Structure and synthesis of adrenaline
Adrenaline belongs to the group of catecholamines and structurally represents a modified tyrosine molecule. It differs from the parent amino acid by the following modifications: cleavage of the COOH group, addition of two hydroxyl groups (–OH) to the aromatic ring to form a catechol moiety, and the addition of a methyl group to the side-chain amino group.
Adrenaline is synthesized in the adrenal medulla (chromaffin cells). Stimuli for its production include physical exertion, emotional stress, and hypoglycemia—states requiring rapid mobilization of energy substrates. The hormone is released upon direct stimulation of sympathetic preganglionic fibers.
Signal transduction mechanisms
Adrenaline exerts its effects via membrane-bound G protein-coupled adrenergic receptors. Two main second messenger systems are involved:
- Adenylyl cyclase system (cAMP) — activated upon binding to β-receptors (predominantly β2). Ligand binding induces the exchange of GDP for GTP on the G-protein α-subunit, activation of adenylyl cyclase, conversion of ATP to cAMP, and activation of protein kinase A (PKA).
- Inositol phosphate system (IP3/DAG) — engaged upon stimulation of α1-adrenergic receptors, leading to the mobilization of intracellular calcium.
Action in the liver: glycogenolysis
In the liver, adrenaline triggers glycogen breakdown via a phosphorylation cascade. Following PKA activation, the enzyme phosphorylates:
- Phosphorylase kinase, converting it into its active form;
- Glycogen synthase, inactivating it and blocking glycogen synthesis.
Active phosphorylase kinase, in turn, phosphorylates glycogen phosphorylase b, converting it into active glycogen phosphorylase a. This enzyme catalyzes the phosphorolytic cleavage of glycogen to form glucose-1-phosphate, which is subsequently used to maintain blood glucose levels.
Action in adipose tissue: lipolysis
In adipocytes, adrenaline activates lipolysis via the same adenylyl cyclase system. Activated PKA phosphorylates hormone-sensitive lipase (HSL), converting it into its active form. The enzyme sequentially hydrolyzes:
- Triacylglycerol → diacylglycerol + fatty acid;
- Diacylglycerol → monoacylglycerol + fatty acid;
- Monoacylglycerol → glycerol + fatty acid.
The released free fatty acids bind to plasma albumin and are transported to the liver, where they serve as a substrate for β-oxidation. Thus, the increase in the rate of hepatic β-oxidation under the action of epinephrine is a mediated effect — through the mobilization of fat from depots.
Action in skeletal muscle
In skeletal muscle, adrenaline activates glycogenolysis via the same mechanism as in the liver: cAMP → PKA → phosphorylase kinase → glycogen phosphorylase. However, the resulting glucose-6-phosphate cannot leave the myocyte (due to the absence of glucose-6-phosphatase) and is used locally for glycolysis and to provide energy for muscle contraction.
Regulation of cAMP levels and the role of phosphodiesterase inhibitors
Intracellular cAMP levels are controlled by the enzyme phosphodiesterase, which converts cAMP into AMP, thereby terminating PKA activation. A number of substances, notably caffeine and theophylline, inhibit phosphodiesterase. This leads to cAMP accumulation, prolonged PKA activation, and enhanced lipolysis and glycogenolysis. This exact mechanism accounts for the tonic and stimulating effects of beverages containing caffeine and methylxanthines.
Key points
- Adrenaline is a catecholamine, a tyrosine derivative synthesized in the adrenal medulla.
- Stimuli for secretion include stress, physical exertion, and hypoglycemia.
- It acts via α- and β-adrenergic receptors coupled to cAMP and IP3 systems.
- In the liver, it activates glycogenolysis via the PKA → phosphorylase kinase → glycogen phosphorylase cascade.
- In adipose tissue, it activates hormone-sensitive lipase and triggers lipolysis.
- Released fatty acids are transported by albumin and undergo β-oxidation in the liver.
- In skeletal muscle, it enhances glycogenolysis for local energy supply.
- Caffeine and theophylline potentiate the effects of adrenaline by inhibiting phosphodiesterase.