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Inactivation of MA Neurotransmitters by Reuptake and Metabolism
The major mechanism for the inactivation of secreted MA is the reuptake into the nerve terminal from which the MA was released. Under conditions of very high neuronal activity, the MA will also be taken up by neighboring glial cells and will overflow into the capillaries perfusing the CNS. Under all three situations, a portion of the MA will be metabolized by enzymes that inactivate the MA, converting them to inactive products. As described below, measurement of these metabolites is used clinically and in research to monitor the activity of the MA systems.
Reuptake of MA Neurotransmitters
High affinity transport (reuptake) into axon terminals is the main process of inactivation of released monoamines. Reuptake requires sodium ions and a source of energy (e.g., ATP) and is mediated by a protein carrier located on the plasma membrane of the monamine neurons. Tricyclic antidepressants and cocaine inhibit the transporters for DA, NE and 5-HT. Within the past ten years the structure of several MA transporters has been determined and shown to consist of a twelve transmembrane protein with both the N and C terminal ends residing within the cytoplasm (Figure 12.11). The powerful addictive drugs cocaine and amphetamine increase the level of MA neurotransmitters in the extracellular space. Cocaine acts by blocking the transport of MA (Figure 12.11) neurotransmitters into the terminal and as a consequence increases MA in the extracellular space. In contrast, amphetamine reverses the transport direction (Figure 12.11), transporting MA neurotransmitters out of the nerve terminal.
Figure 12.11 |
A low affinity uptake of monoamines into surrounding glial cells also inactivates released monoamines. Because this process acts only at very high concentrations of monoamines, it is believed to only come into play when the concentration of released neurotransmitter is very high.
A portion of released catecholamines diffuse to the extracellular space where monoamine oxidase (MAO) and/or catechol-0-methyl-transferase (COMT) eventually catabolize it. This route of inactivation is more prominent following extremely high levels of catecholaminergic neuronal activity.
Metabolism of MA Neurotransmitters
Catecholamines and 5-HT: The enzymatic metabolism of MA neurotransmitters is carried out by MAO, COMT and histamine methyl transferase. These enzymes are widely distributed in tissues.
Monoamine Oxidase (MAO): This metabolic enzyme is located on the outer membrane of the mitochondrion and metabolizes DA, NE and 5-HT by oxidative deamination of (see Figure 12.12) to the corresponding aldehyde (DHPA, DHPGA and 5HIAA, respectively). DHPA and PHPGA are aldehyde intermediates that must be further metabolized by aldehyde reductase or dehydrogenase to alcohols and acids, respectively. These metabolites are excreted (see Table VI below), or further metabolized by methylation through the action of catechol-O-methyltransferase and then excreted (see below). Pargyline, an irreversable inhibitor of MAO, blocks monoamine degradation.
Figure 12.12a |
Figure 12.12b |
Figure 12.12c |
The deamination of three monoamine by mitochondrial MAO. |
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Catechol-O-methyl-transferase (COMT): This extraneuronal enzyme inactivates catecholamines by methylation of the hydroxyls on the catechol ring. COMT methylates either catecholamines that have already been metabolized by MAO or those that have not. The metabolites of catecholamines are shown in Table VI.
Measurement of MA metabolites in CSF, blood or urine provides a useful clinical index of the rate of release or turnover of MA neurotransmitters. Metabolites of catecholamines and serotonin are assayed in the CSF to obtain an index of brain metabolites. This method has been only modestly useful in determining the role of a specific MA neurotransmitters in brain disorders. Likewise, specific catecholamine metabolites in urine or the blood provide an index of peripheral sympathetic neurons and adrenal medullary catecholamines. The metabolites that are routinely measured clinically to assess CNS and peripheral catecholamine function are summarized in Table VI. Two CSF metabolites provide a measure of central DA function: 1) HVA, a methylated DA metabolite (metabolized by both MAO and COMT), and 2) DOPAC, an un-methylated metabolite, (metabolized by only MAO). The CSF metabolite that is measured to assess central NE function is MHPG, a methylated NE metabolite (metabolized by MAO and COMT). The metabolite that provides the best index of autonomic nervous system activity is VMA, a methylated NE metabolite (metabolized by both MAO and COMT). Metanephrine levels are monitored to assess the relative activity of the adrenal medulla or a tumor of this tissue, phaeochromocytoma. 5-HIAA reflects the activity of 5-HT cells.
Histamine: The metabolism of HA is somewhat different than the other MA. HA is taken up into cells where it is first methylated by histamine methyltransferase (HMT) to form telemethylhistamine. MAO subsequently oxidizes telemethylhistamine to the histamine metabolite, telemethylimadazole (TMI).
Figure 12.13 |
| Cross Reference: Links for Dopamine | |||
| Anatomy | Cell Biology | Physiology | Clinical |
| Cross Reference: Links for Norepinephrine | |||
| Anatomy | Cell Biology | Physiology | Clinical |
| Cross Reference: Links for Serotonin | |||
| Anatomy | Cell Biology | Physiology | Clinical |
| Cross Reference: Links for Histamine | ||
| Anatomy | Cell Biology | Clinical |
