Monoamine transporters functional

Fleckenstein, A.E., Hanson, G.R. Impact of psychostimulants on vesicular monoamine transporter function. Eur. J. Pharmacol. 479 283, 2003. 

Monoamine transporter function is also regulated by glycosylation. The large extracellular loop between TMH 111 and TMH IV of the monoamine transporters contains consensus sites for glycosylation (Melikian et al., 1994,1996). The glycosylated form of the transporter is the mature form that undergoes insertion into the plasma membrane (Sitte et al., 2004). 

One primary neurochemical mode of action of MDMA involves an indirectly mediated release of monoamines via reversed plasma membrane monoamine transport function and disruption of vesicular storage. Increased 5-HT release appears to be the dominating feature and DA, NA and acetylcholine release are also observed to be involved, although to a lesser degree. Additional mechanisms include inhibition of tryptophan hydroxylase and MAO-A, as well as involvement of S-ffTjA receptors. 

The transporters for 5HT, noradrenaline and dopamine, biogenic monoamines, are genetically related, exist as single isoforms and are expressed on the surface of nerve cells, which use monoamines as (or convert them into) their cognate neurotransmitter. The single-isoform monoamine transporters fulfil all three fundamental functions (reuptake, limiting synaptic transmission, and control of the extracellular neurotransmitter concentration). Inactivation of DAT, NET, or SERT results in an increased extracellular lifetime and level of monoamine neurotransmitter, but decreased intracellular storage and evoked release (Fig. 3). 

MDMA overdose as well as the concomitant consumption of selective serotonin reuptake inhibitors (SSRI) with other dmgs that exert serotoninergic effects (such as inhibitors of monoamine oxidase) can rapidly lead to the serotonin syndrome. Its symptoms, which are reversible upon cessation, of the drug include confusion, muscle rigidity in the lower limbs, and hyperthermia suggesting an acute reaction to serotonin overflow in the CNS. Blocking the function of SERT outside the brain causes side effects (e.g., nausea), which may be due to elevated 5HT however , impairment of transporter function is not equivalent to direct activation of 5HT recqrtors in causing adverse effects such as fibrosis and pulmonary hypertension. 

Torres GE, Amara SG (2007) Glutamate and monoamine transporters new visions of form and function Curr Opin Neurobiol 17 304-312... 

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... 

Gonzalo, E., Torres, R., Gainetdinov, R. and Caron, M. G. Plasma membrane monoamine transporters structure, regulation and function. Nat. Rev. Neurosci. 4 13-24, 2003. 

The resting membrane potential, monoamine transport and reuptake, and other functions of the cellular membrane are partially related to cation transport mechanisms. This has led to a hypothesis proposing that there is a deficiency in one or more of these transport functions that such a deficit is genetically determined and that the resulting membrane dysfunction predisposes to a mood disorder. 

Molecular cloning has identified two closely related but distinct vesicular monoamine transporters, VMAT1 and VMAT2 (Liu et al., 1992 Erickson et al., 1992 Liu and Edwards, 1997). Sequence analysis predicts 12 transmembrane domains with N- and C-termini in the cytoplasm, and the proteins show no sequence similarity to plasma membrane monoamine transporters (Nguyen et al., 1983 Neal and Chater, 1987 Neyfakh et al., 1991). Rather, they show similarity to bacterial proteins involved in detoxification (Figure 2). These bacterial proteins all function as H+ exchangers, and several are even inhibited by the same drugs that inhibit VMATs (e.g., reserpine). 

Psychostimulants have been demonstrated to affect dopaminergic signaling by altering DAT and VMAT function (Fleckenstein et al., 2009). Such alterations can be neurotoxic and may provide a role for the monoamine transporters in Parkinson s disease (Fleckenstein et al., 2009). 

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