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Glucagon receptor

April 12, 2024

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.

GCGR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGCGR, GGR, GL-R, glucagon receptor, MVAH
External IDsOMIM: 138033 MGI: 99572 HomoloGene: 131 GeneCards: GCGR
Orthologs
SpeciesHumanMouse
Entrez

2642

14527

Ensembl

ENSG00000215644
ENSG00000288269

ENSMUSG00000025127

UniProt

P47871

Q61606

RefSeq (mRNA)

NM_000160

NM_008101

RefSeq (protein)

NP_000151

NP_032127

Location (UCSC)Chr 17: 81.8 – 81.81 MbChr 11: 120.42 – 120.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 edit

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.[5][6]

Structure edit

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

The 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 edit

A 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

  1. ^ a b c ENSG00000288269 GRCh38: Ensembl release 89: ENSG00000215644, ENSG00000288269 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025127 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ Scanes CG (30 June 2014). Sturkie's avian physiology (Sixth ed.). London, England. ISBN 978-0-12-407243-5. OCLC 884590323.{{cite book}}: CS1 maint: location missing publisher (link)
  7. ^ 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. Bibcode:2013Natur.499..444S. doi:10.1038/nature12393. PMC 3820480. PMID 23863937.
  8. ^ 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. Bibcode:2012PNAS..10914393K. doi:10.1073/pnas.1206734109. PMC 3437825. PMID 22908259.
  9. ^ 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. Bibcode:2015NatCo...6.7859Y. doi:10.1038/ncomms8859. PMC 4532856. PMID 26227798.
  10. ^ Weston C, Winfield I, Harris M, Hodgson R, Shah A, Dowell SJ, Mobarec JC, Woodcock DA, Reynolds CA, Poyner DR, Watkins HA, Ladds G (August 2016). "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. doi:10.1074/jbc.M116.751362. PMC 5063977. PMID 27566546.
  11. ^ 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.
  12. ^ 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. S2CID 26951878.
  13. ^ 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.
  14. ^ Yu R (2018). "Mahvash Disease: 10 Years After Discovery". Pancreas. 47 (5): 511–15. doi:10.1097/MPA.0000000000001044. PMID 29702528. S2CID 13871451.

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. 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): 213–7. doi:10.1016/0014-5793(82)80605-4. PMID 6303843. S2CID 22620424.
  • 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. S2CID 5239762.
  • 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. 29 (2): 56–9. doi:10.1055/s-2007-978985. PMID 9105899. S2CID 42132824.
  • 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. 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): 386–90. doi:10.1097/00006676-200205000-00010. PMID 11961492. S2CID 36317323.
  • 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. 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): 127–36. doi:10.1016/j.gene.2007.01.023. PMID 17374560.


 

This transmembrane receptor-related article is a stub. You can help Wikipedia by expanding it.

April 12, 2024
glucagon, receptor, glucagon, receptor, protein, that, activated, glucagon, member, class, protein, coupled, family, receptors, coupled, alpha, lesser, extent, alpha, stimulation, receptor, results, activation, adenylate, cyclase, phospholipase, increased, lev. 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 GCGRAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes3CZF 4ERS 4L6R 2A83 4LF3 5EE7IdentifiersAliasesGCGR GGR GL R glucagon receptor MVAHExternal IDsOMIM 138033 MGI 99572 HomoloGene 131 GeneCards GCGRGene location Human Chr Chromosome 17 human 1 Band17q25 3Start81 804 132 bp 1 End81 814 008 bp 1 Gene location Mouse Chr Chromosome 11 mouse 2 Band11 11 E2Start120 421 525 bp 2 End120 429 812 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inright lobe of liverkidneytibial nervesural nerveislet of Langerhansskin of abdomenbody of pancreasvaginaright adrenal glandleft uterine tubeTop expressed inlobe of liverleft lobe of livermedullary collecting ductislet of Langerhansfootplatekidneyrenal cortexyolk sacproximal tubulemedulla oblongataMore reference expression dataBioGPSn aGene ontologyMolecular functionG protein coupled receptor activity guanyl nucleotide exchange factor activity signal transducer activity peptide hormone binding glucagon receptor activity transmembrane signaling receptor activity G protein coupled peptide receptor activityCellular componentintegral component of membrane endosome membrane plasma membrane integral component of plasma membraneBiological processglucose homeostasis response to nutrient adenylate cyclase modulating G protein coupled receptor signaling pathway cellular response to glucagon stimulus generation of precursor metabolites and energy regulation of glycogen metabolic process regulation of blood pressure cell surface receptor signaling pathway hormone mediated signaling pathway response to starvation signal transduction exocytosis adenylate cyclase activating G protein coupled receptor signaling pathway G protein coupled receptor signaling pathwaySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez264214527EnsemblENSG00000215644ENSG00000288269ENSMUSG00000025127UniProtP47871Q61606RefSeq mRNA NM 000160NM 008101RefSeq protein NP 000151NP 032127Location UCSC Chr 17 81 8 81 81 MbChr 11 120 42 120 43 MbPubMed search 3 4 WikidataView Edit HumanView Edit MouseGlucagon 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 1 Signal transduction pathway 2 Structure 3 Clinical significance 4 References 5 Further readingSignal 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 edit nbsp glucagon glucagon receptor blue with glucagon bound pink The 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 ISBN 978 0 12 407243 5 OCLC 884590323 a href Template Cite book html title Template Cite book cite book a CS1 maint location missing publisher link 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 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 Wong T Chiang V Luis E Estevez A Rondon J Zhang Y Hotzel 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 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 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 Bibcode 2015NatCo 6 7859Y doi 10 1038 ncomms8859 PMC 4532856 PMID 26227798 Weston C Winfield I Harris M Hodgson R Shah A Dowell SJ Mobarec JC Woodcock DA Reynolds CA Poyner DR Watkins HA Ladds G August 2016 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 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 amp Channels 8 3 4 179 88 doi 10 1080 10606820213687 PMID 12529935 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 S2CID 26951878 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 Yu R 2018 Mahvash Disease 10 Years After Discovery Pancreas 47 5 511 15 doi 10 1097 MPA 0000000000001044 PMID 29702528 S2CID 13871451 Further reading editLevey 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 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 7 doi 10 1016 0014 5793 82 80605 4 PMID 6303843 S2CID 22620424 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 S2CID 5239762 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 29 2 56 9 doi 10 1055 s 2007 978985 PMID 9105899 S2CID 42132824 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 S2CID 13804236 Shiota D Kasamatsu T Dib SA Chacra AR Moises 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 S2CID 36317323 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 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 36 doi 10 1016 j gene 2007 01 023 PMID 17374560 nbsp This transmembrane receptor related article is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title Glucagon receptor amp oldid 1176813728, wikipedia, wiki, book, 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