id: PW:0000676
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000676
title: glucagon signaling pathway
description: 'In the pancreatic alpha cells of the islets of Langerhans, glucagon is processed from the
  precursor proglucagon by the prohormone convertase 2 (PC-2). In the intestinal L cells and brainstem
  neurons, prohormone convertase 1 (PC-1) processes the same precursor molecule into several peptides
  distinct from glucagon, including the glucagon-like peptides (GLP) 1 and 2. The resulting peptides bind
  to cognate G-protein coupled receptors (GPCR) to elicit distinct responses. When the levels of circulating
  glucose are low, glucagon is secreted from the alpha cells by mechanisms that are incompletely understood.
  The glucagon signaling pathway promotes production of glucose by the liver by stimulating glycogenolysis
  and gluconeogenesis while inhibiting glycolysis and glycogenesis. Glucagon counterbalances the effects
  of insulin and the action of the two hormones is essential for the maintenance of glucose homeostasis.
  Binding of glucagon triggers conformational changes in the receptor leading to activation of heterotrimeric
  G proteins, primarily the Gs alpha subunit, possibly Gq. Gs signaling activates adenylyl cyclases resulting
  in the production of cAMP and subsequent activation of protein kinase A (PKA) pathway. The glucagon
  receptor is expressed in several tissues but predominantly in liver and kidney. The identity of PKA
  components associated with the glucagon signaling pathway is not well resolved except, to some extent,
  for some of the adenylyl cyclase isoforms. PKA phosphorylates and activates phosphorylase kinase, the
  sole activator of glycogen phosphorylase - the enzyme of the first and rate-limiting step of glycogenolysis
  pathway of glycogen degradation to glucose. Glucagon activated PKA can also inhibit glycogen biosynthesis;
  it is one of several kinases that phosphorylate glycogen synthase, a key enzyme in the glycogen biosynthetic
  pathway. Another key enzyme of glucose metabolism that is regulated by glucagon activated PKA is the
  bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (Pfkfb). The kinase arm leads
  to the production of F2, 6P which is converted back to F6P by the phosphatase arm. F2, 6P is a potent
  allosteric modulator of glucose metabolism: it is an activator of phosphofructokinase and an inhibitor
  of fructose bisphophatase - key enzymes of glycolysis and gluconeogenesis pathways, respectively. Phosphorylation
  by PKA inactivates the kinase, thus promoting a dominant phosphatase activity. The resulting reduction
  in the level of F2, 6P leads to inhibition of glycolysis and promotion of gluconeogenesis. In addition,
  glucagon activated PKA is believed to promote gluconeogenesis by impacting on the expression of glucose-6-phosphatase
  and phosphoenolpyruvate carboxykinase enzymes via phosphorylation and activation of transcription factors
  or co-activators.'
diagram_image: https://rgd.mcw.edu/pathway/PW0000676/glucagon%20signaling%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000676/glucagon%20signaling%20pathway/glucagon%20signaling%20pathway.gpp
diagram_pathway_links:
- id: PW:0000227
  label: G protein mediated signaling pathway via Galphas family
- id: PW:0000532
  label: glycogen biosynthetic pathway
- id: PW:0000534
  label: glycogen degradation pathway
- id: PW:0000543
  label: protein kinase A (PKA) signaling pathway
- id: PW:0000640
  label: glycolysis pathway
- id: PW:0000641
  label: gluconeogenesis pathway
diagram_gene_links:
- id: RGD:71014
  label: Adcy5
- id: RGD:2035
  label: Adcy6
- id: RGD:2668
  label: Gcg
- id: RGD:2669
  label: Gcgr
- id: RGD:2716
  label: Gnas
diagram_chemicals:
- id: PUBCHEM.COMPOUND:5957
  label: ATP
- id: PUBCHEM.COMPOUND:6076
  label: cAMP
diagram_edges:
- source: ATP
  relation: positively_affects
  target: cAMP
- source: Gcg
  relation: associated_with
  target: Gcgr
- source: Gcgr
  relation: associated_with
  target: Gnas
- source: protein kinase A (PKA) signaling pathway
  relation: negatively_affects
  target: glycogen biosynthetic pathway
- source: protein kinase A (PKA) signaling pathway
  relation: negatively_affects
  target: glycolysis pathway
diagram_labels:
- cAMP --+> protein kinase A (PKA) signaling pathway
- expression of gluconeogenic genes
- Gnas --+> Adcy5
- Gnas --+> Adcy6
- protein kinase A (PKA) signaling pathway --+> expression of gluconeogenic genes
- protein kinase A (PKA) signaling pathway --+> gluconeogenesis pathway
- protein kinase A (PKA) signaling pathway --+> glycogen degradation pathway
- reduced F2, 6P levels
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- id: RGD:5129760
  citation: Unson CG Biopolymers. 2002;66(4):218-35.
- id: RGD:5129764
  citation: Mayo KE, etal., Pharmacol Rev. 2003 Mar;55(1):167-94.
- id: RGD:5129766
  citation: Jiang G and Zhang BB, Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E671-8.
- id: RGD:5129908
  citation: Gromada J, etal., Endocr Rev. 2007 Feb;28(1):84-116. Epub 2007 Jan 16.
- id: RGD:5129979
  citation: 'Authier F and Desbuquois B, Cell Mol Life Sci. 2008 Jun;65(12):1880-99. doi: 10.1007/s00018-008-7479-6.'
- id: RGD:5130006
  citation: Bansal P and Wang Q, Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E751-61. Epub 2008 Jul
    22.
- id: RGD:5130009
  citation: Quesada I, etal., J Endocrinol. 2008 Oct;199(1):5-19. Epub 2008 Jul 31.
- id: RGD:10053652
  citation: 'Sandoval DA and D''Alessio DA, Physiol Rev. 2015 Apr;95(2):513-48. doi: 10.1152/physrev.00013.2014.'