Question

Epinephrine and glucagon bind to different receptors on cell surface, but both receptors activate the same G protein and trigger the same series of events in which cAMP is produced and activates downstream proteins to regulate the metabolism of different types of carbohydrates. In lecture, we have learnt that activation of G protein by these two hormones promotes the breakdown of glycogen through the activation of glycogen phosphorylase and inhibition of glycogen synthetase in liver and muscle. In this essay, you are going to look up other metabolic pathways of carbohydrate regulated by epinephrine and glucagon.

In this essay, describe the following topics:

1. Regulation of glucagon secretion by glucose, and

2. Action of glucagon in glycolysis and gluconeogenesis

- Discuss the pathways, enzymes and steps activated/ inactivated (including substrate and product in the enzymatic reactions)

- Explain the mode of regulation: phosphorylation/dephosphorylation, transcriptional control, etc.

- Discuss whether glucagon and epinephrine act in the same way in liver, muscle and heart cells in terms of their effects on glycolysis and gluconeogenesis

Answer 1

Glucagon and epinephrine stimulate the catabolism of glycogen in muscle and liver. The liver is more responsive to glucagon and muscle is more responsive to epinephrine. In above question we are asked to discuss about the regulation of glyolyglyc and gluconeogenesis with reference to glucagon.

First we should know what is glucagon, glucagon is a polypeptide hormone secreted by the alpha cells of pancreatic islets.Usually it works opposite to insulin. Glucagon try to maintain blood glucose levels by activation of gluconeogenesis in hepatocytes.

When the blood glucose level decreases the hormone glucagon signals the liver to produce and release more glucose and to stop consuming itself. The glucose source in liver are glycogen and gluconeogenesis.

The exact hormonal regulation of gluconeogenesis and also glycolysis is mediated by fructose 2,6 bisphosphate which is an allosteric effector for the enzymes PFK -1 and FBPase -1.

when Fructose 2,6-bisphosphate binds to the allosteric site on phosphofructokinase-1( PFK -1) , it automatically increases the enzymes affinity for its substrate fructose 6-phosphate and off course reduces it's affnity for the allosteric inhibitors ATP and citrate.

Fructose 2,6 bisphosphate activates PFK -1 and stimulate glycolysis in liver and at the same time inhibits FBPase -1 ,showing gluconeogenesis.

Fructose 2,6-bisphosphate is an a regulator whose cellular level reflects the level of glucagon in the blood. It rises when blood glucose falls . The cellular concentration of fructose 2,6-bisphosphate is controlled by the relative rates of its formation and breakdown. It is formed by phosphorylation of fructose 6-phosphate and catalysed by phosphofructokinase-2 (PFK-2) and broken-down by fructose 2,6-bisphosphatase-2 ( FBPase-2).

The balance of these two activities in the liver which determines the cellular level of fructose 2,6- bisphosphate is regulated by glucagon and insulin .

Glucagon stimulates the adenylyl cyclase of liver to synthesise 3,5-cyclic AMP(cAMP) from ATP . cAMP activates cAMP dependent protein kinase ,which transfer a phosphoryl grouyfrom ATP to the bifunctional protein PFK-2 /FBPase-2. Phosphorylation of this protein increases its FBPase -2 activity and inhibits it's PFK -2 activity.

Glucagon thereby lowers the cellular level of fructose 2,6- bisphosphate, inhibiting glycolysis and stimulating gluconeogenesis.

In response to glucagon the resulting production of more glucose enables the liver to replenish blood glucose.