Neuronal monoamine transporters

Non-neuronal monoamine transporters is the collective designation for OCT1, OCT2, and EMT the term indicates that these three carriers share some substrates with the neuronal monoamine transporters (such as DAT, NET, SERT) and the vesicular monoamine... 

Grundemann, D., Liebich, G., Kiefer, N., Koster, S., Schomig, E., Selective substrates for non-neuronal monoamine transporters, Mol. Pharmacol. 1999, 56, 1-10. 

Grundemann D, Schomig E. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum Genet 2000 106(6) 627-635. 

The vesicular monoamine transporters (VMATs) were identified in a screen for genes that confer resistance to the parkinsonian neurotoxin MPP+ [2]. The resistance apparently results from sequestration of the toxin inside vesicles, away from its primary site of action in mitochondria. In addition to recognizing MPP+, the transporter s mediate the uptake of dopamine, ser otonin, epinephrine, and norepinephrine by neurons and endocrine cells. Structurally, the VMATs show no relationship to plasma membrane monoamine transporters. 

Monoamines ean also be found in terminals at both symmetrie and asymmetrie synapses, but this may be partly beeause they eo-exist with the elassieal transmitters glutamate and GABA. The faet that vesieular and neuronal uptake transporters for the monoamines ean be deteeted outside a synapse along with appropriate postsynaptie reeeptors does suggest, however, that some monoamine effeets ean oeeur distant from the synaptie junetion (see Piekel, Nirenberg and Milner 1996, and Chapter 6). 

Figure 8.6 Schematic diagram of the proposed structure of the vesicular monoamine transporter. There are 12 transmembrane segments with both the N- and C-termini projecting towards the neuronal cytosol. (Based on Schuldiner 1998)...

Iproniazid also prevents the reserpine syndrome in rats. Reserpine blocks vesicular uptake of monoamines which, as a consequence, leak from the storage vesicles into the cytosol. Although these monoamines would normally be metabolised by MAO, they are conserved when a MAO inhibitor (MAOI) is present, and so co-administration of reserpine and a MAOI leads to accumulation of monoamines in the neuronal cytosol. It is now known that, when the concentration of cytoplasmic monoamines is increased in this way, they are exported to the synapse on membrane-bound monoamine transporters. The ensuing increase in monoamine transmission, despite the depletion of the vesicular pool, presumably accounts for the effects of iproniazid on the behaviour of reserpine-pretreated rats. 

The main problems with early, irreversible MAOIs were adverse interactions with other drugs (notably sympathomimetics, such as ephedrine, phenylpropanolamine and tricyclic antidepressants) and the infamous "cheese reaction". The cheese reaction is a consequence of accumulation of the dietary and trace amine, tyramine, in noradrenergic neurons when MAO is inhibited. Tyramine, which is found in cheese and certain other foods (particularly fermented food products and dried meats), is normally metabolised by MAO in the gut wall and liver and so little ever reaches the systemic circulation. MAOIs, by inactivating this enzymic shield, enable tyramine to reach the bloodstream and eventually to be taken up by the monoamine transporters on serotonergic and noradrenergic neurons. Fike amphetamine, tyramine reduces the pH gradient across the vesicle membrane which, in turn, causes the vesicular transporter to fail. Transmitter that leaks out of the vesicles into the neuronal cytosol cannot be metabolised because... 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Figure 6.1 Histamine synthesis and metabolism in neurons. L-histidine is transported into neurons by the L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by the specific enzyme histidine decarboxylase. Subsequently, histamine is taken up into vesicles by the vesicular monoamine transporter and stored there until released. In the absence of a high-affinity uptake mechanism in the brain, released histamine is rapidly degraded by histamine methyltransferase, which is located postsynaptically and in glia, to telemethylhistamine, a metabolite that does not show any histamine-like activity.

Histamine is stored within and released from neurons but a neuronal transporter for histamine has not been found. Newly synthesized neuronal histamine is transported into TM neuronal vesicles by the vesicular monoamine transporter VMAT2 [16]. Both in vivo and in vitro studies show that depolarization of nerve terminals activates the exocytotic release of histamine by a voltage- and calcium-dependent mechanism. Once released, histamine activates both postsynaptic and presynaptic receptors. Unlike the nerve terminals from other amine transmitters, however, histaminergic nerve terminals do not exhibit a high-affinity uptake system for histamine [5, 9, 23]. Astrocytes may contain a histamine transport system. 

Additional evidence for a role of 5-HT in the development of neonatal rodent SSC derives from the transient barrel-Hke distribution of 5-HT, 5-HTib, and 5-HT2A receptors, and of the 5-HT transporter (Lebrand et al. 1996 Mansour-Robaey et al. 1998).The transient barrel-Hke 5-HT pattern visualized in layer IV of the SSC of neonatal rodents stems from 5-HT uptake and vesicifiar storage in thalamocortical neurons, transiently expressing at this developmental stage both 5-HT transporter and the vesicular monoamine transporter (VMAT2) despite their later glutamatergic phenotype (Lebrand et al. 1996). 

The norepinephrine transporter (NET) and the vesicular monoamine transporter (VMAT) are presynaptic components of the sympathetic neurons. NET is a Na+ /Cl -dependent transport protein and responsible for the neurotransmitter uptake from the synaptic cleft into the cytoplasm of the neurons. This transport process, called uptake-1, reduces the amount and, thus, the effect of NE released into the synaptic cleft. NE is stored in the cytoplasm of the neurons in specialized vesicles by the H+-dependent transport protein VMAT. Two isoforms VMAT1 and VMAT2, are known. VMAT is localized in the vesicle membranes, and the vesicular storage protects NE from metabolism by monoamine oxidase (MAO), which is localized on the surface membrane of the mitochondria. Vice versa, nerve depolarisation causes NE release from the vesicles into the synaptic cleft by Ca+-mediated exocytose (Fig. 12) [79,132-136],... 

Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). and C show the effects of amphetamine and cocaine on these pathways. See text for details. 

Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left Cocaine inhibits the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration. Right Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further increasing extracellular DA concentrations. 

Cocaine (Fig. 13—3) has two major properties it is both a local anesthetic and an inhibitor of monoamine transporters, especially dopamine (Fig. 13—4). Cocaine s local anesthetic properties are still used in medicine, especially by ear, nose, and throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine also has similar but less important actions at the norepinephrine and the serotonin transporters (Fig. 13—3). Cocaine may do more than merely block the transporter—it may actually release dopamine (or norepinephrine or serotonin) by reversing neurotransmitter out of the presynaptic neuron via the monoamine transporters (Fig. 13—4). 

Amphetamine s primary effects (increased wakefulness, appetite suppression, and increased locomotor activity) are thought to be mediated by the release of norepinephrine from noradrenergic neurons in the CNS (36). However, research points to the role of plasma transport inhibition of dopamine, norepinephrine, and serotonin as well as inhibition of the vesicular monoamine transporter (138). Wisor et al. (139) summarize evidence that dopamine reuptake inhibition produces a greater alerting effect than norepinephrine transport blockade. 

Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (1996) Distinct pharmacologicalal properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sd US A 93 5166-5171. 

Nirenberg MJ, Chan J, Liu Y, Edwards RH, Pickel VM (1996) Ultrastructural localization of the vesicular monoamine transporter-2 in midbrain dopaminergic neurons potential sites for somatodendritic storage and release of dopamine. J Neurosci 16 4135 1145. 

Wang YM, Gainetdinov RR, FumagaUi F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19 1285-1296. 

Weihe E, Schafer MK, Erickson JD, Eiden LE (1994) Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat. J Mol Neurosci 5 149-164. 

Methamphetamine (MAP) is a psychostimulant that induces enhanced arousal and euphoria acutely, and psychosis and addiction chronically. MAP enters the terminals/neuron via the monoamine transporters (dopamine transporter DAT, serotonin transporter SERT, or norepinephrine transporter NET), displaces... 

Local modulation through the dendritic release of DA occurs in both the SN and the VTA. Ultrastructural observations have been made with immunolocalization of the vesicular monoamine transporter-2 as marker for sites of intracellular monoamine storage within SN and VTA dopaminergic neurons identified by TH immunoreactivity (Nirenberg et al., 1996a). This study has reported that DA is stored in and may be released from dendritic small synaptic vesicles or large dense-core vesicles, while the smooth endoplasmic reticulum represents the main site for the DA storage. 

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