General characteristics of catecholamines
Catecholamines are a group of biogenic amines including epinephrine, norepinephrine, and dopamine. Structurally, they are derivatives of tyrosine, containing a catechol core (a benzene ring with two hydroxyl groups) and an amino group in the side chain.
Epinephrine is synthesized and secreted by the adrenal medulla. The main stimuli for production—physical exercise, stress, hypoglycemia—are mediated through the activation of the sympathetic nervous system.
Structure of epinephrine and its relation to tyrosine
The epinephrine molecule can be viewed as a modified tyrosine with the following changes:
- removal of the carboxyl group (decarboxylation);
- introduction of two hydroxyl groups: one at position 3 of the aromatic ring (forming the catechol structure) and one on the β-carbon of the side chain;
- attachment of a methyl group to the amino group (N-methylation), which distinguishes epinephrine from norepinephrine.
Receptors and signal transduction mechanisms
Epinephrine acts through membrane adrenergic receptors coupled with G-proteins. There are α- and β-types; for metabolic effects, α1- and β2-receptors are primarily significant.
Adenylate cyclase system (β-receptors)
- binding of epinephrine to the β-receptor activates the Gs protein;
- the Gs α-subunit exchanges GDP for GTP and stimulates adenylate cyclase;
- adenylate cyclase converts ATP into cAMP;
- cAMP activates protein kinase A (PKA), which phosphorylates key metabolic enzymes.
Inositol phosphate system (α1-receptors)
- activation of the Gq protein stimulates phospholipase C;
- IP3 and DAG are formed; IP3 causes the release of Ca²⁺ from the ER;
- Ca²⁺ activates protein kinase C and binds to calmodulin;
- the Ca²⁺-calmodulin complex activates phosphorylase kinase.
Glycogen mobilization in the liver
Epinephrine triggers glycogenolysis via two pathways leading to the same result—phosphorylation of carbohydrate metabolism enzymes.
- Via β2-receptors: PKA phosphorylates glycogen synthase (converting it to the inactive form) and phosphorylase kinase; active kinase phosphorylates glycogen phosphorylase b, converting it to active form a.
- Via α1-receptors: protein kinase C also phosphorylates glycogen synthase; the Ca²⁺-calmodulin complex activates phosphorylase kinase without phosphorylation.
The result is the breakdown of glycogen to glucose-1-phosphate, and subsequently to glucose, which enters the bloodstream.
Glycogenolysis in skeletal muscles
In muscles, epinephrine acts similarly—via β2-receptors and the adenylate cyclase system. The cAMP → PKA → phosphorylase kinase → glycogen phosphorylase cascade leads to the breakdown of muscle glycogen. Unlike the liver, muscles do not contain glucose-6-phosphatase, so the resulting glucose is used locally for glycolysis and muscle contraction.
Activation of lipolysis and β-oxidation
Epinephrine enhances fatty acid β-oxidation in the liver indirectly—through the mobilization of fat from adipose tissue.
- In adipocytes, the adenylate cyclase system is activated, and cAMP levels rise.
- PKA phosphorylates hormone-sensitive lipase (HSL), converting it to an active state.
- HSL sequentially hydrolyzes triacylglycerol to diacylglycerol, monoacylglycerol, and ultimately to glycerol and three free fatty acids.
- Fatty acids bind to albumin and are transported via the bloodstream to the liver and muscles, where they undergo β-oxidation to produce acetyl-CoA and ATP.
Regulation of cAMP levels: phosphodiesterase
cAMP levels are limited by the enzyme phosphodiesterase, which hydrolyzes cAMP to AMP and inactivates the signal. Phosphodiesterase inhibitors—caffeine, theophylline, taurine-containing drinks—prevent cAMP breakdown. As a result, the effect of epinephrine is prolonged: lipolysis and glycogenolysis are enhanced, which is subjectively perceived as a surge of energy.
Key points
- Epinephrine is an adrenal catecholamine, a tyrosine derivative with an N-methylated amino group.
- The signal is mediated via β-receptors (adenylate cyclase → cAMP → PKA) and α1-receptors (phospholipase C → IP3/DAG → Ca²⁺).
- In the liver and muscles, epinephrine activates glycogen phosphorylase and inactivates glycogen synthase, initiating glycogenolysis.
- In adipose tissue, epinephrine activates hormone-sensitive lipase via PKA and stimulates lipolysis.
- Fatty acid β-oxidation in the liver is enhanced indirectly through the influx of free fatty acids from adipocytes.
- The Ca²⁺-calmodulin complex is an alternative pathway for activating phosphorylase kinase during α1-signaling.
- Phosphodiesterase degrades cAMP; its inhibitors (caffeine) enhance and prolong the effects of epinephrine.