Catecholamines Dopamine, Noradrenaline

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

These alkaloids have a phenyl or phenylpropyl nucleus. The group includes simple phenyl amine (tyramine, hordenine), catecholamine (dopamine, noradrenaline, adrenaline), simple tetrahydroisoquinoline (mescaline, anhalamine, anhalonine, anhalonidine), benzylisoquinoline (e.g., papaverine), phthalideiso-quinoline (e.g., noscapine), phenethylisoquinoline (autumnaline, floramultine and kreysigine), tetrahydroisoquinoline (emehne and cephaeline) and terpenoid tetrahydroisoquinoline (secologanin and ipecoside) alkaloids. 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

Dopamine is synthesized from the amino acid tyrosine by the enzymes tyrosine hydroxylase (TH which forms L-3,4-dihydroxylphenylalanine, l-DOPA) and L-amino acid decarboxylase (AADC) in dopaminergic neurons. The mRNA expression of the TH (which is the rate-limiting enzyme in the synthesis of dopamine) is abundant throughout the human mesencephalon (Fig. 1) TH is a phenotypic marker for all catecholamines, dopamine, noradrenaline and adrenaline. Evidence for the presence of TH has been documented in the mesencephalon from at least 4.5 to 7 weeks of human fetal life... 

With pain, catecholamines (dopamine, noradrenaline, adrenaline) are released, heart-rate and blood pressure increase, the pupils ate dilated, and possibly motor reactions work to counteract pain generation. With visceral pain, it can bring about nausea, vomiting, sweating and a fall in blood pressure. The emotional processing of pain can be individually quite unique and situation-dependent. 

Tyrosine is the precursor for dihydroxyphenylala-nine (dopa), which can successively be converted to the catecholamines dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine). Although only a small proportion of tyrosine is used in this pathway, this metabolic route is extremely relevant. Dopamine is an important neurotransmitter in different parts of the brain and is involved in movement and affects pleasure and motivation. Disruption of dopamine neurons in the basal ganglia is the cause of Parkinson s disease. Noradrenaline and ardrenaline are the most important neurotransmitters in the sympathetic nervous system. The... 

A number of the products of the decarboxylation of amino acids are important as neurotransmitters and hormones—5-hydroxytryptamine, the catecholamines dopamine, noradrenaline, and adrenaline, and histamine and 7-aminobutyrate (GABA)—and as the diamines and polyamines involved in the regulation of DNA metabolism. The decarboxylation of phosphatidylserine to phosphatidylethanola-mine is important in phospholipid metabolism. 

Monoamine oxidases (MAOs) are mitochondrial outer membrane-bound flavoenzymes that catalyze the degradation of biogenic amines, more specifically the oxidative deamination of several important neurotransmitters, including 5-hydroxytiyptamine (5-HT) (or serotonin), histamine, and the catecholamines dopamine, noradrenaline, and adrenaline. There are two isoforms... 

Catecholamines are biogenic amines with a catechol (o-dihydroxy-benzol) structure. They are synthesized in nerve endings from tyrosine and include dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine). 

It is an alkaloid obtained from the roots of Ramvolfia serpentina. It is known to deplete the catecholamines - adrenaline, noradrenaline and dopamine from the various sites in the body. It also depletes 5-hydroxytryptamine (serotonin). 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

A 1,2-dihydrobenzene structure, exemplified by the catecholamine transmitters noradrenaline and dopamine. 

Ceruloplasmin, a protein from the a-globulin fraction of human plasma, is usually considered to be the major copper transport protein. However, it also catalyzes the oxidation of biogenic amines, including catecholamines, adrenaline, noradrenaline, dopamine, and the indoleamine 5-hydroxytrypta-mine (5HT). 

The catecholamines - dopamine, norepinephrine, and epinephrine are successively derived from tyrosine. S m-thesis occurs in the nerve terminals and in the adrenal gland. Tyrosine hydroxylase catalyzes the first step (Figure 10.2a) and is the major site of regulation (inhibition by dopamine and noradrenaline, activation by cAMP). This step gives rise to 3,4-dihydroxyphenylalanine (L-DOPA), which in turn is a substrate for L-aromatic acid decarboxylase. De-... 

Endogenous biogenic amines in the brain include catecholamines [NE (noradrenaline, NA), dopamine (DA), epinephrine (adrenaline)] 5-HT, histamine, and the so-called trace amines (P-phenylethylamine, tyramine, tryptamine, and octopamine). These amines have in common a arylalkylamine stmcture, and all have been implicated in the etiology of one or more psychiatric disorders and/or in therapeutic and/or adverse effects of drugs used to treat such disorders. In this review on depression, the focus in the case of biogenic amines will be on 5-HT, NE, and DA, although epinephrine and histamine and trace amines have also been implicated (see the section on Other Antidepressant Approaches and Targets ). 

Catecholamines (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline) (plasma approx. 2 min) are metabolised by two enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). These enzymes are present in large amounts in the liver and kidney and account for most of the metabolism of injected catecholamines. MAO is also present in the intestinal mucosa (and in nerve endings, peripheral and central). Because of these enzymes catecholamines are ineffective when swallowed, but noncatecholamines, e.g. salbutamol, amphetamine, are effective orally. 

DOPAMINE HYDROXYLASE INHIBITORS interfere with a stage in the biosynthesis of the catecholamine neurotransmitters, or hormones, dopamine, noradrenaline... 

Some of the major neurotransmitters are heterocyclic (histamine, 5-hydroxytryptamine), others are not heterocyclic (catecholamines adrenaline, noradrenaline, dopamine acetylcholine). These neurotransmitters are present in both the peripheral and central systems, although dopamine acts mainly in the latter. The CNS also has other neurotransmitters, including the amino acids glycine, glutamic acid and gamma-aminobutyric acid (GABA). 

S5mthesized via tyramine (Fig. 30-26), apparently functions in place of noradrenaline. Note fhe precursor-product relationship between dopamine, noradrenaline, and adrenaline. The synthetic pathways to these neurotransmitters involve decarboxylation and hydroxylahon, types of reacfion imporfanf in formation of other transmitters as well. The most important process for ferminafing fhe acfion of released catecholamine transmitters is reuptake by the neurons. High-affinity uptake systems transport the catecholamine molecules back into the neurons and then into the synaptic vesicles. The uptake is specifically blocked by the drug reserpine (Fig. 25-12).7 The dopamine transporter is a major binding site for cocaine (see Fig. 30-28).7 7-7Si Catecholamine trans-miffers are catabolized by two enzymes. One is the... 

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