Monoamine oxidase, location

Figure 5 Schematic of presynaptic mechanisms involved with the uptake of dopamine (DA). MAO, monoamine oxidase (located on the surface of the mitoehondrion) VMAT, vesicular monoamine transporter DAT dopamine transporter. Cellular maehinery has been enlarged to show detail.

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Since the enzyme that converts dopamine to norepinephrine (dopamine (3-hydroxylase) is located only within the vesicles, the transport of dopamine into the vesicle is an essential step in the synthesis of norepinephrine. This same transport system is essential for the storage of norepinephrine. There is a tendency for norepinephrine to leak from the vesicles into the cytosol. If norepinephrine remains in the cytosol, much of it will be destroyed by a mitochondrial enzyme, monoamine oxidase MAO). However, most of the norepinephrine that leaks out of the vesicle is rapidly returned to the storage vesicles by the same transport system that carries dopamine into the storage vesicles. It is important for a proper understanding of drug action to remember that this single transport system, called vesicular transport, is an essential element of both synthesis and storage of norepinephrine. 

Amine oxidation. As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes, which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxy try pt-amine, they may be involved in the metabolism of foreign compounds. 

Monoamine Oxidase Inhibitors. Monoamine oxidase (MAO) is an enzyme that is located at amine synapses and helps remove released transmitters through enzymatic destruction. Drugs that inhibit this enzyme allow more of the transmitter to remain in the synaptic cleft and continue to exert an effect.74 As with... 

As shown in Fig. 3 (Top Panel), dietary tyrosine is transported into axon terminals of DA neurons and converted in the cytoplasm to DOPA by the rate limiting enzyme TH. DOPA is then rapidly decarboxylated by DDC to DA which is taken up and stored in synaptic vesicles until release. Excess newly synthesized DA is metabolized by mitochondrial monoamine oxidase (MAO) to DOPAC which rapidly diffuses out of neurons and is taken up and converted to homovanillic acid (HVA) by catechol-O-methyltransferase (COMT)-containing glial cells in the neuropil (Hansson and Sellstrom, 1983 Kimelberg, 1986). Upon arrival of an action potential at the axon terminal, vesicular DA is released into the synapse via calcium-dependent exocytosis where it is free to interact with stimulatory Di and/or inhibitory D2 DA receptors on postsynaptic target cells and inhibitory D2 autoreceptors on presynaptic terminals. A major portion of DA is removed from the synapse by high affinity DA transporters located on presynaptic terminals, and recaptured DA is either metabolized to DOPAC by mitochondrial MAO or stored in synaptic vesicles for subsequent re-release. A small portion of DA can also be taken up from the synapse by glia and metabolized to 3-methoxytyramine (3MT) and HVA. 

Monoamine oxidase (MAO) enzymes have an important function in modulating the intraneuronal content of neurotransmitter. The enzymes exist in two principal forms, A and B, defined by specific substrates some of which cannot be metabolised by the other form (Table 20.3). The therapeutic importance of recognising these two forms arises because they are to some extent present in different tissues, and the enzyme at these different locations can be selectively inhibited by the individual inhibitors moclobemide for MAO-A (used for depression, p. 379) and selegiline for MAO-B (Table 20.3). 

Other mono-oxygenases are not cytochrome P450 dependent, such as flavoproteins located in the endoplasmic reticulum that are involved in the oxidation of tertiary amines to N-oxides and of various sulfur compounds. Yet other oxidative enzymes, including alcohol and aldehyde dehydrogenases and monoamine oxidases, are located in the mitochondria or cytosol. 

Cases O, Lebrand C, Giros B, Vitalis T, De Maeyer E, et al. 1998. Plasma membrane transporters of serotonin, dopamine, and norepinephrine mediate serotonin accumulation in atypical locations in the developing brain of monoamine oxidase A knock-outs. J. Neurosci. 18 6914-27... 

Adrenaline is contraindicated in cases of diabetes, hyperthyroidism, serious heart arrhythmias and coronary insufficiency or in combination with beta-blockers or monoamine oxidase (MAO) inhibitors. Lidocaine with adrenaline has a very rapid onset of action. Its duration of action is longer than that of lidocaine without adrenaline. However, inadvertent injection of a lidocaine-adrenaline solution into the vessels located near the nerve trunks increases the heart rate (immediate sinus tachycardia at over 130 beats per minute, spontaneously reversible in around 15 minutes) and increases ventricular excitability (risk of fibrillation). It can trigger angina attacks that may lead to a heart attack. It is therefore preferable not to use adrenaline before a full-face phenol peel. 

Researchers have discovered that there are two types of monoamine oxidase enzyme MAO-A and MAO-B, each located in different regions of the body. Older MAOIs, such as Nardil, inhibit both versions of monoamine oxidase, resulting in increased serotonin and norepinephrine inside the cell (and also leakage into the synapse, thus activating receptors). Increases in serotonin and noreinephrine receptor activation can lead to several over-stimulating side effects. These central nervous system effects include tremors, insomnia, agitation, and occasionally, precipitation of a mania in patients with bipolar depression. 

Monoamine oxidase A (MAOA) seems to be the principal serotonin degrading enzyme. The gene is located on chromosome Xpll [77]. Recent reports have shown that a low activity genetic variant of monoamine oxidase A (MAOA) is likely to be related to aggressive behavior, but only when paired with abusive experience in childhood. It also has been found that the low activity form of MAOA was associated with more adult symptoms of antisocial alcoholism than the high activity variant [113]. No studies related to autism have been carried out with this polymorphism (for more details see section 5 in Serotonergic innervations). 

Norepinephrine (NE) is taken up into the nerve terminus of the adrenergic neuron by neuronal reuptake mechanisms ( pumps ). It is then degraded intracellularly, by monoamine oxidase (MAO) (primarily MAOa, a mitochondrial enzyme) to form dihydroxymandelic acid. This is further inactivated by the tissue enzyme catechol-O-methyl transferase (COMT). Transmitter remaining in the synaptic cleft is rapidly degraded, first by COMT, located on postsynaptic membranes, to form normetanephrine. This in turn is taken into the neuron and converted to 3-methoxy, 4-hydroxy mandelic acid (VMA) through the actions of MAO (see Figure, top of next page). 

Norepinephrine Noradrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegmental area of the pons. These neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input. Excitatory effects are produced by activation of alpha and beta, receptors. Inhibitory effects are caused by activation of alphaj and beta, receptors. CNS stimulants, monoamine oxidase inhibitors, and tricyclic antidepressants affect the activity of noradrenergic pathways. 

A and B are composed of two subunits, each of which contains an FAD molecule Monoamine oxidase is located in the outer mitochondrial membrane and is distributed peripherally in neuronal and nonneuronal tissues (liver, intestines) as well as in the central nervous system. Few organs have exclusively one form of the enzyme. Thus, in human placenta over 99% of the enzyme is of the A type while platelets lymphocytes... 

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