Glucagon

GCG
Available structures PDB Human UniProt search: PDBe RCSB showList of PDB id codes 1BH0, 1NAU, 2G49, 2M5P, 2M5Q,%%s4ZGM, 4APD, 3IOL, 1D0R,%%s2L64, 2L63
Identifiers
Aliases	GCG, GLP1, glucagon, GRPP, GLP-1, GLP2
External IDs	OMIM: 138030 HomoloGene: 136497 GeneCards: GCG
showGene location (Human) Chr. Chromosome 2 (human)[1] Band 2q24.2 Start 162,142,882 bp[1] End 162,152,404 bp[1]
showRNA expression pattern More reference expression data
showGene ontology Molecular function • GO:0001948 protein binding • identical protein binding • hormone activity • glucagon receptor binding • signaling receptor binding Cellular component • cytoplasm • endoplasmic reticulum lumen • extracellular region • secretory granule lumen • extracellular space Biological process • negative regulation of execution phase of apoptosis • G protein-coupled receptor signaling pathway • regulation of insulin secretion • cellular response to glucagon stimulus • positive regulation of peptidyl-serine phosphorylation • positive regulation of calcium ion import • positive regulation of histone H3-K4 methylation • positive regulation of peptidyl-threonine phosphorylation • feeding behavior • positive regulation of ERK1 and ERK2 cascade • positive regulation of protein binding • cell population proliferation • signal transduction • positive regulation of protein kinase activity • adenylate cyclase-modulating G protein-coupled receptor signaling pathway • protein kinase A signaling • positive regulation of insulin secretion involved in cellular response to glucose stimulus • response to starvation • negative regulation of apoptotic process • regulation of signaling receptor activity • adenylate cyclase-activating G protein-coupled receptor signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2641	n/a
Ensembl	ENSG00000115263	n/a
UniProt	P01275	n/a
RefSeq (mRNA)	NM_002054	n/a
RefSeq (protein)	NP_002045	n/a
Location (UCSC)	Chr 2: 162.14 – 162.15 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

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.^[3] 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.^[4] It is produced from proglucagon, encoded by the GCG gene.

The pancreas releases glucagon when the amount of glucose in the bloodstream is too low. Glucagon causes the liver to engage in glycogenolysis: converting stored glycogen into glucose, which is released into the bloodstream.^[5] High blood-glucose levels, on the other hand, stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues. Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable. Glucagon increases energy expenditure and is elevated under conditions of stress.^[6] Glucagon belongs to the secretin family of hormones.

Function[]

Glucagon generally elevates the concentration of glucose in the blood by promoting gluconeogenesis and glycogenolysis.^[7] Glucagon also decreases fatty acid synthesis in adipose tissue and the liver, as well as promoting lipolysis in these tissues, which causes them to release fatty acids into circulation where they can be catabolised to generate energy in tissues such as skeletal muscle when required.^[8]

Glucose is stored in the liver in the form of the polysaccharide glycogen, which is a glucan (a polymer made up of glucose molecules). Liver cells (hepatocytes) have glucagon receptors. When glucagon binds to the glucagon receptors, the liver cells convert the glycogen into individual glucose molecules and release them into the bloodstream, in a process known as glycogenolysis. As these stores become depleted, glucagon then encourages the liver and kidney to synthesize additional glucose by gluconeogenesis. Glucagon turns off glycolysis in the liver, causing glycolytic intermediates to be shuttled to gluconeogenesis.

Glucagon also regulates the rate of glucose production through lipolysis. Glucagon induces lipolysis in humans under conditions of insulin suppression (such as diabetes mellitus type 1).^[9]

Glucagon production appears to be dependent on the central nervous system through pathways yet to be defined. In invertebrate animals, eyestalk removal has been reported to affect glucagon production. Excising the eyestalk in young crayfish produces glucagon-induced hyperglycemia.^[10]

Mechanism of action[]

Metabolic regulation of glycogen by glucagon.

Glucagon binds to the glucagon receptor, a G protein-coupled receptor, located in the plasma membrane of the cell. The conformation change in the receptor activates G proteins, a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the GDP molecule that was bound to the α subunit with a GTP molecule.^[11] This substitution results in the releasing of the α subunit from the β and γ subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase.

Adenylate cyclase manufactures cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates protein kinase A (cAMP-dependent protein kinase). This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b (PYG b), converting it into the active form called phosphorylase a (PYG a). Phosphorylase a is the enzyme responsible for the release of glucose 1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with Gɑβ