Noradrenaline degradation, metabolic

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

The intracellular signaltransduction of ofi-adrenoceptors is effectuated by a G-protein-dependent activation of the phospholipase C. This enzyme cleaves phosphatidylinositol, a phospholipid present in cell membranes, into inositol-1,4-5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is a strong inductor of intracellular calcium release which leads to an increase of smooth muscle tone or the liberation of hormones stored in vesicles. Noradrenaline which is released by exocytosis, spreads by diffusion only. Only a small fraction of the total amount of the transmitter released will actually reach the postsynaptic membrane and bind to its specific receptors. Another fraction escapes the synapic cleft by diffusion and is finally enzymatically degraded in the interstitial fluid. Another fraction is taken up postsynaptically and metabolized enzymatically by the target cells (uptake 2). By far most of the transmitter (90%) is actively taken up by the releasing neuron itself (uptake 1 or neuronal re-uptake). In the... 

The mechanism of deprenyl s action is unclear. In addition to enhancing dopaminergic activity in the brain by inhibiting dopamine degradation, deprenyl is metabolized into various stimulant metabolites. In spontaneously hyperactive rats used in an animal model of ADHD, chronic deprenyl administration improved im-pulsivity (but not hyperactivity or attention) along with altering levels of noradrenaline, dopamine, and serotonin and their metabolites (Boix et ah, 1998). 

Aggressive behavior is related to the monoamine neurotransmitters serotonin, dopamine, and noradrenaline. The enzymes monoamine oxidase (MAO) A and B play roles in the metabolism of catecholamines in the brain and peripheral tissues. MAOA degrades dopamine, serotonin, and noradrenaline. 

Activity Like the chemically and physiologically related (R)- noradrenaline (/f)-A., as an adrenal hormone, increases the degradation of glycogen in the liver and of fat in adipose tissue as well as the oxidative metabolism in muscle. As neutrotransmitter of the adrenergic nerve system (R)-A. increases heart rate as a sympathicomimetic, constricts blood vessels of the skin, mucous membranes, and abdominal viscera, and dilates vessels of the skeletal musculature and liver. The relaxation of smooth musculature in the intestine or bronchi effected by (R)-A. leads to a reduction of peristalsis (intestinal movements) or to dilatation of the bronchi. (S)-A. is about 12 times less active than (R)-adrenaline. 

Catecholamines and their metabolites The catecholamines, adrenaline, noradrenaline, and dopamine are essential components of the central nervous system acting as neurotransmitters both within the brain and at peripheral nerves. All are synthesized in the adrenal medulla from phenylalanine or tyrosine and are metabolized by a mixture of enzymatic side chain oxidation and methylation of the hydroxy groups on the ring. If the metabolism is complete, adrenaline and noradrenaline are degraded to 4-hydroxy-3-methoxy mandelic acid (HMMA, commonly called vanillylmandelic acid - VMA), while dopamine is broken down to homovanillic acid (HVA). Urinary excretion of these metabolites and their conjugates is the major route of elimination of catecholamines from the body, although small amounts are excreted unchanged as the free catecholamines. 

As low levels of MAO-A were detected in serotonergic neurons, selective MAO-A inhibitors were shown to increase brain 5-HT and to exert an antidepressant effect. MAO-B is also present in serotonergic neurons and, by degrading other amines, it may contribute to the purity of 5-HT delivered to the synaptic cleft. Both MAO-A and -B are found in noradrenergic neurons. Within synaptosomes of these neurons, MAO-A plays an important role in the deamination of noradrenaline and dopamine in the hypothalamus and striatum, respectively. On the other hand, MAO-B exerts a major role in the extraneuronal dopamine metabolism when dopamine uptake is impaired [2]. 

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