School of Medicine

University of Washington School of Medicine
CVANS: The Structure Function

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Catecholamines as Neurotransmitters/Hormones

Synthesis of catecholamines

Tyrosine hydroxylation

The amino acid tyrosine is the starting material. It is taken up into catecholaminergic nerves by an active transport system. Once inside the nerve, an additional hydroxyl group is added to the aromatic ring of tyrosine by the enzyme tyrosine hydroxylase. Tyrosine hydroxylation is the rate limiting step in the synthesis of catecholamines and is subject to feedback inhibition by the end products. This forms the catechol (dihydroxybenzene) part of the molecule responsible for the family name. The product is dihydroxyphenylalanine (DOPA).

DOPA decarboxylation

Dihydroxyphenylalanine (DOPA) is acted upon by aromatic-L-amino acid decarboxylase. This forms dopamine (DA), one of three naturally occurring catecholamines. L-DOPA is used to treat certain diseases in which it is desired to increased dopaminergic transmission at certain sites. For example, L-DOPA is used in the treatment of Parkinson's disease. In this application of L-DOPA as a drug, the action of the decarboxylase enzyme inside certain cells in the brain is desirable, but its action in the peripheral circulation is undesirable. This is because it reduces the concentration and thus the uptake of the amino acid into the brain (the amino acid is taken into the brain by certain carriers, whereas dopamine is not). Carbidopa is an inhibitor of the decarboxylase enzyme in the peripheral circulation that has been used in combination with L-DOPA in the treatment of Parkinson's disease. However, other enzymes can also inactivate DOPA in the circulation. See below for a drug combination designed to address this problem.

Dopamine hydroxylation

DA in catecholaminergic nerves is taken up into synaptic vesicles and is converted to norepinephrine (NE) by the addition of a hydroxyl group on the carbon second (beta) from the amino group (except in a few dopaminergic neurons). Beta hydroxylation is carried out by the enzyme dopamine-beta-hydroxylase (DBH).


DBH is located in the synaptic vesicles so the final step in the synthesis of NE occurs in the vesicle in which NE is packaged along with ATP and other material for eventual release. In adrenal medulla cells, NE in the cytosol is acted upon by phenylethanolamine-N-methyltransferase. This adds a methyl group to the amino nitrogen and forms epinephrine (EPI). The addition of a methyl group significantly alters the pharmacology of the catecholamine. Most of the EPI formed in this process is taken into synaptic vesicles and stored for eventual release into the blood stream. The adrenal medulla releases catecholamines into the blood. In humans, catecholamines released from the adrenal medulla are about 80% EPI and 20% NE. Because these catecholamines are released into the blood and act on receptors in target tissues at some distance these catecholamines act as circulating hormones.

In summary, synthesis of catecholamines is a multistep process. No wonder, then, that instead of being destroyed they are 'recycled' in large part.

Storage of catecholamines

Synaptic vesicles actively take up DA, as well as NE (and EPI, if present). Thus, there is a high concentration of catecholamines in synaptic vesicles and a relatively low concentration of catecholamines in the cytosol of catecholaminergic cells. In addition to catecholamines and DBH, some vesicles contain substantial amounts of ATP, ascorbic acid and some specific proteins, chromogranins. Almost all of the catecholamine content of a sympathetically innervated tissue is contained in the synaptic vesicles inside the catecholaminergic nerves. There is a normal background leak of catecholamines out of the vesicles, but the balance is very much in favor of vesicular storage. Reserpine is a drug that inhibits the vesicular catecholamine pump. By preventing the active uptake of catecholamines into the synaptic vesicles, reserpine can result in depletion of catecholamines. This causes some degree of failure of catecholaminergic transmission at essentially all catecholamine junctions because reserpine is a lipid soluble drug that penetrates the blood-brain barrier (BBB). In experimental animals reserpine can cause in essentially total depletion of tissue catecholamines and complete failure of catecholaminergic transmission. At much lower doses in humans, reserpine has been used in the treatment of hypertension. The low concentration of catecholamines in the cytosol of catecholaminergic nerves is maintained in part by the vesicular amine uptake pump and in part by the mitochondrial enzyme, monoamine oxidase (MAO). If cytosolic concentrations of catecholamines increase (for example, as caused by reserpine), then metabolism by MAO inactives them inside the nerve. Thus, reserpine normally results in depletion of catecholamines, not release. Release of catecholamines, means release in physiologically or pharmacologically active form that results in effector organ responses. The MAO metabolites of catecholamines are essentially inactive. Postganglionic sympathetic nerves (except to sweat glands) release mainly NE into the neuroeffector junction. This NE thus acts as a neurotransmitter.

Release of catecholamines

Nerve-induced release of catecholamines, like synaptic release at other junctions, is based on quantal release of vesicles containing preformed neurotransmitter molecules. Vesicular release depends on depolarization of the nerve terminal and the influx of calcium ion. In ways not yet understood in detail, the influx of calcium promotes simultaneous exocytosis of many vesicles. The release of vesicular contents allows release of catecholamines and ATP (both have short life spans outside the cell) and DBH. The plasma level of DBH has been used as a measure of the turnover of catecholaminergic vesicles, or as a way of trying to quantify the integral of recent sympathetic nerve activity. The release of catecholamines can also be promoted by certain drugs. In the adrenal medulla, ACh acting as the neurotransmitter of the sympathetic ganglion acts on nicotinic receptors and promotes the release of catecholamines into the circulation. Under certain experimental conditions it is possible to mimic this nicotinic effect of acetylcholine not only at the adrenal medulla but at other sympathetic ganglia. Thus, agonists of nicotinic cholinergic receptors of the ganglionic, or neuronal, type (Nn) can cause substantial catecholamine release at postganlionic sympathetic neuroeffectors junctions as well as massive release of catecholamines from the adrenal medulla into the circulation.

Dimethylphenylpiperazinium (DMPP) is a classical drug that is a relatively selective agonist of Nn receptors. epibatidine is a more recent and more selective example. Another mechanism of release of catecholamines is based on an action at the sympathetic nerve terminal. It is not applicable in the adrenal medulla. Indirectly acting sympathomimetic amines such as tyramine, ephedrine and amphetamine are taken up into sympathetic nerve terminals by the amine uptake pump. Normally, this pump serves to inactivate catecholamines in the catecholaminergic neuroeffector juction. However, structurally related compounds can be taken up into the nerve terminal by this transporter. Once inside the catecholaminergic nerve terminal, the indirectly acting sympathomimetic amines cause displacement of catecholamines from storage sites in vesicles, or from other binding sites. The release of catecholamines can be blocked by certain drugs, most notably bretylium (Bretylol®) and guanethidine (Ismelin®).

Inactivation of catecholamines

Inactivation of the effects of catecholamines at the sympathetic neuroeffector junction can take place by one or more of several mechanisms:
  • uptake or reuptake
  • O-methylation
  • oxidative deamination

Uptake or reuptake of catecholamines including NE into (postganglionic) sympathetic nerve terminals is facilitated by an amine uptake pump. This is a part of a family of membrane proteins that transport different transmitter substances across the plasma membrane of the nerve terminal. This pump is driven indirectly by a sodium gradient, which is in turn generated by another plasma membrane protein, the Na+,K+-ATPase, or sodium, potassium 'pump'. The amine uptake pump is selective for NE > Epi but does not take up isoproterenol. Catecholamines which diffuse into the circulation or are released as neurohormones may also be taken up into sympathetic nerve terminals. For example, the small content of epinephrine in postganglionic sympathetic nerve terminals is probably provided by epinephrine from the adrenal medulla that has been taken up.

The amine uptake pump is inhibited by cocaine or tricyclic antidepressants, such as imipramine. Uptake of NE is a major mechanism for terminating sympathetic neuroeffector transmission. For this reason, inhibitors of the amine uptake pump potentiate responses to stimulation of the sympathetic nervous system, or to injected compounds that are taken up by the sympathetic nerve terminals. In a sympathetically innervated tissue, such as the heart, the major uptake of catecholamines is neuronal uptake, or so-called uptake-1.

An extraneuronal uptake of catecholamines can occur; so-called uptake-2 (not shown). This uptake is into the parenchymal cells of the organ. It is not blocked by cocaine or imipramine. The importance of uptake-2 is uncertain.

MAO Effect

Both inside catecholaminergic cells, and in the circulation, oxidative deamination of NE is facilitated by the enzyme monoamine oxidase (MAO). The product of the oxidative deamination of EPI or NE is 3,4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is subject to reduction to the corresponding alcohol (3,4-dihydroxyphenylethylene glycol, DOPEG) or oxidation to the corresponding carboxylic acid (3,4-dihydroxymandelic acid, DOMA); the latter being the major pathway.

The product of oxidative deamination of NE (or Epi) is DOPGAL. DOPGAL may be reduced to DOPEG or oxidized to DOMA.

Metabolic disposition of catecholamines is important for circulating compounds. Catechol-O-methyl transferase (COMT) plays a major role in terminating catecholamines in the circulation following injection or release from the adrenal medulla. Methylation at the 3 position of the ring of catecholamines is facilitated by COMT and results in loss of the characteristic catecholaminergic activities. Methylation can also occur on L-DOPA, especially if its metabolism in the peripheral circulation is inhibited by carbidopa, the inhibitor of aromatic amino acid decarboxylase (see above).

Until a few years ago, there were no clinically useful inhibitors of COMT. Recently tolcapone and entecapone have been introduced as COMT inhibitors that facilitate the entry of L-DOPA into the brain by reducing its destruction in the peripheral circulation. A combination of L-DOPA, carbidopa and entecapone is marketed for the treatment of Parkinson's disease.

Final metabolic disposition of catecholamines typically involves the action of both COMT and MAO. MAO is important in regulating the levels of catecholamines in tissues (particularly intraneuronally), but can also act on the 3-O-methyl metabolites of catecholamines (i.e., COMT then MAO). Thus, the major metabolite of norepinephrine and epinephrine that appears in the urine is 3-methoxy-4-hydroxymandelic acid, also called vanillylmandelic acid, or VMA.

Metabolic disposition of catecholamine also includes pathways in which COMT acts on the respective MAO-derived metabolites (MAO then COMT). By this process the final product that ends up in the urine is also VMA.