Glucagon receptor

Last updated
GCGR
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GCGR , GGR, GL-R, glucagon receptor, MVAH
External IDs OMIM: 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 Mb Chr 11: 120.42 – 120.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.

Contents

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. [5] [6]

Structure

glucagon/glucagon receptor (blue) with glucagon bound(pink) 184-Glucagon glucagonreceptor.tif
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

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]

Related Research Articles

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Alpha cell</span>

Alpha cells are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.

<span class="mw-page-title-main">Gastric inhibitory polypeptide</span> Mammalian protein found in Homo sapiens

Glucose-dependent insulinotropic polypeptide (GIP), also known as Gastric inhibitory polypeptide or gastric inhibitory peptide, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role is to stimulate insulin secretion.

<span class="mw-page-title-main">Glucagon-like peptide-1</span> Gastrointestinal Peptide Hormone Involved in Glucose Homeostasis

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from the tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of G protein-coupled receptors. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Gastric inhibitory polypeptide receptor</span> Protein-coding gene in the species Homo sapiens

The gastric inhibitory polypeptide receptor (GIP-R), also known as the glucose-dependent insulinotropic polypeptide receptor, is a protein that in humans is encoded by the GIPR gene. GIP-R is a member of the 7-transmembrane protein family, a class of G protein coupled receptors. GIP-R is found on beta-cells in the pancreas where it serves as the receptor for the hormone Gastric inhibitory polypeptide (GIP).

<span class="mw-page-title-main">PKC alpha</span> Protein-coding gene in the species Homo sapiens

Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the PRKCA gene.

G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

<span class="mw-page-title-main">Glucagon-like peptide-2 receptor</span> Protein-coding gene in the species Homo sapiens

Glucagon-like peptide-2 receptor (GLP-2R) is a protein that in human is encoded by the GLP2R gene located on chromosome 17.

<span class="mw-page-title-main">Hepatocyte nuclear factor 4 alpha</span> Protein-coding gene in the species Homo sapiens

Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 is a nuclear receptor that in humans is encoded by the HNF4A gene.

<span class="mw-page-title-main">PDX1</span> A protein involved in the pancreas and duodenum differentiation

PDX1, also known as insulin promoter factor 1, is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In humans this protein is encoded by the PDX1 gene, which was formerly known as IPF1. The gene was originally identified in the clawed frog Xenopus laevis and is present widely across the evolutionary diversity of bilaterian animals, although it has been lost in evolution in arthropods and nematodes. Despite the gene name being Pdx1, there is no Pdx2 gene in most animals; single-copy Pdx1 orthologs have been identified in all mammals. Coelacanth and cartilaginous fish are, so far, the only vertebrates shown to have two Pdx genes, Pdx1 and Pdx2.

<span class="mw-page-title-main">HNF1B</span> Mammalian protein found in Homo sapiens

HNF1 homeobox B, also known as HNF1B or transcription factor 2 (TCF2), is a human gene.

Muscarinic acetylcholine receptor M<sub>3</sub> Protein-coding gene in the species Homo sapiens

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.

<span class="mw-page-title-main">GNAQ</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Together with GNA11, it functions as a Gq alpha subunit.

<span class="mw-page-title-main">GPR119</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 6</span> Mammalian protein found in Homo sapiens

Glutamate receptor, metabotropic 6, also known as GRM6 or mGluR6, is a protein which in humans is encoded by the GRM6 gene.

<span class="mw-page-title-main">RAPGEF4</span>

Rap guanine nucleotide exchange factor (GEF) 4 (RAPGEF4), also known as exchange protein directly activated by cAMP 2 (EPAC2) is a protein that in humans is encoded by the RAPGEF4 gene.

<span class="mw-page-title-main">GNAT3</span>

Guanine nucleotide-binding protein G(t) subunit alpha-3, also known as gustducin alpha-3 chain, is a protein subunit that in humans is encoded by the GNAT3 gene.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

References

  1. 1 2 3 ENSG00000288269 GRCh38: Ensembl release 89: ENSG00000215644, ENSG00000288269 - Ensembl, May 2017
  2. 1 2 3 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.
  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.

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