Plasma membrane monoamine transporters

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. 

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. 

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. 

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 generally act by increasing the level of extracellular monoamine. The mechanisms responsible include inhibition of plasma membrane monoamine transport and, in particular, stimulation of flux reversal, which may occur by... 

Although plasma membrane monoamine transporters are responsible for the reuptake of neurotransmitters from the synapse, vesicular monoamine transporters (VMAT) sequester monoamines into synaptic vesicles in preparation for fusion with the plasma membrane and release into the synapse (Schuldiner et ah, 1995). Vesicular uptake is coupled to a proton gradient across the vesicle membrane rather than the sodium gradient used with the plasma membrane transporters (Schuldiner et ah, 1995). These vesicular transporters are not neurotransmitter-speciflc rather, they transport the monoamines nonselectively (Johnson, Jr., 1988 Henry et ah, 1998). 

VMAT is predicted to have similar membrane topology to the plasma membrane monoamine transporters, although they do not share homologous sequences (Erickson et ah, 1992). Hydrophobicity studies predict 12 TMHs with amino and carboxy termini located in the cytoplasm (Erickson et al., 1992). The large extracellular loop between TMHs III and IV of the plasma membrane transporters is located between TMHI and II in VMAT (Erickson et al., 1992). VMATl is located in the neuroendocrine cells of the adrenal medulla and intestinal tract, whereas VMAT2 is found in monoaminergic neurons of the central nervous system (Erickson et al., 1996). 

These transporters represent established targets of many psychostimulants and antidepressants, which exert their potent psychotropic action via interference with transporter function, resulting in a rise in extracellular levels of monoamines (4,8). Some neuron-specific toxins can enter the cells through plasma membrane monoamine transporters, thereby revealing the additional functional role of transporters as a molecular gateway for neurotoxins (6,9). 

In addition to terminating the actions of released monoamines, the plasma membrane monoamine transporters present at neuronal locations function in sequence with vesicular monoamme transporters to recycle catecholamines for rerelease (Figure 29-3). Thus most of the norepinephrine released and recaptured by sympathetic nerves is sequestered back into storage vesicles, thereby substantially reducing the requirements for synthesis of new transmitter. 

Zhou, M., Xia, L. and Wang, J. (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35 (10), 1956—1962. 

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. 

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