This commentary is about the intra-neuronal storage of monoamines in vesicles.
The vesicular monoamine transporter (VMAT2) is responsible for actively taking up all monoamines (i.e. dopamine (DA), serotonin (5-HT), norepinephrine (NE), epinephrine (EPI) and histamine (HIS)) from within the neurone into the storage granules (vesicles) ready for release into the synapse, which is a nerve-impulse-dependent phenomenon.
It is important to know about recent developments of knowledge concerning this transporter because some of the drugs used in psychiatry effect VMAT2 and there is evidence that such drugs can produce neuro-toxic effects. Such effects are relevant in the damage caused by the street drug ecstasy, and also, probably, by the therapeutic drug amphetamine, and perhaps others. Methylphenidate has recently been shown to cause loss of dopaminergic neurones and to potentiate the toxicity of MPTP (1). So, there are some interesting and potentially serious and consequential issues revolving around the mechanism of action of such drugs and the consequences of their therapeutic use.
There can be few things more worrying than the possibility, even if remote, that a drug given therapeutically to children, over long periods of time, could possibly lead to Parkinson's, depression or dementia in later life.
Also, there are few things that are more intellectually satisfying than weaving together an understanding of some new aspect of neuro-pharmacology with an explanation of how things have come about on a grand evolutionary scale. That is the prospect we have as we start to look at the origin and function of VMAT2.
If you have an apple or banana close at hand then cut it and watch. There, believe it or not, you have an model that is the ancient (by some 300 million years) ancestor of dopamine-mediated neuro-toxicity. L-dopa is contained in many plants (2, 3) because it is a reactive species when converted to dopamine, which then serves as a plant defence mechanism, triggered when the plant is damaged. It protects the plants against fungal and bacterial infection. So when you expose those (damaged) plant tissues to air, any reactive dopamine that is released spontaneously oxidises and polymerises to the brown pigment melanin.
Neuronal dopamine is stored in the intra-neuronal pre-synaptic vesicles at a pH substantially lower than normal cellular pH (around 5.5, as opposed to 7.2) because that increases its stability and keeps it apart from molecules with which it would otherwise react (4). Once it is released into synapses, or the neuronal cytoplasm, it is much more reactive at the higher pH and has the potential to create oxidative damage to cell contents. We now need to be aware that some of the drugs we are using to alter DA function may be potentiating the neuronal damage done by DA and its metabolites and thus may be causing medium to long-term damage to these pathways (5).
As most people will appreciate the gene sequence, and a good approximation of the three-dimensional molecular structure, of the monoamine uptake transporters, have been known for some time as a result of the advances in all the relevant molecular biology techniques. So it will come as no surprise to learn that the vesicular monoamine transporters, designated VMAT1 and VMAT2, have also been located and sequenced (6-10). What is fascinating and extraordinary is that they bear a definite relationship to the bacterial structures that extrude toxins from bacterial cells, a similar process of exo-cytosis: indeed it takes only three mutations of the VMAT2 to restore the toxin-extruding properties that the equivalent bacterial transporter possesses (11).
Thus far, psychiatric journals and texts say little or nothing, mostly nothing, about VMAT and many people may not be familiar with mechanism of action of those drugs that are now known to affect VMAT2, especially since they are little used in psychiatry (e.g. pramipexole, ketanserin, reserpine & tetrabenazine). However, this is a key to understanding differences between amphetamines and most other drugs. They both (reserpine & tetrabenazine ) competitively inhibit VMAT2 and therefore deplete vesicular amine content.
One key difference between the neuronal & vesicular transporter mechanisms is that other monoamines (5-HT, NE, DA) are all packaged into the storage granules against a concentration gradient by the same transporter mechanism, i.e. VMAT2, whereas they each have a separate transporter on the neuronal outer membrane (viz. SERT, NET, DAT).
The history and current knowledge on this topic has recently been reviewed by Eiden (4), whose lab first cloned human VMAT1 and VMAT2. If you are interested in how these mechanisms evolved, this review explains how VMAT evolved from bacterial transporters that dealt with toxins, a fascinating story that gives insights into why neuro-transmitters themselves are toxic, and, as Guillot states (12):
“It is increasingly evident that VMAT2 provides neuro-protection from both endogenous and exogenous toxicants and that while VMAT2 has been adapted by eukaryotes for synaptic transmission, it is derived from phylo-genetically ancient proteins that originally evolved for the purpose of cellular protection.”
Sulzer’s recent review of Amphetamine (and other drugs of addiction) is an intoxicating Pierian spring of knowledge, all 14 pages, a whole weekends read for us older folk (13) and is available full text free
It has excellent diagrams illustrating various other key processes that I will outline in a future post, because they link in to much of the above data.
1. Sadasivan, S, Pond, BB, Pani, AK, Qu, C, et al., Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One, 2012. 7(3): p. e33693.
2. Modi, KP, Patel, NM, and Goyal, RK, Estimation of L-dopa from Mucuna pruriens LINN and formulations containing M. pruriens by HPTLC method. Chem. Pharm. Bull. (Tokyo). 2008. 56(3): p. 357-9.
3. Romphophak, T, Ririphanich, J, Ueda, Y, Abe, K, et al., Changes in concentrations of phenolic compounds and polyphenol oxidase activity in banana peel during storage. Food Preserv Sci, 2005. 31: p. 111-115.
4. Eiden, LE and Weihe, E, VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann. N. Y. Acad. Sci., 2011. 1216: p. 86-98.
5. Qi, Z, Miller, GW, and Voit, EO, Computational modeling of synaptic neurotransmission as a tool for assessing dopamine hypotheses of schizophrenia. Pharmacopsychiatry, 2010. 43 Suppl 1: p. S50-60.
6. Erickson, JD, Varoqui, H, Schafer, MK, Modi, W, et al., Functional identification of a vesicular acetylcholine transporter and its expression from a "cholinergic" gene locus. J Biol Chem, 1994. 269(35): p. 21929-32.
7. Schafer, MK, Weihe, E, Varoqui, H, Eiden, LE, et al., Distribution of the vesicular acetylcholine transporter (VAChT) in the central and peripheral nervous systems of the rat. J. Mol. Neurosci., 1994. 5(1): p. 1-26.
8. Eiden, LE, The vesicular neurotransmitter transporters: current perspectives and future prospects. FASEB J., 2000. 14(15): p. 2396-400.
9. Takahashi, N and Uhl, G, Murine vesicular monoamine transporter 2: molecular cloning and genomic structure. Brain Res. Mol. Brain Res., 1997. 49(1-2): p. 7-14
10. Hoffman, BJ, Hansson, SR, Mezey, E, and Palkovits, M, Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front. Neuroendocrinol., 1998. 19(3): p. 187-231.
11. Gros, Y and Schuldiner, S, Directed evolution reveals hidden properties of VMAT, a neurotransmitter transporter. J Biol Chem, 2010. 285(7): p. 5076-84.
12. Guillot, TS and Miller, GW, Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons. Mol. Neurobiol., 2009. 39(2): p. 149-70.
13. Sulzer, D, How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron, 2011. 69(4): p. 628-49.