Glucagon receptor

Protein-coding gene in the species Homo sapiens

GCGR

Available structures

PDB

Ortholog search: PDBe RCSB

List of PDB id codes
3CZF, 4ERS, 4L6R, 2A83, 4LF3, 5EE7

Identifiers

Aliases

GCGR, GGR, GL-R, glucagon receptor, MVAH

External IDs

OMIM: 138033 MGI: 99572 HomoloGene: 131 GeneCards: GCGR

Gene location (Human)

Chr.	Chromosome 17 (human)^[1]

Band	17q25.3	Start	81,804,132 bp^[1]
Band	17q25.3	End	81,814,008 bp^[1]

Gene location (Mouse)

Chr.	Chromosome 11 (mouse)^[2]

Band	11\|11 E2	Start	120,421,525 bp^[2]
Band	11\|11 E2	End	120,429,812 bp^[2]

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

right lobe of liver

kidney

tibial nerve

sural nerve

islet of Langerhans

skin of abdomen

body of pancreas

vagina

right adrenal gland

left uterine tube

Top expressed in

lobe of liver

left lobe of liver

medullary collecting duct

islet of Langerhans

footplate

kidney

renal cortex

yolk sac

proximal tubule

medulla oblongata

More reference expression data

BioGPS

n/a

Gene ontology
Molecular function	G 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 activity
Cellular component	integral component of membrane endosome membrane plasma membrane integral component of plasma membrane
Biological process	glucose 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 pathway
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

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, 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 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 IP_3.^[5]^[6]

Structure

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]

References

^ ^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.{{cite book}}: 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, 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.
^ 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 & 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.

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.

Cell surface receptor: G protein-coupled receptors

Class A: Rhodopsin-like

Neurotransmitter

Adrenergic	α1 (A B D) α2 (A B C) β1 β2 β3
Purinergic	Adenosine (A1 A2A A2B A3) P2Y (1 2 4 5 6 8 9 10 11 12 13 14)
Serotonin	(all but 5-HT3) 5-HT1 (A B D E F) 5-HT2 (A B C) 5-HT (4 5A 6 7)
Other	Acetylcholine (M1 M2 M3 M4 M5) Dopamine D1 D2 D3 D4 D5 GHB receptor Histamine H1 H2 H3 H4 Melatonin (1A 1B 1C) TAAR (1 2 5 6 8 9)

Metabolites and
signaling molecules

Eicosanoid	CysLT (1 2) LTB4 1 2 FPRL1 OXE Prostaglandin DP (1 2), EP (1 2 3 4), FP Prostacyclin Thromboxane
Other	Bile acid Cannabinoid (CB1 CB2, GPR (18 55 119)) EBI2 Estrogen Free fatty acid (1 2 3 4) Hydroxycarboxylic acids 1 2 3 Lysophosphatidic acid (1 2 3 4 5 6) Lysophospholipid (1 2 3 4 5 6 7 8) Oxoglutarate PAF Sphingosine-1-phosphate (1 2 3 4 5) Succinate

Peptide

Neuropeptide

B/W (1
2)
FF (1
2)
S
Y (1
2
4
5)
Neuromedin (B
U (1
2))
Neurotensin (1
2)

Other

Anaphylatoxin (C3a
C5a (1
2))
Angiotensin (1
2)
Apelin
Bombesin
- BRS3
- GRPR
- NMBR)
- Bradykinin (B1
- B2)
Chemokine
Cholecystokinin (A
B)
Endothelin
- A
- B
Formyl peptide (1
2
3)
FSH
Galanin (1
2
3)
Gonadotropin-releasing hormone (1
2)
Ghrelin
Kisspeptin
Luteinizing hormone/choriogonadotropin
MAS (1
1L
D
E
F
G
X1
X2
X3
X4)
Melanocortin (1
2
3
4
5)
MCHR (1
2)
Motilin
Opioid (Delta
Kappa
Mu
Nociceptin & Zeta, but not Sigma)
Orexin (1
2)
Oxytocin
Prokineticin (1
2)
Prolactin-releasing peptide
Relaxin (1
2
3
4)
Somatostatin (1
2
3
4
5)
Tachykinin (1
2
3)
Thyrotropin
Thyrotropin-releasing hormone
Urotensin-II
Vasopressin (1A
1B
2)

Miscellaneous

Taste, bitter	TAS2R 1 3 4 5 7 8 9 10 13 14 16 19 20 30 31 38 39 40 41 42 43 45 46 50 60 Vomeronasal receptor type 1
Orphan	GPR (1 3 4 6 12 15 17 18 19 20 21 22 23 25 26 27 31 32 33 34 35 37 39 42 44 45 50 52 55 61 62 63 65 68 75 78 81 82 83 84 85 87 88 92 101 103 109A 109B 119 120 132 135 137B 139 141 142 146 148 149 150 151 152 153 160 161 162 171 173 174 176 177 182 183)
Other	Adrenomedullin Olfactory Opsin (3 4 5 1LW 1MW 1SW RGR RRH) Protease-activated (1 2 3 4) SREB (1 2 3)

Class B: Secretin-like

Adhesion	ADGRB Brain-specific angiogenesis inhibitor 1 2 3 ADGRC Cadherin 1 2 3 ADGRE EMR 1 2 3 CD97 ADGRG 1 2 3 4 5 6 7 ADGRL Latrophilin 1 2 3 ELTD1
Orphan	GPR (56 64 97 98 110 111 112 113 114 115 116 123 124 125 126 128 133 143 144 155 157)
Other	Calcitonin CALCRL Corticotropin-releasing hormone (1 2) Glucagon (GR GIPR GLP1R GLP2R) Growth-hormone-releasing hormone PACAPR1 GPR Methuselah-like proteins Parathyroid hormone (1 2) Secretin Vasoactive intestinal peptide (1 2)

Class C: Metabotropic glutamate / pheromone

Taste, sweet	TAS1R 1 2 3 Vomeronasal receptor, type 2
Other	Calcium-sensing receptor GABA_B (1 2) Glutamate receptor (Metabotropic glutamate (1 2 3 4 5 6 7 8)) GPRC6A GPR (156 158 179) RAIG (1 2 3 4)