Noradrenaline Reuptake and Metabolism

Re-uptake of released NE into presynaptic nerve terminals is responsible for the rapid termination of neurotransmission in noradrenergic synapses. Transport of NE by the neuronal NE transporter (NET) is dependent on extracellular Na+ and Cl_. cDNAs of a series of neurotransmitter transporters have been cloned, and the NET has been shown to be a member of the superfamily of structurally related Na + - and Cl~-dependent transporters for monoamines (dopa-mine, serotonin, and NE) and certain amino acids such as GABA and glycine. Transporters of this family are structurally characterized by 12 transmembrane domains, intracellular amino and carboxy termini, and a large second extracellular loop (Fig. 4). Three consensus sequences for phosphorylation by protein kinase C are found: one in the second intracellular loop and two in the carboxy-terminal end. Phosphorylation of NET by protein kinase C results in down-regulation of NE transport, presumably corresponding to a diminution of the number of transporters expressed to the membrane. NET is one of the different pharmacological targets of several psychotropic substances, such as tricyclic antidepressants and psychostimulants (amphetamine and cocaine) (Fig. 8).

Following re-uptake, monoamine oxidase (MAO) is essential in the neuronal degradation of NE (Fig. 3). Two isoforms of MAO were described, MAO-A and MAO-B. MAO-A is predominant in noradrenergic neurons, whereas MAO-B is found in serotonergic cells. MAO is located on the outer membrane of mitochondria where it uses the FAD cofactor to

Figure 4 NE transporter. NE transporter is a 12-transmembrane-domain protein with intracellular amino and carboxy termini, a large glycosylated second extracellular loop, and five sites of phosphorylation (P), three of which are consensus sites for protein kinase C (PKC). NE is cotransported with sodium (Na+) and chloride (Cl_).

Figure 4 NE transporter. NE transporter is a 12-transmembrane-domain protein with intracellular amino and carboxy termini, a large glycosylated second extracellular loop, and five sites of phosphorylation (P), three of which are consensus sites for protein kinase C (PKC). NE is cotransported with sodium (Na+) and chloride (Cl_).

convert NE into dihydroxyphenylglycolalde-hyde, which is reduced into dihydroxyphenylglycol (DHPG). DHPG is further metabolized into methoxy-hydroxyphenylglycol (MHPG) outside neurons.

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