Glucagon receptor

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Glucagon receptor
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols GCGR ; GGR; GL-R
External IDs OMIM138033 MGI99572 HomoloGene131 IUPHAR: 251 ChEMBL: 1985 GeneCards: GCGR Gene
Orthologs
Species Human Mouse
Entrez 2642 14527
Ensembl ENSG00000215644 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:
120.53 – 120.54 Mb
PubMed search [1] [2]

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, coupled to G alpha i, Gs and to a lesser extent G alpha q.[1] Stimulation of the receptor results in activation of adenylate cyclase and increased levels of intracellular cAMP. In humans, the glucagon receptor is encoded by the GCGR gene.[2][3]

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.

Structure[edit]

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

The 3D crystallographic structures of the seven transmembrane helical domain (7TM)[4] and the extracellular domain (ECD)[5] and an electron microscopy (EM) map of full length glucagon receptor[6] have been determined.

Clinical significance[edit]

A missense mutation in the GCGR gene is associated with diabetes mellitus type 2.[7]

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.[8]

References[edit]

  1. ^ 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): 179–88. doi:10.1080/10606820213687. PMID 12529935. 
  2. ^ Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB (Mar 1994). "The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization". Gene 140 (2): 203–9. doi:10.1016/0378-1119(94)90545-2. PMID 8144028. 
  3. ^ Menzel S, Stoffel M, Espinosa R, Fernald AA, Le Beau MM, Bell GI (Mar 1994). "Localization of the glucagon receptor gene to human chromosome band 17q25". Genomics 20 (2): 327–8. doi:10.1006/geno.1994.1179. PMID 8020989. 
  4. ^ PDB: 4L6R​; Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC (Jul 2013). "Structure of the human glucagon class B G-protein-coupled receptor". Nature 499 (7459): 444–9. doi:10.1038/nature12393. PMC 3820480. PMID 23863937. 
  5. ^ PDB: 4ERS​; Koth CM, Murray JM, Mukund S, Madjidi A, Minn A, Clarke HJ, Wong T, Chiang V, Luis E, Estevez A, Rondon J, Zhang Y, Hötzel I, Allan BB (Sep 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): 14393–8. doi:10.1073/pnas.1206734109. PMC 3437825. PMID 22908259. 
  6. ^ Yang L, Yang D, de Graaf C, Moeller A, West GM, Dharmarajan V, Wang C, Siu FY, Song G, Reedtz-Runge S, Pascal BD, Wu B, Potter CS, Zhou H, Griffin PR, Carragher B, Yang H, Wang MW, Stevens RC, Jiang H (July 2015). "Conformational states of the full-length glucagon receptor". Nature Communications 6: 7859. doi:10.1038/ncomms8859. PMID 26227798. 
  7. ^ Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, Velho G, Carcassi C, Contu L, Julier C (Mar 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. 
  8. ^ Zhou C, Dhall D, Nissen NN, Chen CR, Yu R (Nov 2009). "Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor". Pancreas 38 (8): 941–6. doi:10.1097/MPA.0b013e3181b2bb03. PMC 2767399. PMID 19657311. 

Further reading[edit]

  • Levey GS, Weiss SR, Ruiz E (Apr 1975). "Characterization of the glucagon receptor in a pheochromocytoma". The Journal of Clinical Endocrinology and Metabolism 40 (4): 720–3. doi:10.1210/jcem-40-4-720. PMID 165216. 
  • Nakamura S, Rodbell M (Aug 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): 7150–4. 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): 213–7. doi:10.1016/0014-5793(82)80605-4. PMID 6303843. 
  • MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP (Jan 1994). "Cloning and expression of a human glucagon receptor". Biochemical and Biophysical Research Communications 198 (1): 328–34. doi:10.1006/bbrc.1994.1046. PMID 7507321. 
  • Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Fukuda M, Ogihara T (Aug 1995). "A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus". Diabetologia 38 (8): 983–5. doi:10.1007/BF00400589. PMID 7589886. 
  • Unson CG, Macdonald D, Merrifield RB (Feb 1993). "The role of histidine-1 in glucagon action". Archives of Biochemistry and Biophysics 300 (2): 747–50. doi:10.1006/abbi.1993.1103. PMID 8382034. 
  • Chambers SM, Morris BJ (Feb 1996). "Glucagon receptor gene mutation in essential hypertension". Nature Genetics 12 (2): 122. doi:10.1038/ng0296-122. PMID 8563746. 
  • Yamato E, Ikegami H, Takekawa K, Fujisawa T, Nakagawa Y, Hamada Y, Ueda H, Ogihara T (Feb 1997). "Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1)". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme 29 (2): 56–9. doi:10.1055/s-2007-978985. PMID 9105899. 
  • Strazzullo P, Iacone R, Siani A, Barba G, Russo O, Russo P, Barbato A, D'Elia L, Farinaro E, Cappuccio FP (Oct 2001). "Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant". Journal of Molecular Medicine 79 (10): 574–80. doi:10.1007/s001090100257. PMID 11692154. 
  • 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): 386–90. doi:10.1097/00006676-200205000-00010. PMID 11961492. 
  • Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS (Jul 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): 28005–10. 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): 1346–58. doi:10.1002/pmic.200300770. PMID 15188402. 
  • 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): 127–36. doi:10.1016/j.gene.2007.01.023. PMID 17374560.