Glucagon receptor

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, 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.

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; OMA:GCGR - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q25.3 Start 81,804,132 bp[1] End 81,814,008 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 E2 Start 120,421,525 bp[2] End 120,429,812 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver tibial nerve sural nerve human kidney gonad islet of Langerhans skin of abdomen body of pancreas skin of leg muscle layer of sigmoid colon Top expressed in lobe of liver left lobe of liver right kidney medullary collecting duct islet of Langerhans footplate human kidney renal cortex yolk sac proximal tubule 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
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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

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]