Glucagon receptor

GCGR
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3CZF, 4ERS, 4L6R, 2A83, 4LF3, 5EE7
Identifiers
Aliases	GCGR , GGR, GL-R, glucagon receptor, MVAH
External IDs	OMIM: 138033; MGI: 99572; HomoloGene: 131; GeneCards: GCGR; OMA:GCGR - orthologs
Gene location (Human) Chr. Chromosome 17 (human) [1] Band 17q25.3 Start 81,804,132 bp [1] End 81,814,008 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 E2 Start 120,421,525 bp [2] End 120,429,812 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver tibial nerve sural nerve human kidney gonad islet of Langerhans skin of abdomen body of pancreas skin of leg muscle layer of sigmoid colon Top expressed in lobe of liver left lobe of liver right kidney medullary collecting duct islet of Langerhans footplate human kidney renal cortex yolk sac proximal tubule More reference expression data BioGPS n/a
Gene ontology Molecular function G protein-coupled receptor activity guanyl-nucleotide exchange factor activity signal transducer activity peptide hormone binding glucagon receptor activity transmembrane signaling receptor activity G protein-coupled peptide receptor activity Cellular component integral component of membrane endosome membrane plasma membrane integral component of plasma membrane Biological process glucose homeostasis response to nutrient adenylate cyclase-modulating G protein-coupled receptor signaling pathway cellular response to glucagon stimulus generation of precursor metabolites and energy regulation of glycogen metabolic process regulation of blood pressure cell surface receptor signaling pathway hormone-mediated signaling pathway response to starvation signal transduction exocytosis adenylate cyclase-activating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2642 14527 Ensembl ENSG00000215644 ENSG00000288269 ENSMUSG00000025127 UniProt P47871 Q61606 RefSeq (mRNA) NM_000160 NM_008101 RefSeq (protein) NP_000151 NP_032127 Location (UCSC) Chr 17: 81.8 – 81.81 Mb Chr 11: 120.42 – 120.43 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors (secretin receptor family), coupled to G alpha i, G_s and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. In humans, the glucagon receptor is encoded by the GCGR gene.

Glucagon receptors are mainly expressed in liver and in kidney with lesser amounts found in heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex, and gastrointestinal tract.

Signal transduction pathway

A glucagon receptor, upon binding with the signaling molecule glucagon, initiates a signal transduction pathway that begins with the activation of adenylate cyclase, which in turn produces cyclic AMP (cAMP). Protein kinase A, whose activation is dependent on the increased levels of cAMP, is responsible for the ensuing cellular response in the form of protein kinase 1 and 2. The ligand-bound glucagon receptor can also initiate a concurrent signaling pathway that is independent of cAMP by activating phospholipase C. Phospholipase C produces DAG and IP₃ from PIP₂, a phospholipid phospholipase C cleaves off of the plasma membrane. Ca²⁺ stores inside the cell release Ca²⁺ when its calcium channels are bound by IP_3. ^{[5] [6]}

Structure

glucagon/glucagon receptor (blue) with glucagon bound (pink)

The 3D crystallographic structures of the seven transmembrane helical domain (7TM) ^[7] and the extracellular domain (ECD) ^[8] and an electron microscopy (EM) map of full length glucagon receptor ^[9] have been determined. Furthermore, the structural dynamics of an active state complex of the Glucagon receptor, Glucagon, the Receptor activity-modifying protein, and the G-protein C-terminus has been determined using a computational and experimental approach. ^[10]

Clinical significance

A missense mutation at 17q25 ^[11] in the GCGR gene is associated with diabetes mellitus type 2. ^[12]

Inactivating mutation of glucagon receptor in humans causes resistance to glucagon and is associated with pancreatic alpha cell hyperplasia, nesidioblastosis, hyperglucagonemia, and pancreatic neuroendocrine tumors, also known as Mahvash disease. ^{[13] [14]}

References

1. ENSG00000288269 GRCh38: Ensembl release 89: ENSG00000215644, ENSG00000288269 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025127 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Urry LA, Cain ML, Wasserman SA, Minorsky PV, Reece JB, Campbell NA. Campbell biology (Eleventh ed.). New York, NY. ISBN   0-13-409341-0. OCLC   956379308.
6. Scanes CG (30 June 2014). Sturkie's avian physiology (Sixth ed.). London, England: Academic Press. ISBN   978-0-12-407243-5. OCLC   884590323.
7. PDB: 4L6R ​; Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, et al. (July 2013). "Structure of the human glucagon class B G-protein-coupled receptor". Nature. 499 (7459): 444–449. Bibcode:2013Natur.499..444S. doi:10.1038/nature12393. PMC   3820480 . PMID   23863937.
8. PDB: 4ERS ​; Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, et al. (September 2012). "Molecular basis for negative regulation of the glucagon receptor". Proceedings of the National Academy of Sciences of the United States of America. 109 (36): 14393–14398. Bibcode:2012PNAS..10914393K. doi: 10.1073/pnas.1206734109 . PMC   3437825 . PMID   22908259.
9. Yang L, Yang D, de Graaf C, Moeller A, West GM, Dharmarajan V, et al. (July 2015). "Conformational states of the full-length glucagon receptor". Nature Communications. 6: 7859. Bibcode:2015NatCo...6.7859Y. doi:10.1038/ncomms8859. PMC   4532856 . PMID   26227798.
10. Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, et al. (October 2016). "Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors". The Journal of Biological Chemistry. 291 (42): 21925–21944. doi: 10.1074/jbc.M116.751362 . PMC   5063977 . PMID   27566546.
11. Brubaker PL, Drucker DJ (2002). "Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors". Receptors & Channels. 8 (3–4): 179–188. doi:10.1080/10606820213687. PMID   12529935.
12. Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, et al. (March 1995). "A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus". Nature Genetics. 9 (3): 299–304. doi:10.1038/ng0395-299. PMID   7773293. S2CID   26951878.
13. Zhou C, Dhall D, Nissen NN, Chen CR, Yu R (November 2009). "Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor". Pancreas. 38 (8): 941–946. doi:10.1097/MPA.0b013e3181b2bb03. PMC   2767399 . PMID   19657311.
14. Yu R (2018). "Mahvash Disease: 10 Years After Discovery". Pancreas. 47 (5): 511–515. doi:10.1097/MPA.0000000000001044. PMID   29702528. S2CID   13871451.

Further reading

• Levey GS, Weiss SR, Ruiz E (April 1975). "Characterization of the glucagon receptor in a pheochromocytoma". The Journal of Clinical Endocrinology and Metabolism. 40 (4): 720–723. doi:10.1210/jcem-40-4-720. PMID   165216.
• Nakamura S, Rodbell M (August 1991). "Glucagon induces disaggregation of polymer-like structures of the alpha subunit of the stimulatory G protein in liver membranes". Proceedings of the National Academy of Sciences of the United States of America. 88 (16): 7150–7154. Bibcode:1991PNAS...88.7150N. doi: 10.1073/pnas.88.16.7150 . PMC   52251 . PMID   1908089.
• Horuk R, Wright DE (May 1983). "Partial purification and characterization of the glucagon receptor". FEBS Letters. 155 (2): 213–217. Bibcode:1983FEBSL.155..213H. doi: 10.1016/0014-5793(82)80605-4 . PMID   6303843. S2CID   22620424.
• MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP (January 1994). "Cloning and expression of a human glucagon receptor". Biochemical and Biophysical Research Communications. 198 (1): 328–334. doi:10.1006/bbrc.1994.1046. PMID   7507321.
• Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, et al. (August 1995). "A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus". Diabetologia. 38 (8): 983–985. doi: 10.1007/BF00400589 . PMID   7589886.
• Unson CG, Macdonald D, Merrifield RB (February 1993). "The role of histidine-1 in glucagon action". Archives of Biochemistry and Biophysics. 300 (2): 747–750. doi:10.1006/abbi.1993.1103. PMID   8382034.
• Chambers SM, Morris BJ (February 1996). "Glucagon receptor gene mutation in essential hypertension". Nature Genetics. 12 (2): 122. doi: 10.1038/ng0296-122 . PMID   8563746. S2CID   5239762.
• Yamato E, Ikegami H, Takekawa K, Fujisawa T, Nakagawa Y, Hamada Y, et al. (February 1997). "Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1)". Hormone and Metabolic Research. 29 (2): 56–59. doi:10.1055/s-2007-978985. PMID   9105899. S2CID   42132824.
• Strazzullo P, Iacone R, Siani A, Barba G, Russo O, Russo P, et al. (October 2001). "Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant". Journal of Molecular Medicine. 79 (10): 574–580. doi:10.1007/s001090100257. PMID   11692154. S2CID   13804236.
• Shiota D, Kasamatsu T, Dib SA, Chacra AR, Moisés RS (May 2002). "Role of the Gly40Ser mutation in the glucagon receptor gene in Brazilian patients with type 2 diabetes mellitus". Pancreas. 24 (4): 386–390. doi:10.1097/00006676-200205000-00010. PMID   11961492. S2CID   36317323.
• Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS (July 2003). "Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus". The Journal of Biological Chemistry. 278 (30): 28005–28010. doi: 10.1074/jbc.M301085200 . PMID   12724331.
• Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S (May 2004). "Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry". Proteomics. 4 (5): 1346–1358. doi:10.1002/pmic.200300770. PMID   15188402. S2CID   6773754.
• Mortensen OH, Dichmann DS, Abrahamsen N, Grunnet N, Nishimura E (May 2007). "Identification of a novel human glucagon receptor promoter: regulation by cAMP and PGC-1alpha". Gene. 393 (1–2): 127–136. doi:10.1016/j.gene.2007.01.023. PMID   17374560.