Neurochemistry Of Noradrenaline

The effects of drugs on the synthesis, storage, release and destruction of noradrenaline, summarised in Fig. 8.4, are discussed in the following sections.

Presynaptic terminal

Norepinephrine Pathways Brain

MAO inhibitors

Irreversible, non-selective:

Plierwliine Irreversible, selective.

Dcprcry) (MAO-B) ftEverslble, selective: Moclobemid (MAO-A, RIKA)

Vesicular uptake inhibitors

Rcserpine Tetrabi niiine

Figure 8.4 The site of action of drugs that modify noradrenergic transmission

MAO inhibitors

Irreversible, non-selective:

Plierwliine Irreversible, selective.

Dcprcry) (MAO-B) ftEverslble, selective: Moclobemid (MAO-A, RIKA)

Vesicular uptake inhibitors

Rcserpine Tetrabi niiine

¡1

Wochcmdriori

w

Receptor

Transporter

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Vsside

*

Monoamine

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oxidase

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COMT

Figure 8.4 The site of action of drugs that modify noradrenergic transmission

SYNTHESIS

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 (7-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholamine-releasing 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

Phenylalanine Norepinephrine Pathway

Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol

Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol that all the factors (enzymes and storage vesicles) which are vital for this process undergo axoplasmic transport after their assembly in the cell body.

It was recognised as early as the 1960s that conversion of tyrosine to /-DOPA was the rate-limiting step in the synthesis of noradrenaline. This emerged from experiments showing that incubation of tissues with high concentrations of tyrosine had no effect on the rate of synthesis of noradrenaline, whereas incubation with high concentrations of /-DOPA or dopamine increased it. More evidence came from experiments showing that the rate of conversion of [3H]tyrosine to [3H]DOPA was increased if the sympathetic nerves innervating the test tissue were stimulated, whereas stimulation of nerves innervating tissues incubated in a medium containing [3H]DOPA did not accelerate synthesis of [3H]dopamine or [3H]noradrenaline.

Because the enzymes, DOPA decarboxylase and DpH, have a high affinity for their substrates, neither /-DOPA nor dopamine accumulate in noradrenergic nerve terminals under normal conditions. Exceptionally, DpH can become the rate-limiting enzyme, such as during /-DOPA treatment of Parkinson's disease which greatly increases the intraneuronal pool of dopamine. It is thought that DpH can also be rate-limiting during periods of intense or prolonged impulse-evoked release of noradrenaline. This is because a high release rate compromises the supply of vesicles that not only store and release noradrenaline but are also the site of its synthesis after uptake of dopamine from the cytosol. Evidence suggests that vesicular uptake of dopamine is reduced after periods of intense neurotransmission; this results in its accumulation in the cytosol until new vesicles are delivered to the terminals.

TH is a mixed-function oxidase with an absolute requirement for reduced pterin co-factor, 6^-tetrahydrobiopterin, molecular oxygen and Fe2+. The Km of the enzyme for its substrate is thought to be well below tissue concentrations of tyrosine and so the enzyme is probably normally about 80% saturated. This makes it unlikely that the supply of tyrosine limits enzyme activity and synthesis of noradrenaline under normal circumstances. However, it was clear from the earliest studies of noradrenergic neurons that the synthesis of noradrenaline was increased during neuronal activity, whether this is induced pharmacologically (e.g. by blockade of presynaptic a2-adrenoceptors which inhibit release of noradrenaline) or by physiological stimuli (e.g. cold exposure or hypoglycaemia). Such findings suggested that synthesis and release are coupled in some way.

It is now known that regulation of this enzyme involves multiple mechanisms affecting both rapid, transient changes in enzyme activity and long-latency, long-lasting changes in enzyme synthesis involving increased TH gene transcription. The factors controlling the synthesis of noradrenaline have been studied more, and are better understood, than those of most other neurotransmitters and therefore justify detailed consideration.

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