Biology:Glucagon receptor
 Generic protein structure example |
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. 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 IP3.[1][2]
Structure
File:184-Glucagon glucagonreceptor.tif 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]
References
- ↑ Urry, Lisa A; Cain, Michael L; Wasserman, Steven Alexander; Minorsky, Peter V; Reece, Jane B; Campbell, Neil A. Campbell biology (Eleventh ed.). New York, NY. ISBN 0-13-409341-0. OCLC 956379308.
- ↑ Sturkie's avian physiology (Sixth ed.). London, England. 30 June 2014. ISBN 978-0-12-407243-5. OCLC 884590323.
- ↑ PDB: 4L6R; "Structure of the human glucagon class B G-protein-coupled receptor". Nature 499 (7459): 444–9. Jul 2013. doi:10.1038/nature12393. PMID 23863937. Bibcode: 2013Natur.499..444S.
- ↑ PDB: 4ERS; "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. Sep 2012. doi:10.1073/pnas.1206734109. PMID 22908259. Bibcode: 2012PNAS..10914393K.
- ↑ "Conformational states of the full-length glucagon receptor". Nature Communications 6: 7859. July 2015. doi:10.1038/ncomms8859. PMID 26227798. Bibcode: 2015NatCo...6.7859Y.
- ↑ "Receptor activity modifying protein-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors receptor". The Journal of Biological Chemistry 291 (42): 21925–21944. August 2016. doi:10.1074/jbc.M116.751362. PMID 27566546.
- ↑ "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. 2002. doi:10.1080/10606820213687. PMID 12529935.
- ↑ "A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus". Nature Genetics 9 (3): 299–304. Mar 1995. doi:10.1038/ng0395-299. PMID 7773293.
- ↑ "Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor". Pancreas 38 (8): 941–6. Nov 2009. doi:10.1097/MPA.0b013e3181b2bb03. PMID 19657311.
- ↑ "Mahvash Disease: 10 Years After Discovery". Pancreas 47 (5): 511–15. 2018. doi:10.1097/MPA.0000000000001044. PMID 29702528.
Further reading
- "Characterization of the glucagon receptor in a pheochromocytoma". The Journal of Clinical Endocrinology and Metabolism 40 (4): 720–3. Apr 1975. doi:10.1210/jcem-40-4-720. PMID 165216.
- "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. Aug 1991. doi:10.1073/pnas.88.16.7150. PMID 1908089. Bibcode: 1991PNAS...88.7150N.
- "Partial purification and characterization of the glucagon receptor". FEBS Letters 155 (2): 213–7. May 1983. doi:10.1016/0014-5793(82)80605-4. PMID 6303843.
- "Cloning and expression of a human glucagon receptor". Biochemical and Biophysical Research Communications 198 (1): 328–34. Jan 1994. doi:10.1006/bbrc.1994.1046. PMID 7507321.
- "A mutation in the glucagon receptor gene (Gly40Ser): heterogeneity in the association with diabetes mellitus". Diabetologia 38 (8): 983–5. Aug 1995. doi:10.1007/BF00400589. PMID 7589886.
- "The role of histidine-1 in glucagon action". Archives of Biochemistry and Biophysics 300 (2): 747–50. Feb 1993. doi:10.1006/abbi.1993.1103. PMID 8382034.
- "Glucagon receptor gene mutation in essential hypertension". Nature Genetics 12 (2): 122. Feb 1996. doi:10.1038/ng0296-122. PMID 8563746.
- "Tissue-specific and glucose-dependent expression of receptor genes for glucagon and glucagon-like peptide-1 (GLP-1)". Hormone and Metabolic Research 29 (2): 56–9. Feb 1997. doi:10.1055/s-2007-978985. PMID 9105899.
- "Altered renal sodium handling and hypertension in men carrying the glucagon receptor gene (Gly40Ser) variant". Journal of Molecular Medicine 79 (10): 574–80. Oct 2001. doi:10.1007/s001090100257. PMID 11692154.
- "Role of the Gly40Ser mutation in the glucagon receptor gene in Brazilian patients with type 2 diabetes mellitus". Pancreas 24 (4): 386–90. May 2002. doi:10.1097/00006676-200205000-00010. PMID 11961492.
- "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. Jul 2003. doi:10.1074/jbc.M301085200. PMID 12724331.
- "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. May 2004. doi:10.1002/pmic.200300770. PMID 15188402.
- "Identification of a novel human glucagon receptor promoter: regulation by cAMP and PGC-1alpha". Gene 393 (1–2): 127–36. May 2007. doi:10.1016/j.gene.2007.01.023. PMID 17374560.
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