VMAT

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. 

Transport by the VMATs involves the exchange of two lumenal protons for one cytoplasmic, apparently protonated molecule of transmitter, predicting accumulation of transmitter inside vesicles 104-105 the... 

VMATs are irreversibly inhibited by the potent antihypertensive drug reserpine. The depressive effects of reserpine helped to formulate the original monoamine hypothesis of affective disorders. Reseipine also appears to interact with the transporters near the site of substrate recognition. Tetrabenazine, which is used in treatment of movement disorders, inhibits VMAT2 much more potently than VMAT1, consistent with the less hypotensive action of this agent. 

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

VMAT is short for Vesicular Monoamine Transporter. Vesicular Transporters... 

Much of the early work on these transporters was carried out on the chromaffin granules of the bovine adrenal medulla. These studies revealed the transporter to be a polypeptide of 80kDa. However, two VMATs have now been characterised and these are the products of different genes. Evidence suggests that both have 12... 

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... 

Once returned to the presynaptic terminal, dopamine is repackaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) or metabolized to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO). Two alternative pathways are available for dopamine catabolism in the synapse, depending on whether the first step is catalyzed by MAO or catechol-O-methyltransferase (COMT). Thus, dopamine can be either deaminated to 3,4-dihydroxyphenylacetic acid (DOPAC) or methylated to 3-methoxytyramine (3-MT). In turn, deamination of 3-MT and methylation of DOPAC leads to homovanillic acid (HVA). In humans, cerebrospinal fluid levels of HVA have been used as a proxy for levels of dopaminergic activity within the brain (Stanley et al. 1985). 

The neuronal membrane norepinephrine transporter (NET), the dopamine transporter (DAT) and the vesicular membrane transporter (VMAT-2), which is the same in all catecholamine-containing neurons, have similar numbers of predicted transmembrane segments. They have different numbers of amino acids, pharmacological properties and chromosomal localizations. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

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],... 

VMAT Transport of dopamine and norepinephrine into adrenergic vesicles in nerve endings Target of reserpine... 

MDR1, multidrug resistance protein-1 MRP1, multidrug resistance-associated protein 1 NET, norepinephrine transporter SERT, serotonin reuptake transporter VMAT, vesicular monoamine transporter. 

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