Adrenaline glycogen phosphorylase

The next key point is to realize that each enzyme in the pathway exists in both active and inactive forms. cAMP initiates a cascade of reactions by activating protein kinase A (PK-A)," the active form of which activates the next enzyme in the sequence, and so on. At the end of the day, glycogen phosphorylase is activated and glucose or ATP is produced. This signaling pathway is a marvelous amplification system. A few molecules of glucagon or adrenaline may induce formation of many molecules of cAMP, which may activate many of PK-A, and so on. The catalytic power of enzymes is magnified in cascades of this sort. 

The existence of cAMP as a compound mediating the action of adrenaline and glucagon on glycogen phosphorylase was first recognized in 1956 by Sutherland.168169 However, for many years most biochemists regarded cAMP as a curiosity and the regulatory chemistry of phosphorylase as an unusual specialization. That view was altered drastically when cAMP was found to function as a second messenger in the action of over 20 different hormones. Phosphorylation by... 

Glycogenolysis (breakdown of glycogen) is a hormonal response to adrenaline/epinephrine (threat or stress), or glucagon (triggered by low glucose levels). Both hormones cause the conversion of inactive glycogen phosphorylase b to the active glycogen phosphorylase a. 

Adrenaline exerts its effect by binding to a receptor site on the cell surfaces of liver and muscle cells, where it initiates a series of signals that ultimately causes an inactive form of the enzyme glycogen phosphorylase to become active. This enzyme is the first in a sequence that leads to the breakdown of glycogen to glucose and other products. 

Protein kinase A provides a means for hormones to control metabolic pathways. Adrenaline and many other hormones increase the intracellular concentration of the allosteric regulator 3, 5 -cychc AMP (cAMP), which is referred to as a hormonal second messenger (Fig. 9.10). cAMP binds to regulatory subunits of protein kinase A, which dissociate and release the activated catalytic subunits (Fig. 9.11). Dissociation of inhibitory regulatory subunits is a common theme in enzyme regulation. The active catalytic subunits phosphorylate glycogen phosphorylase and other enzymes at serine residues. 

In the example shown in Figure 9.9, adrenaline indirectly increases cAMP, which activates protein kinase A, which phosphorylates phosphorylase kinase, which phosphorylates glycogen phosphorylase. The sequence of events in which one kinase phosphorylates another kinase is called a phosphorylation cascade. Because each stage of the phosphorylation cascade is associated with one enzyme molecule activating many enzyme molecules, the initial activating event is greatly amphfied. 

The branched structure of glycogen means that there are a great many points at which glycogen phosphorylase can act in response to stimulation by adrenaline (section 10.3) there can be a very rapid release of glucose 1-phosphate from glycogen. 

Figure 10.6 Hormonal regulation of glycogen synthetase and glycogen phosphorylase — responses to glucagon or adrenaline and insulin.

Adrenaline, released from the adrenal glands in response to fear or fright, acts on cell-surface receptors, leading to the formation of cAMP, which leads to increased activity of protein kinase and increased activity of glycogen phosphorylase (see Figure 10.6). 

Skeletal muscle glycogen delivers glucose primarily as a response to contractile stress. Regulation occurs through both modification of the enzyme phosphorylase, primarily by the action of epinephrine-adrenaline and allosteric regulation of phosphorylase related to a demand for ATP. 

In rat liver, 3-blockers do not completely abolish the response to adrenaline due to the presence of the second type of adrenaline receptor, the a-receptor. a-Receptors are characterized by their sensitivity to phenoxybenzamine. The binding of adrenaline to a-receptors does not increase the cAMP concentration, but nevertheless it stimulates glycogen breakdown by causing an increase in the cytosolic concentration of free Ca ions. This calcium is initially released from the endoplasmic reticulum. The non-phosphorylated form of phos-phorylase kinase is activated by calcium ions so that an increase in cytoplasmic calcium concentration increases the activity of phosphorylase kinase, and hence glycogen breakdown, independently of a change in cAMP. Thus Ca ions act as a second messenger for the a-receptor-mediated effects of adrenaline. In most tissues there are more than a receptors but the ratio varies with both the tissue and the species of animal and also with age. The significance of such variation is not understood. 

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