Noradrenaline vesicle uptake transporter

Whereas acetylcholine is degraded by a membrane-anchored acetylcholine esterase (ACE) in the synaptic cleft (choline is afterwards taken up presynaptically), the biogenic amines adrenaline, noradrenaline, serotonin, and dopamine are taken up by the presynaptic membrane by transporters (Fig. 3) or by extraneuronal cells in which they are degraded by a catecholamine O-methyltransferase (COMT). These transporter have similar structure and contain 12 transmembrane regions. Once in the presynapse, the neurotransmitters are either degraded by monoamine oxidase (MAO) or taken up by synaptic vesicles. A proton pumping ATPase of the vesicle membrane (V-type ATPase as in plant vacuoles) causes an increase of hydrogen ion concentrations in the vesicles. Uptake of the neurotransmitter serotonin, adrenaline and noradrenaline could be partly achieved either via a diffusion of the free base into the vesicles where they become protonated and concentrated by an "ion trap" mechanism and via specific proton-coupled antiporters. The excitatory amino acids, acetylcholine and ATP cannot diffuse and enter the vesicles via specific transporters. 

Uptake of noradrenaline into the vesicles depends on an electrochemical gradient driven by an excess of protons inside the vesicle core. This gradient is maintained by an ATP-dependent vesicular H+-triphosphatase. Uptake of one molecule of noradrenaline into the vesicle by the transporter is balanced by the counter-transport of two H+ ions (reviewed by Schuldiner 1998). It is thought that either binding or translocation of one H+ ion increases the affinity of the transporter for noradrenaline and that binding of the second H+ actually triggers its translocation. 

Reserpine irreversibly inhibits the triphosphatase that maintains the proton gradient and so it depletes neurons of their vesicular store of transmitter. This explains why restoration of normal neuronal function rests on delivery of new vesicles from the cell bodies. Some amphetamine derivatives, including methylenedioxymethamphetamine (MDMA), are also substrates for the transporter and, as a result, competitively inhibit noradrenaline uptake. Another way of inhibiting the transporter is by dissipation of the pH gradient across the vesicular membrane i-chloroamphetamine is thought to act in this way. 

In other respects the storage of 5-HT resembles that of noradrenaline with its uptake by vesicles resting on energy-dependent, vesicular monoamine transporters (VMATs) (see Chapter 8). Functional disruption of this transporter, either through competitive inhibition (e.g. by methylenedioxymethamphetamine (MDMA, Ecstasy )) or dissipation... 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

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... 

The application of R. leads to a reduction in the levels of noradrenaline, dopamine, and serotonin in the synapses R. binds irreversibly to the transport system of noradrenaline (NA) so that the re-uptake of NA in the vesicles of the synapses is inhibited. Thus, transmission of stimuli is reduced, the blood pressure decreases with a concomitant central sedation. R. thus acts as a neuroleptic agent. The side effects of an overdose may include diarrhea, elevated secretion of saliva and gastric juices, depression, and Parkinson s disease. R. is suspected of being carcinogenic since in female patients an increased incidence of breast cancer seems to occur. The roots of R. serpentirm have been used in India for centuries as a sedative they also contain yohimbine. The first total synthesis was achieved by Woodward, for stereospecific synthesis, see Lit.. Deserpidine (11-demethoxyreserpine, canescine, recanescine, CsaHjgNjOg, Mr 578.64, cryst., mp. 228-230°C, [a]o-163° (pyridine) is also aRauvo/-fia alkaloid it exists in polymorphic forms and also lowers the blood pressure. 

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