Nomenclature: glucagon receptor

Family: Glucagon receptor family

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class B G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 477 17q25 GCGR glucagon receptor 15,17
Mouse 7 485 11 E2 Gcgr glucagon receptor 2
Rat 7 485 10q32.3 Gcgr glucagon receptor 12,24
Previous and Unofficial Names
GGR
MGC93090
GL-R
glucagon receptor perhaps same as Niddm3
GR
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Selected 3D Structures
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:  13
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:  23
Natural/Endogenous Ligands
glucagon {Sp: Human, Mouse, Rat}
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
glucagon {Sp: Human, Mouse, Rat} Hs Full agonist 9.0 pEC50 20
pEC50 9.0 [20]
glucagon-(1-21) Rn Full agonist 6.0 pEC50 27
pEC50 6.0 [27]
glucagon-(1-6) Rn Partial agonist 4.0 pEC50 28
pEC50 4.0 [28]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
des-His1-[Glu9]glucagon-NH2 Rn Antagonist 7.2 pA2 25-26
pA2 7.2 [25-26]
NNC 92-1687 Hs Antagonist 5.0 pKi 16
pKi 5.0 (Ki 9.1x10-6 M) [16]
des-His1-[Leu4-Glu9]glucagon-NH2 Rn Antagonist 8.7 pIC50 1
pIC50 8.7 [1]
L-168,049 Hs Antagonist 8.4 pIC50 5
pIC50 8.4 (IC50 3.7x10-9 M) [5]
N-[3-cyano-6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutanamide Hs Antagonist 7.1 – 7.5 pIC50 6,21
pIC50 7.5 [6]
pIC50 7.1 [21]
View species-specific antagonist tables
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  18
Tissue Distribution
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

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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]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays
Measurement of adenylate cyclase activity.
Species:  Rat
Tissue:  Liver.
Response measured:  Increase in cAMP production.
References:  20
Physiological Functions
Glycogenolysis.
Species:  Human
Tissue:  Liver
References:  3
Gluconeogenesis.
Species:  Rat
Tissue:  Liver
References:  8
Lipolysis.
Species:  Rat
Tissue:  Fat tissue
References:  14
Physiological Consequences of Altering Gene Expression
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:  9,19
Phenotypes, Alleles and Disease Models 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
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.
References:  10,22
Available Assays
DiscoveRx PathHunter® CHO-K1 GCGR β-Arrestin Cell Line (Cat no. 93-0241C2)
PathHunter® eXpress GCGR CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0241E2CP0M)
more info

REFERENCES

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 Peptide Res58: 151-158. [PMID:11532074]

2. Burcelin R, Charron MJ. (1995) Cloning and sequence analysis of the murine glucagon receptor-encoding gene. Gene164: 305-310. [PMID:7590348]

3. Cahill GF, Zottu S, Earle AS. (1957) In vivo effects of glucagon on hepatic glycogen, phosphorylase and glucose-6-phosphatase. Endocrinology60: 265-269. [PMID:13397492]

4. Campos RV, Drucker DJ. (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology134: 2156-2164. [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, Qureshi SA, Saperstein R, Szalkowski D, Tong S, Tota LM, Xie D, Yang X, Zafian P, Zheng S, Chapman KT, Zhang BB, Tata JR. (2005) Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett15: 1401-1405. [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: 179-186. [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 Rev18: 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, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA100: 1438-1443. [PMID:12552113]

10. Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, Velho G, Carcassi C, Contu L, Julier C. (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. Peptides16: 1163-1166. [PMID:8532603]

12. Jelinek LJ, Lok S, Rosenberg GB, Smith RA, Grant FJ, Biggs S, Bensch PA, Kuijper JL, Sheppard PO, Sprecher CA. (1993) Expression cloning and signaling properties of the rat glucagon receptor. Science259 (5101): 1614-6. [PMID:8384375]

13. 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. U.S.A.109 (36): 14393-8. [PMID:22908259]

14. Lefebvre P. (1966) The physiological effect of glucagon on fat mobilization. Diabetologia2: 130-132. [PMID:6005201]

15. 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. Gene140 (2): 203-9. [PMID:8144028]

16. 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]

17. Menzel S, Stoffel M, Espinosa R, Fernald AA, Le Beau MM, Bell GI. (1994) Localization of the glucagon receptor gene to human chromosome band 17q25. Genomics20: 327-328. [PMID:8020989]

18. 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 Chem258: 11369-11376. [PMID:6309844]

19. 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]

20. Pohl SL, Birnbaumer L, Rodbell M. (1969) Glucagon-sensitive adenyl cylase in plasma membrane of hepatic parenchymal cells. Science164: 566-567. [PMID:4305077]

21. Qureshi SA, Rios Candelore M, Xie D, Yang X, Tota LM, Ding VD, Li Z, Bansal A, Miller C, Cohen SM, Jiang G, Brady E, Saperstein R, Duffy JL, Tata JR, Chapman KT, Moller DE, Zhang BB. (2004) A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes53: 3267-3273. [PMID:15561959]

22. 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: 722-726. [PMID:11707539]

23. 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,  [Epub ahead of print]. [PMID:23863937]

24. Szpirer C, Szpirer J, Vanvooren P, Riviere 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 Genome8: 586-588. [PMID:9250867]

25. Unson C, Merrifield RB. (1987) Synthetic peptide antagonists of glucagon. Proc. Natl. Acad. Sci. U.S.A.84: 4083-4087. [PMID:3035568]

26. Unson CG, Gurzenda EM, Merrifield RB. (1989) Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides10 (6): 1171-7. [PMID:2560175]

27. 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: 6338-6340. [PMID:210180]

28. 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]

To cite this database page, please use the following:

Dominique Bataille, Philippe Delagrange, Daniel J. Drucker, Burkhard Göke, Rebecca Hills, Kelly E. Mayo, Laurence J. Miller, Bernard Thorens.
Glucagon receptor family: glucagon receptor. Last modified on 18/12/2013. Accessed on 25/10/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=251.

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