Glucagon receptor

Glucagon receptor

Glucagon receptor
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; GGR; GL-R
External IDs IUPHAR: ChEMBL: GeneCards:
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.

Contents

  • Structure 1
  • Clinical significance 2
  • References 3
  • Further reading 4

Structure

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

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

  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". Recept. Channels 8 (3-4): 179–88.  
  2. ^ Lok S, Kuijper JL, Jelinek LJ, Kramer JM, Whitmore TE, Sprecher CA, Mathewes S, Grant FJ, Biggs SH, Rosenberg GB (March 1994). "The human glucagon receptor encoding gene: structure, cDNA sequence and chromosomal localization". Gene 140 (2): 203–9.  
  3. ^ Menzel S, Stoffel M, Espinosa R, Fernald AA, Le Beau MM, Bell GI (March 1994). "Localization of the glucagon receptor gene to human chromosome band 17q25". Genomics 20 (2): 327–8.  
  4. ^ ​; 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 M-W, Stevens RC (July 2013). "Structure of the human glucagon class B G-protein-coupled receptor". Nature 499 (7459): 444–449.  
  5. ^ ​; 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 (September 2012). "Molecular basis for negative regulation of the glucagon receptor". Proc. Natl. Acad. Sci. U.S.A. 109 (36): 14393–8.  
  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.  
  7. ^ Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, Velho G, Carcassi C, Contu L, Julier C (March 1995). "A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus". Nat. Genet. 9 (3): 299–304.  
  8. ^ Zhou C, Dhall D, Nissen NN, Chen CR, Yu R (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.  

Further reading

  • Levey GS, Weiss SR, Ruiz E (1975). "Characterization of the glucagon receptor in a pheochromocytoma.". J. Clin. Endocrinol. Metab. 40 (4): 720–3.  
  • Nakamura S, Rodbell M (1991). "Glucagon induces disaggregation of polymer-like structures of the alpha subunit of the stimulatory G protein in liver membranes.". Proc. Natl. Acad. Sci. U.S.A. 88 (16): 7150–4.  
  • Horuk R, Wright DE (1983). "Partial purification and characterization of the glucagon receptor.". FEBS Lett. 155 (2): 213–7.  
  • MacNeil DJ, Occi JL, Hey PJ, et al. (1994). "Cloning and expression of a human glucagon receptor.". Biochem. Biophys. Res. Commun. 198 (1): 328–34.  
  • Fujisawa T, Ikegami H, Yamato E, et al. (1995). "A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus.". Diabetologia 38 (8): 983–5.  
  • Unson CG, Macdonald D, Merrifield RB (1993). "The role of histidine-1 in glucagon action.". Arch. Biochem. Biophys. 300 (2): 747–50.  
  • Chambers SM, Morris BJ (1996). "Glucagon receptor gene mutation in essential hypertension.". Nat. Genet. 12 (2): 122.  
  • Yamato E, Ikegami H, Takekawa K, et al. (1997). "Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1).". Horm. Metab. Res. 29 (2): 56–9.  
  • Strazzullo P, Iacone R, Siani A, et al. (2001). "Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant.". J. Mol. Med. 79 (10): 574–80.  
  • Shiota D, Kasamatsu T, Dib SA, et al. (2002). "Role of the Gly40Ser mutation in the glucagon receptor gene in Brazilian patients with type 2 diabetes mellitus.". Pancreas 24 (4): 386–90.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • Runge S, Gram C, Brauner-Osborne H, et al. (2003). "Three distinct epitopes on the extracellular face of the glucagon receptor determine specificity for the glucagon amino terminus.". J. Biol. Chem. 278 (30): 28005–10.  
  • Hassel S, Eichner A, Yakymovych M, et al. (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.  
  • Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7.  
  • Mortensen OH, Dichmann DS, Abrahamsen N, et al. (2007). "Identification of a novel human glucagon receptor promoter: regulation by cAMP and PGC-1alpha.". Gene 393 (1-2): 127–36.