Adrenaline pathway

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... 

Fig. 2.20 Efferent pathways into bulb showing (a) cholinergic (ACh) fibres projecting to MOB from basal forebrain nuclei. AON = ant. olfactory nucleus, OT = olfactory tract, DB = diagonal band nuc. (from Davis et al., 1978). (b) Nor-Adrenalin input to AOB, via MFB pathway from brain stem centres (nuclei A1-2, A6) (from Keveme, 1971).

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

The next key point is to realize that each enzyme in the pathway exists in both active and inactive forms. cAMP initiates a cascade of reactions by activating protein kinase A (PK-A)," the active form of which activates the next enzyme in the sequence, and so on. At the end of the day, glycogen phosphorylase is activated and glucose or ATP is produced. This signaling pathway is a marvelous amplification system. A few molecules of glucagon or adrenaline may induce formation of many molecules of cAMP, which may activate many of PK-A, and so on. The catalytic power of enzymes is magnified in cascades of this sort. 

The switch for the activation of an intracellular signaling pathway is in most cases an increase in the concentration of the freely circulating hormone. This leads to an increase in the concentration of the hormone-receptor complex, which results in an increased activation of subsequent reactions in the cell. The concentration of the circulating hormone is thus the main regulatory parameter in cellular conummication. The relation between hormone concentration, binding of the hormone to the receptor, and subsequent reaction in the cell is illustrated in fig. 3.7 for the case of adrenaline and the P-adrenergic receptor. 

However, Van der Wender and Spoerlein have recently described the presence of an enzyme system in rat brain that is capable of oxidizing DOPA to melanitic pigments43 (an aminochrome, i.e. dopachrome, must be formed as an essential intermediate in this process) the same enzyme system apparently oxidizes adrenaline to adrenochrome.43 Kaliman has demonstrated the presence of an enzyme system in rabbit heart tissue which oxidizes adrenaline via the quinonoid pathway (presumably to adrenochrome).44 Heart, kidney, and brain tissues of white rats were also shown by Kaliman and Koshlyak to possess similar activity.45... 

Although the two major routes for metabolism of adrenaline and noradrenaline are well established, and involve either methylation of the 3-hydroxyl group on the aromatic nucleus or oxidative deamination (cf. refs. 35, 93, 94, 229-231), the evidence to date does not warrant the complete rejection of a further possible metabolic pathway involving oxidation to an aminochrome (such as adrenochrome or noradrenochrome) in some instances. 

Adrenal Conical Hormones. The adrenal gland is made up of two parts, the medulla and the cortex, each of which secretes characteristic hormones. The hormones of the adrenal medulla art- the catecholamines, epinephrine adrenalin and norepinephrine (noradrenalint. which are closely related chemically, dil lning only in that epinephrine has an added methyl group. See Table I. In fact, animal experiments have established a metabolic pathway lor Ihe biosynthesis of both compounds Irom Ihe ammo acid pheny lal.inine. which involves enzy malic oxidation and decarboxylation reactions It is also to he noted ihui the isomeric form of norepinephrine is most important the natural D-lonn (which incidentally, is levorntatory) has many times die uciiviiy of die synthetic isomer. Epinephrine has a pronounced action upon the circulatory system, increasing both blood... 

Non-channel synapses have membrane-bound neuroreceptors (which are not ion channels). When activated by the neurotransmitter they initiate an intracellular signalling pathway in particular they can alter the number and sensitivity of the ion-channel receptors in the same cell. These synapses are involved in slow and long-lasting responses such as learning and memory. Typical neurotransmitters are adrenaline (epinephrine), noradrenaline, dopamine, serotonin, endorphin, angiotensin and acetylcholine. 

---