= 15670850 |doi= 10.1016/j.febslet.2004.12.056 }}
*{{cite journal  | author=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=Mol. Endocrinol. |volume=19 |issue= 3 |pages= 812-23 |year= 2005 |pmid= 15528268 |doi= 10.1210/me.2004-0312 }}
*{{cite journal  |vauthors=de Graaf C, Donnelly C, Wootten D, etal |title=Glucagon-Like Peptide-1 and Its Class B G Protein–Coupled Receptors: A Long March to Therapeutic Successes |journal=Pharmacol. Rev. |volume= 68 |issue=4 |pages= 954–1013 |year= 2016 |doi= 10.1124/pr.115.011395 }}
*{{cite journal  | author=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 Lett. |volume=579 |issue= 3 |pages= 803-7 |year= 2005 |pmid= 15670850 |doi= 10.1016/j.febslet.2004.12.056 }}
*{{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 |title = Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators) |journal = Nature |doi= 10.1038/nature22378}}
}}
{{Refend}}
{{refend}}


==External links==
==External links==
*[http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2288 IUPHAR GPCR Database - GLP-1 receptor]
*{{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2288 | title = Glucagon Receptor Family: GLP-1 | accessdate = | date = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = }}
* {{MeshName|glucagon-like+peptide+receptor}}
* {{MeshName|glucagon-like+peptide+receptor}}


{{membrane-protein-stub}}
{{G protein-coupled receptors}}
{{G protein-coupled receptors}}
{{Peptidergics}}
{{DEFAULTSORT:Glucagon-Like Peptide 1 Receptor}}
[[Category:G protein coupled receptors]]
[[Category:G protein coupled receptors]]
{{WikiDoc Sources}}

Latest revision as of 21:53, 14 November 2017

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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.[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 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]

Human receptor ligands

GLP1R binds glucagon-like peptide-1 (GLP1) and glucagon as its natural endogenous agonists.[10]

Receptor agonists:

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.[12] Consequently, GLP1R has been a target for developing drugs usually referred to as GLP1R agonists to treat diabetes.[13] Exendin-4 is the peptide used therapeutically to treat diabetes, and its biological binding mode to the GLP-1R has been demonstrated using generically engineered amino acids.[11]

GLP1R is also expressed in the brain[14] where it is involved in the control of appetite.[15] Furthermore, mice which over express GLP1R display improved memory and learning.[16]

Insulin release pathways

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.[17]

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.[18]

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.[17]

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.[17]

See also

References

  1. ↑ 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. PMID 1326760.
  2. ↑ Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE III (October 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. PMID 8404634.
  3. ↑ 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.
  4. ↑ Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S (June 2010). "Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor". Journal of Biological Chemistry. 285 (1): 723–730. doi:10.1074/jbc.M109.033829. PMC 2804221. PMID 19861722.
  5. ↑ 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. "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators)". Nature. doi:10.1038/nature22378.
  6. ↑ 6.0 6.1 Wooten D, Reynolds CA, Koole C, Smith KJ, Mobarec JC, Simms J, Quon T, Coudrat T, Furness SG, Miller LJ, Christopolous A, Sexton PM (March 2016). "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". Molecular Pharmacology. 89 (3): 335–347. doi:10.1124/mol.115.101246. PMID 26700562.
  7. ↑ 7.0 7.1 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. PMID 27315480.
  8. ↑ 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.
  9. ↑ 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. PMID 27569426.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Maguire JJ, Davenport AP. "GLP-1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 13 September 2015.
  11. ↑ 11.0 11.1 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. doi:10.1074/jbc.M117.779496. PMID 28283573.
  12. ↑ 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. PMID 3033647.
  13. ↑ 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.
  14. ↑ 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. PMID 26500843.
  15. ↑ Kinzig KP, D'Alessio DA, Seeley RJ (1 December 2002). "The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness". J. Neurosci. 22 (23): 10470–6. PMID 12451146.
  16. ↑ 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.
  17. ↑ 17.0 17.1 17.2 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. PMID 18984744.
  18. ↑ Drucker DJ. "Resurrecting the Beta Cell in Type 2 Diabetes: Beta-cell Function, Preservation, and Neogenesis". PowerPoint slides. Medscape.

Further reading

External links

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