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glucagon receptor

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Target not currently curated in GtoImmuPdb

Target id: 251

Nomenclature: glucagon receptor

Family: Glucagon receptor family

Contents:

Gene and Protein Information Click here for help
class B G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 477 17q25.3 GCGR glucagon receptor 18,20
Mouse 7 485 11 E2 Gcgr glucagon receptor 2
Rat 7 485 10q32.3 Gcgr glucagon receptor 13,29
Previous and Unofficial Names Click here for help
GGR | GL-R | GR
Database Links Click here for help
Specialist databases
GPCRdb glr_human (Hs), glr_mouse (Mm), glr_rat (Rn)
Other databases
Alphafold P47871 (Hs), Q61606 (Mm), P30082 (Rn)
CATH/Gene3D 4.10.1240.10
ChEMBL Target CHEMBL1985 (Hs), CHEMBL4773 (Mm), CHEMBL4720 (Rn)
DrugBank Target P47871 (Hs)
Ensembl Gene ENSG00000215644 (Hs), ENSMUSG00000025127 (Mm), ENSRNOG00000036692 (Rn)
Entrez Gene 2642 (Hs), 14527 (Mm), 24953 (Rn)
Human Protein Atlas ENSG00000215644 (Hs)
KEGG Gene hsa:2642 (Hs), mmu:14527 (Mm), rno:24953 (Rn)
OMIM 138033 (Hs)
Pharos P47871 (Hs)
RefSeq Nucleotide NM_000160 (Hs), NM_008101 (Mm), NM_172091 (Rn)
RefSeq Protein NP_000151 (Hs), NP_032127 (Mm), NP_742088 (Rn)
SynPHARM 84366 (in complex with NNC0640)
84753 (in complex with NNC1702)
UniProtKB P47871 (Hs), Q61606 (Mm), P30082 (Rn)
Wikipedia GCGR (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of the extracellular domain of the glucagon receptor in complex with mAb1
PDB Id:  4ERS
Resolution:  1.5Å
Species:  Human
References:  16
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the class B human glucagon G protein coupled receptor
PDB Id:  4L6R
Resolution:  3.3Å
Species:  Human
References:  28
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human glucagon receptor (GCGR) in complex with the antagonist MK-0893.
PDB Id:  5EE7
Ligand:  MK-0893
Resolution:  2.5Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of the full-length human glucagon receptor in an inactive conformation in complex with a negative allosteric modulator NNC0640, and antigen-binding fragment (Fab) of an inhibitory antibody, mAb1.
PDB Id:  5XEZ
Ligand:  NNC0640
Resolution:  3.0Å
Species:  Human
References:  35
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the glucagon receptor in complex with a glucagon peptide analogue
PDB Id:  5YQZ
Ligand:  NNC1702
Resolution:  3.0Å
Species:  Human
References:  36
Natural/Endogenous Ligands Click here for help
glucagon {Sp: Human, Mouse, Rat}

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
glucagon {Sp: Human, Mouse, Rat} Peptide Approved drug Primary target of this compound Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 9.0 pEC50 25
⤷ pEC50 9.0 [25]
glucagon-(1-21) Peptide Rn Full agonist 6.0 pEC50 32
⤷ pEC50 6.0 [32]
glucagon-(1-6) Peptide Rn Partial agonist 4.0 pEC50 33
⤷ pEC50 4.0 [33]
NNC1702 Peptide Hs Agonist 7.3 pIC50 36
⤷ pIC50 7.3 (IC50 5.35x10-8 M) [36]
[125I]glucagon (human, mouse, rat) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist - -
⤷
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
des-His1-[Glu9]glucagon-NH2 Peptide Rn Antagonist 7.2 pA2 30-31
⤷ pA2 7.2 [30-31]
adomeglivant Small molecule or natural product Approved drug Hs Antagonist 8.2 pKi 14-15
⤷ pKi 8.2 (Ki 6.66x10-9 M) [14-15]
NNC 92-1687 Small molecule or natural product Hs Antagonist 5.0 pKi 19
⤷ pKi 5.0 (Ki 9.1x10-6 M) [19]
des-His1-[Leu4-Glu9]glucagon-NH2 Peptide Rn Antagonist 8.7 pIC50 1
⤷ pIC50 8.7 [1]
L-168,049 Small molecule or natural product Hs Antagonist 8.4 pIC50 5
⤷ pIC50 8.4 (IC50 3.7x10-9 M) [5]
hGCGR antagonist Small molecule or natural product Hs Antagonist 7.1 – 7.5 pIC50 6,26
⤷ pIC50 7.5 [6]
pIC50 7.1 [26]
BAY27-9955 Small molecule or natural product Hs Antagonist - - 24
⤷ [24]
View species-specific antagonist tables
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MK-0893 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Negative 8.2 pIC50 34
⤷ pIC50 8.2 (IC50 6.6x10-9 M) [34]
NNC0640 Small molecule or natural product Ligand has a PDB structure Hs Negative 7.2 pIC50 35
⤷ pIC50 7.2 (IC50 6.92x10-8 M) [35]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
crotedumab Peptide Rn Antagonist 10.8 pKd 22
⤷ pKd 10.8 (Kd 1.5x10-11 M) [22]
crotedumab Peptide Mm Antagonist 10.1 – 10.5 pKd 22
⤷ pKd 10.1 – 10.5 (Kd 8.99x10-11 – 3.05x10-11 M) [22]
crotedumab Peptide Monkey Antagonist 9.4 – 10.5 pKd 22
⤷ pKd 9.4 – 10.5 (Kd 3.86x10-10 – 3.03x10-11 M) [22]
crotedumab Peptide Primary target of this compound Hs Antagonist 9.8 – 10.0 pKd 22
⤷ pKd 9.8 – 10.0 (Kd 1.62x10-10 – 1.09x10-10 M) [22]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family Adenylyl cyclase stimulation
References:  21
Tissue Distribution Click here for help
Liver and kidney.
Fetal and adult pancreas, lung, jejunumn and ileum.
Not large intestine.
Species:  Mouse
Technique:  Northern Blot and RT-PCR
References:  4
Highest expression in the liver and kidney.
Also expressed in the spleen, thymus, adrenal glands, pancreas, cerebral cortex, lung and throught the gastrointestinal tract.
Species:  Rat
Technique:  Southern blot and RT-PCR.
References:  7
High levels in the liver, kidney, heart, adipose tissue, spleen, pancreatic islets, ovary and thymus.
Lower levels found in the stomach, small intestine, adrenal gland, thyroid and skeletal muscle.
Species:  Rat
Technique:  Ribonuclease protection assay
References:  11
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of adenylate cyclase activity.
Species:  Rat
Tissue:  Liver.
Response measured:  Increase in cAMP production.
References:  25
Physiological Functions Click here for help
Glycogenolysis.
Species:  Human
Tissue:  Liver
References:  3
Gluconeogenesis.
Species:  Rat
Tissue:  Liver
References:  8
Lipolysis.
Species:  Rat
Tissue:  Fat tissue
References:  17
Physiological Consequences of Altering Gene Expression Click here for help
Gcgr knock out mice show slight hypoglycaemia, normoinsulinemia, improved glucose tolerance, alpha cell hyperplasia and a striking increase of glucagon content in the pancreas and blood.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  9,23
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0001780 decreased brown adipose tissue amount PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0005560 decreased circulating glucose level PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0005668 decreased circulating leptin level PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0009283 decreased gonadal fat pad weight PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0009295 decreased interscapular fat pad weight PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0001935 decreased litter size PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0010025 decreased total body fat amount PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0005318 decreased triglyceride level PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0000189 hypoglycemia PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0005292 improved glucose tolerance PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0006087 increased body mass index PMID: 12552113 
Gcgrtm1Jcp Gcgrtm1Jcp/Gcgrtm1Jcp
DBA/1LacJ		 MGI:99572  MP:0002712 increased circulating glucagon level PMID: 11785978 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0002712 increased circulating glucagon level PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0000182 increased circulating LDL cholesterol level PMID: 12552113 
Gcgrtm1(GCGR)Kasu Gcgrtm1(GCGR)Kasu/Gcgrtm1(GCGR)Kasu
involves: 129S7/SvEvBrd * C57BL/6J		 MGI:99572  MP:0002169 no abnormal phenotype detected PMID: 10621976 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0005491 pancreatic islet hyperplasia PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0002082 postnatal lethality PMID: 12552113 
Gcgrtm1Mjch Gcgrtm1Mjch/Gcgrtm1Mjch
involves: 129/Sv * C57BL/6J * SJL		 MGI:99572  MP:0002080 prenatal lethality PMID: 12552113 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  A naturally occurring single heterozygous Gly40->Ser missense polymorphism has been found in 2-8% of white populations. A point mutation occurring at codon 40 of exon 2 of the receptor gene results in the substitution of a serine for a glycine in the receptor structure.
This mutation has been shown to cause alterations in body fat accumulation and distribution.
Amino acid change:  G40S
References:  10,27

References

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1. Ahn JM, Medeiros M, Trivedi D, Hruby VJ. (2001) Development of potent glucagon antagonists: structure-activity relationship study of glycine at position 4. J Pept Res, 58 (2): 151-8. [PMID:11532074]

2. Burcelin R, Li J, Charron MJ. (1995) Cloning and sequence analysis of the murine glucagon receptor-encoding gene. Gene, 164 (2): 305-10. [PMID:7590348]

3. CAHILL Jr GF, EARLE AS, ZOTTU S. (1957) In vivo effects of glucagon on hepatic glycogen, phosphorylase and glucose-6-phosphatase. Endocrinology, 60 (2): 265-9. [PMID:13397492]

4. Campos RV, Lee YC, Drucker DJ. (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology, 134 (5): 2156-64. [PMID:8156917]

5. Cascieri MA, Koch GE, Ber E, Sadowski SJ, Louizides D, de Laszlo SE, Hacker C, Hagmann WK, MacCoss M, Chicchi GG et al.. (1999) Characterization of a novel, non-peptidyl antagonist of the human glucagon receptor. J Biol Chem, 274 (13): 8694-7. [PMID:10085108]

6. Duffy JL, Kirk BA, Konteatis Z, Campbell EL, Liang R, Brady EJ, Candelore MR, Ding VD, Jiang G, Liu F et al.. (2005) Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett, 15 (5): 1401-5. [PMID:15713396]

7. Dunphy JL, Taylor RG, Fuller PJ. (1998) Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expression. Mol Cell Endocrinol, 141 (1-2): 179-86. [PMID:9723898]

8. Exton JH, Park CR. (1966) The stimulation of gluconeogenesis from lactate by epinephrine, glucagon and cyclic 3í-5í-adenylate in the perfused rat liver. Pharmacol Rev, 18: 181-188. [PMID:5904135]

9. Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C et al.. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA, 100 (3): 1438-43. [PMID:12552113]

10. Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, Velho G, Carcassi C, Contu L, Julier C et al.. (1995) A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Nat Genet, 9 (3): 299-304. [PMID:7773293]

11. Hansen LH, Abrahamsen N, Nishimura E. (1995) Glucagon receptor mRNA distribution in rat tissues. Peptides, 16 (6): 1163-6. [PMID:8532603]

12. Jazayeri A, Doré AS, Lamb D, Krishnamurthy H, Southall SM, Baig AH, Bortolato A, Koglin M, Robertson NJ, Errey JC et al.. (2016) Extra-helical binding site of a glucagon receptor antagonist. Nature, 533 (7602): 274-7. [PMID:27111510]

13. Jelinek LJ, Lok S, Rosenberg GB, Smith RA, Grant FJ, Biggs S, Bensch PA, Kuijper JL, Sheppard PO, Sprecher CA et al.. (1993) Expression cloning and signaling properties of the rat glucagon receptor. Science, 259 (5101): 1614-6. [PMID:8384375]

14. Kazda CM, Ding Y, Kelly RP, Garhyan P, Shi C, Lim CN, Fu H, Watson DE, Lewin AJ, Landschulz WH et al.. (2016) Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies. Diabetes Care, 39 (7): 1241-9. [PMID:26681715]

15. Kelly RP, Garhyan P, Raddad E, Fu H, Lim CN, Prince MJ, Pinaire JA, Loh MT, Deeg MA. (2015) Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab, 17 (4): 414-22. [PMID:25656305]

16. Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A et al.. (2012) Molecular basis for negative regulation of the glucagon receptor. Proc Natl Acad Sci USA, 109 (36): 14393-8. [PMID:22908259]

17. Lefebvre P. (1966) The physiological effect of glucagon on fat mobilization. Diabetologia, 2: 130-132. [PMID:6005201]

18. Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB et al.. (1994) The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization. Gene, 140 (2): 203-9. [PMID:8144028]

19. Madsen P, Knudsen LB, Wiberg FC, Carr RD. (1998) Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J Med Chem, 41 (26): 5150-7. [PMID:9857085]

20. Menzel S, Stoffel M, Espinosa 3rd R, Fernald AA, Le Beau MM, Bell GI. (1994) Localization of the glucagon receptor gene to human chromosome band 17q25. Genomics, 20 (2): 327-8. [PMID:8020989]

21. Northup JK, Smigel MD, Sternweis PC, Gilman AG. (1983) The subunits of the stimulatory regulatory component of adenylate cyclase. Resolution of the activated 45,000-dalton (alpha) subunit. J Biol Chem, 258: 11369-11376. [PMID:6309844]

22. Okamoto H, Kim J, Aglione J, Lee J, Cavino K, Na E, Rafique A, Kim JH, Harp J, Valenzuela DM et al.. (2015) Glucagon Receptor Blockade With a Human Antibody Normalizes Blood Glucose in Diabetic Mice and Monkeys. Endocrinology, 156 (8): 2781-94. [PMID:26020795]

23. Parker JC, Andrews KM, Allen MR, Stock JL, McNeish JD. (2002) Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun, 290: 839-843. [PMID:11785978]

24. Petersen KF, Sullivan JT. (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia, 44 (11): 2018-24. [PMID:11719833]

25. Pohl SL, Birnbaumer L, Rodbell M. (1969) Glucagon-sensitive adenyl cylase in plasma membrane of hepatic parenchymal cells. Science, 164 (3879): 566-7. [PMID:4305077]

26. Qureshi SA, Rios Candelore M, Xie D, Yang X, Tota LM, Ding VD, Li Z, Bansal A, Miller C, Cohen SM et al.. (2004) A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes, 53 (12): 3267-73. [PMID:15561959]

27. Siani A, Iacone R, Russo O, Barba G, Russo P, Cappuccio FP, Galletti F, Strazzullo P. (2001) Gly40Ser polymorphism of the glucagon receptor gene is associated with central adiposity in men. Obes Res, 9 (11): 722-6. [PMID:11707539]

28. Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS et al.. (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature, 499 (7459): 444-9. [PMID:23863937]

29. Szpirer C, Szpirer J, Vanvooren P, Rivière M, Maget B, Svoboda M, Shiozawa M, Simon JS, Jacob HJ, Koike G. (1997) Localization of the rat genes encoding glucagon, glucagon receptor, and insulin receptor, candidates for diabetes mellitus susceptibility loci. Mamm Genome, 8 (8): 586-8. [PMID:9250867]

30. Unson CG, Andreu D, Gurzenda EM, Merrifield RB. (1987) Synthetic peptide antagonists of glucagon. Proc Natl Acad Sci USA, 84 (12): 4083-7. [PMID:3035568]

31. Unson CG, Gurzenda EM, Merrifield RB. (1989) Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides, 10 (6): 1171-7. [PMID:2560175]

32. Wright DE, Hruby VJ, Rodbell M. (1978) A reassessment of structure-function relationships in glucagon. Glucagon1-21 is a full agonist. J Biol Chem, 253 (18): 6338-40. [PMID:210180]

33. Wright DE, Rodbell M. (1979) Glucagon1-6 binds to the glucagon receptor and activates hepatic adenylate cyclase. J Biol Chem, 254: 268-269. [PMID:216670]

34. Xiong Y, Guo J, Candelore MR, Liang R, Miller C, Dallas-Yang Q, Jiang G, McCann PE, Qureshi SA, Tong X et al.. (2012) Discovery of a novel glucagon receptor antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes. J Med Chem, 55 (13): 6137-48. [PMID:22708876]

35. Zhang H, Qiao A, Yang D, Yang L, Dai A, de Graaf C, Reedtz-Runge S, Dharmarajan V, Zhang H, Han GW et al.. (2017) Structure of the full-length glucagon class B G-protein-coupled receptor. Nature, 546 (7657): 259-264. [PMID:28514451]

36. Zhang H, Qiao A, Yang L, Van Eps N, Frederiksen KS, Yang D, Dai A, Cai X, Zhang H, Yi C et al.. (2018) Structure of the glucagon receptor in complex with a glucagon analogue. Nature, 553 (7686): 106-110. [PMID:29300013]

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