Glucagon receptor explained

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, 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 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.^{[1] [2]}

Structure

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

Clinical significance

A missense mutation at 17q25^[7] in the GCGR gene is associated with diabetes mellitus type 2.^[8]

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.^{[9] [10]}

Further reading

• Levey GS, Weiss SR, Ruiz E . Characterization of the glucagon receptor in a pheochromocytoma . The Journal of Clinical Endocrinology and Metabolism . 40 . 4 . 720–723 . April 1975 . 165216 . 10.1210/jcem-40-4-720 .
• Nakamura S, Rodbell M . 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 . August 1991 . 1908089 . 52251 . 10.1073/pnas.88.16.7150 . free . 1991PNAS...88.7150N .
• Horuk R, Wright DE . Partial purification and characterization of the glucagon receptor . FEBS Letters . 155 . 2 . 213–217 . May 1983 . 6303843 . 10.1016/0014-5793(82)80605-4 . 22620424 . free . 1983FEBSL.155..213H .
• MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP . Cloning and expression of a human glucagon receptor . Biochemical and Biophysical Research Communications . 198 . 1 . 328–334 . January 1994 . 7507321 . 10.1006/bbrc.1994.1046 .
• Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Ueda H, Fukuda M, Ogihara T . A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus . Diabetologia . 38 . 8 . 983–985 . August 1995 . 7589886 . 10.1007/BF00400589 . free .
• Unson CG, Macdonald D, Merrifield RB . The role of histidine-1 in glucagon action . Archives of Biochemistry and Biophysics . 300 . 2 . 747–750 . February 1993 . 8382034 . 10.1006/abbi.1993.1103 .
• Chambers SM, Morris BJ . Glucagon receptor gene mutation in essential hypertension . Nature Genetics . 12 . 2 . 122 . February 1996 . 8563746 . 10.1038/ng0296-122 . 5239762 . free .
• Yamato E, Ikegami H, Takekawa K, Fujisawa T, Nakagawa Y, Hamada Y, Ueda H, Ogihara T . 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 Metabolisme . 29 . 2 . 56–59 . February 1997 . 9105899 . 10.1055/s-2007-978985 . 42132824 .
• Strazzullo P, Iacone R, Siani A, Barba G, Russo O, Russo P, Barbato A, D'Elia L, Farinaro E, Cappuccio FP . Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant . Journal of Molecular Medicine . 79 . 10 . 574–580 . October 2001 . 11692154 . 10.1007/s001090100257 . 13804236 .
• Shiota D, Kasamatsu T, Dib SA, Chacra AR, Moisés RS . Role of the Gly40Ser mutation in the glucagon receptor gene in Brazilian patients with type 2 diabetes mellitus . Pancreas . 24 . 4 . 386–390 . May 2002 . 11961492 . 10.1097/00006676-200205000-00010 . 36317323 .
• Runge S, Gram C, Brauner-Osborne H, Madsen K, Knudsen LB, Wulff BS . 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 . July 2003 . 12724331 . 10.1074/jbc.M301085200 . free .
• Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S . 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 . May 2004 . 15188402 . 10.1002/pmic.200300770 . 6773754 .
• Mortensen OH, Dichmann DS, Abrahamsen N, Grunnet N, Nishimura E . Identification of a novel human glucagon receptor promoter: regulation by cAMP and PGC-1alpha . Gene . 393 . 1–2 . 127–136 . May 2007 . 17374560 . 10.1016/j.gene.2007.01.023 .

Notes and References

1. Book: Urry LA, Cain ML, Wasserman SA, Minorsky PV, Reece JB, Campbell NA . Campbell biology . 0-13-409341-0. Eleventh. New York, NY. 956379308.
2. Book: Sturkie's avian physiology. Scanes CG . 30 June 2014. 978-0-12-407243-5. Sixth. London, England . Academic Press . 884590323.

3. 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 . Structure of the human glucagon class B G-protein-coupled receptor . Nature . 499 . 7459 . 444–449 . July 2013 . 23863937 . 3820480 . 10.1038/nature12393 . 2013Natur.499..444S .

4. 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 . 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 . September 2012 . 22908259 . 3437825 . 10.1073/pnas.1206734109 . free . 2012PNAS..10914393K .

5. 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 . Conformational states of the full-length glucagon receptor . Nature Communications . 6 . 7859 . July 2015 . 26227798 . 4532856 . 10.1038/ncomms8859 . 2015NatCo...6.7859Y .
6. Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodlock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G . 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 . October 2016 . 27566546 . 5063977 . 10.1074/jbc.M116.751362 . free .
7. Brubaker PL, Drucker DJ . 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 . 2002 . 12529935 . 10.1080/10606820213687 .
8. Hager J, Hansen L, Vaisse C, Vionnet N, Philippi A, Poller W, Velho G, Carcassi C, Contu L, Julier C . A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus . Nature Genetics . 9 . 3 . 299–304 . March 1995 . 7773293 . 10.1038/ng0395-299 . 26951878 .
9. Zhou C, Dhall D, Nissen NN, Chen CR, Yu R . Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor . Pancreas . 38 . 8 . 941–946 . November 2009 . 19657311 . 2767399 . 10.1097/MPA.0b013e3181b2bb03 .
10. Yu R . Mahvash Disease: 10 Years After Discovery . Pancreas . 47 . 5 . 511–515 . 2018 . 29702528 . 10.1097/MPA.0000000000001044 . 13871451 .