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glucagon receptor

Family: Glucagon receptor family

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Selected 3D Structures
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
References
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 14,16
Mouse 7 485 11 E2 Gcgr glucagon receptor 2
Rat 7 485 10q32.3 Gcgr glucagon receptor 12,22
Previous and Unofficial Names
GGR
MGC93090
GL-R
glucagon receptor perhaps same as Niddm3
GR
Database Links
ChEMBL Target 146 (Hs), 11141 (Mm), 11142 (Rn)
DrugBank Target 584 (Hs)
Ensembl ENSG00000215644 (Hs), ENSMUSG00000025127 (Mm), ENSRNOG00000036692 (Rn)
Entrez Gene 2642 (Hs), 14527 (Mm), 24953 (Rn)
GeneCards GCGR (Hs)
GenitoUrinary Development Molecular Anatomy Project Gcgr (Mm)
HomoloGene 131 (Hs)
Human Protein Reference Database 00678 (Hs)
InterPro P47871 (Hs), Q61606 (Mm), P30082 (Rn)
KEGG Gene hsa:2642 (Hs), mmu:14527 (Mm), rno:24953 (Rn)
OMIM 138033 (Hs)
PharmGKB Gene PA28607 (Hs)
PhosphoSitePlus P47871 (Hs), Q61606 (Mm), P30082 (Rn)
Protein Ontology (PRO) PRO:000007892 (Hs)
RefSeq Nucleotide NM_000160 (Hs), NM_008101 (Mm), NM_172091 (Rn)
RefSeq Protein NP_000151 (Hs), NP_032127 (Mm), NP_742088 (Rn)
TreeFam ENSG00000215644 (Hs), ENSMUSG00000025127 (Mm), ENSRNOG00000036692 (Rn)
UniGene Hs. 208 (Hs)
UniProt P47871 (Hs), Q61606 (Mm), P30082 (Rn)
Wikipedia glucagon receptor
Glucagon receptor family
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: 
Search for other structures on the PDB
Search by keyword: Glucagon receptor family glucagon receptor Search by accession number: P30082, P47871, Q61606
Natural/Endogenous Ligand(s)
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 19
glucagon-(1-21) Rn Full agonist 6.0 pEC50 26
glucagon-(1-6) Rn Partial agonist 4.0 pEC50 25
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 23-24
NNC 92-1687 Hs Antagonist 5.0 pKi 15
des-His1-[Leu4-Glu9]glucagon-NH2 Rn Antagonist 8.7 pIC50 1
L-168,049 Hs Antagonist 8.4 pIC50 5
N-[3-cyano-6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutanamide Hs Antagonist 7.5 pIC50 6
N-[3-cyano-6-(1,1-dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutanamide Hs Antagonist 7.1 pIC50 20
View species-specific antagonist tables

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gs family Adenylate cyclase stimulation
References:  17
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:  10
Expression Datasets

Click here to show/hide data

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
Measurement of adenylate cyclase activity.
Species:  Rat
Tissue:  Liver.
Response measured:  Increase in cAMP production.
References:  19
Physiological Functions
Glycogenolysis.
Species:  Human
Tissue:  Liver
References:  3
Gluconeogenesis.
Species:  Rat
Tissue:  Liver
References:  8
Lipolysis.
Species:  Rat
Tissue:  Fat tissue
References:  13
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:  9,18
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

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
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.
Type:  Single nucleotide polymorphism.
Species:  Human
References:  11,21

REFERENCES

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1. Ahn, J. M., Medeiros, M., Trivedi, D. and Hruby, V. J. (2001) Development of potent glucagon antagonists : structure-activity relationship study of glycine at position 4. J Peptide Res, 58: 151-158. [PMID:11532074]

2. Burcelin, R. and Charron, M. J. (1995) Cloning and sequence analysis of the murine glucagon receptor-encoding gene. Gene, 164: 305-310. [PMID:7590348]

3. Cahill, G. F., Zottu, S. and Earle, A. S. (1957) In vivo effects of glucagon on hepatic glycogen, phosphorylase and glucose-6-phosphatase. Endocrinology, 60: 265-269. [PMID:13397492]

4. Campos, R. V. and Drucker, D. J. (1994) Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in the mouse. Endocrinology, 134: 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, J. L., Kirk, B. A., Konteatis, Z., Campbell, E. L., Liang, R., Brady, E. J., Candelore, M. R., Ding, V. D., Jiang, G., Liu, F., Qureshi, S. A., Saperstein, R., Szalkowski, D., Tong, S., Tota, L. M., Xie, D., Yang, X., Zafian, P., Zheng, S., Chapman, K. T., Zhang, B. B. and Tata, J. R. (2005) Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett, 15: 1401-1405. [PMID:15713396]

7. Dunphy, J. L., Taylor, R. G. and Fuller, P. J. (1998) Tissue distribution of rat glucagon receptor and GLP-1 receptor gene expression. Mol Cell Endocrinol., 141: 179-186. [PMID:9723898]

8. Exton, J. H. and Park, C. R. (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, R. W., Du, X. Q., Dichmann, D. S., Romer, J., Huang, H., Cui, L., Obici, S., Tang, B., Holst, J. J., Fledelius, C., Johansen, P. B., Rossetti, L., Jelicks, L. A., Serup, P., Nishimura, E. and Charron, M. J. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA, 100: 1438-1443. [PMID:12552113]

10. Hansen, L. H., Abrahamsen, N. and Nishimura, E. (1995) Glucagon receptor mRNA distribution in rat tissues. Peptides, 16: 1163-1166. [PMID:8532603]

11. J. Hager, , L. Hansen, , C. Vaisse, , N. Vionnet, , A. Philippi, , W. Poller, , G. Velho, , C. Carcassi, , L. Contu, , C. Julier, , F. Cambien, , P. Passa, , M. Lathrop, , W. Kindsvogel, , F. Demenais, , , and , . (1995) A missense mutation in the glucagon receptor gene is associated with non–insulin–dependent diabetes mellitus. Nature Genetics, 9: 299-304. [PMID:7773293]

12. Jelinek, L. J. et al.. (1993) Expression cloning and signalling properties of the rat glucagon receptor. Science, 259: 1614-1616. [PMID:8384375]

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

14. Lok, S. et al.. (1994) The human glucagon receptor encoding gene: Structure, cDNA sequence and chromosomal localization. Gene, 140: 203-209. [PMID:8144028]

15. 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]

16. Menzel, S., Stoffel, M., Espinosa, R., Fernald, A. A., Le Beau, M. M. and Bell, G. I. (1994) Localization of the glucagon receptor gene to human chromosome band 17q25. Genomics, 20: 327-328. [PMID:8020989]

17. Northup, J. K., Smigel, M. D., Sternweis, P. C. and Gilman, A. G. (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]

18. Parker, J. C., Andrews, K. M., Allen, M. R., Stock, J. L. and McNeish, J. D. (2002) Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun., 290: 839-843. [PMID:11785978]

19. Pohl, S. L., Birnbaumer, L. and Rodbell, M. (1969) Glucagon-sensitive adenyl cylase in plasma membrane of hepatic parenchymal cells. Science, 164: 566-567. [PMID:4305077]

20. Qureshi, S. A., Rios Candelore, M., Xie, D., Yang, X., Tota, L. M., Ding, V. D., Li, Z., Bansal, A., Miller, C., Cohen, S. M., Jiang, G., Brady, E., Saperstein, R., Duffy, J. L., Tata, J. R., Chapman, K. T., Moller, D. E. and Zhang, B. B. (2004) A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes, 53: 3267-3273. [PMID:15561959]

21. Siani, A., Iacone, R., Russo, O., Barba, G., Russo, P., Cappuccio, F. P., Galletti, F. and Strazzullo, P. (2001) Gly40Ser polymorphism of the glucagon receptor gene is associated with central adiposity in men. Obes Res., 9: 722-726. [PMID:11707539]

22. Szpirer, C., Szpirer, J., Vanvooren, P., Riviere, M., Maget, B., Svoboda, M., Shiozawa, M., Simon, J. S., Jacob, H. J. and Koike, G. (1997) Localization of the rat genes encoding glucagon, glucagon receptor, and insulin receptor, candidates for diabetes mellitus susceptibility loci. Mamm Genome, 8: 586-588. [PMID:9250867]

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

24. 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]

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

26. Wright, D. E., Hruby, V. J. and 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]

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 08/03/2013. Accessed on 25/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=251.


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