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, Gs 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
editA 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 IP3.[5][6]
Structure
editThe 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
editA 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
edit- ^ a b c ENSG00000288269 GRCh38: Ensembl release 89: ENSG00000215644, ENSG00000288269 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025127 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ Scanes CG (30 June 2014). Sturkie's avian physiology (Sixth ed.). London, England: Academic Press. ISBN 978-0-12-407243-5. OCLC 884590323.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
edit- 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 = Hormon- und Stoffwechselforschung = Hormones et Metabolisme. 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.
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