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 circulatin
g 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. To see the ontology report for annotations, GViewer and download click here...(less)
Based on sequence similarity, the Galpha genes have been grouped into four classes. Effectors of activated Galphas are adenylyl cyclases that catalyzed the formation of cAMP
