vesicular monoamine transporter 2

File:Brain-Imaging-of-Vesicular-Monoamine-Transporter-Type-2-in-Healthy-Aging-Subjects-by-18F-FP-(+)-pone.0075952.s001.ogv

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene.{{cite journal | vauthors = Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR | title = A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs | journal = FEBS Letters | volume = 318 | issue = 3 | pages = 325–330 | date = March 1993 | pmid = 8095030 | doi = 10.1016/0014-5793(93)80539-7 | s2cid = 8062412 | doi-access = free | bibcode = 1993FEBSL.318..325S }} VMAT2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.{{cite journal | vauthors = Eiden LE, Schäfer MK, Weihe E, Schütz B | title = The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 636–640 | date = February 2004 | pmid = 12827358 | doi = 10.1007/s00424-003-1100-5 | s2cid = 20764857 }} In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, VMAT2 function is also necessary for the vesicular release of the neurotransmitter GABA.{{cite journal | vauthors = Tritsch NX, Ding JB, Sabatini BL | title = Dopaminergic neurons inhibit striatal output through non-canonical release of GABA | journal = Nature | volume = 490 | issue = 7419 | pages = 262–6 | date = October 2012 | pmid = 23034651 | pmc = 3944587 | doi = 10.1038/nature11466 | bibcode = 2012Natur.490..262T }}

Binding sites and ligands

VMAT2 is believed to possess at least two distinct binding sites, which are characterized by tetrabenazine (TBZ) and reserpine binding to the transporter. Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on VMAT2 to inhibit its function.{{cite journal | vauthors = Sulzer D, Sonders MS, Poulsen NW, Galli A | title = Mechanisms of neurotransmitter release by amphetamines: a review | journal = Progress in Neurobiology | volume = 75 | issue = 6 | pages = 406–433 | date = April 2005 | pmid = 15955613 | doi = 10.1016/j.pneurobio.2005.04.003 | quote = They also demonstrated competition for binding between METH and reserpine, suggesting they might bind to the same site on VMAT. George Uhl's laboratory similarly reported that AMPH displaced the VMAT2 blocker tetrabenazine (Gonzalez et al., 1994). Tetrabenazine and reserpine are thought to bind to different sites on VMAT (Schuldiner et al., 1993a) | s2cid = 2359509 }} VMAT2 inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through VMAT2; the inhibition of SLC18A2 uptake by these drugs prevents the storage of neurotransmitters in synaptic vesicles and reduces the quantity of neurotransmitters that are released through exocytosis. Although many substituted amphetamines induce the release of neurotransmitters from vesicles through VMAT2 while inhibiting uptake through VMAT2, they may facilitate the release of monoamine neurotransmitters into the synaptic cleft by simultaneously reversing the direction of transport through the primary plasma membrane transport proteins for monoamines (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter) in monoamine neurons. Other VMAT2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.{{cite journal | vauthors = Alvers KM, Beckmann JS, Zheng G, Crooks PA, Dwoskin LP, Bardo MT | title = The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats | journal = Psychopharmacology | volume = 224 | issue = 2 | pages = 255–262 | date = November 2012 | pmid = 22638813 | pmc = 3680349 | doi = 10.1007/s00213-012-2748-3 }}

Researchers have found that inhibiting the dopamine transporter (but not VMAT2) will block the effects of amphetamine and cocaine; while, in another experiment, observing that disabling VMAT2 (but not the dopamine transporter) prevents any notable action in test animals after amphetamine administration yet not cocaine administration. This suggests that amphetamine may be an atypical substrate with little to no ability to prevent dopamine reuptake via binding to the dopamine transporter but, instead, uses it to enter a neuron where it then interacts with VMAT2 to induce efflux of dopamine from their vesicles into the cytoplasm whereupon dopamine transporters with amphetamine substrates attached move this recently liberated dopamine into the synaptic cleft.{{cite journal | vauthors = Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, Pizzo AB, Zhang Y, Farino ZJ, Chen A, Martin CA, Kopajtic TA, Fei H, Hu G, Lin YY, Mosharov EV, McCabe BD, Freyberg R, Wimalasena K, Hsin LW, Sames D, Krantz DE, Katz JL, Sulzer D, Javitch JA | title = Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain | journal = Nature Communications | volume = 7 | pages = 10652 | date = February 2016 | pmid = 26879809 | pmc = 4757768 | doi = 10.1038/ncomms10652 | bibcode = 2016NatCo...710652F }}

Although most amphetamines and other monoamine releasing agents (MRA) act on VMAT2, several MRAs, including phentermine, phenmetrazine, and benzylpiperazine (BZP), are inactive at VMAT2.{{cite journal | vauthors = Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL | title = Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter | journal = Drug Alcohol Depend | volume = 147 | issue = | pages = 1–19 | date = February 2015 | pmid = 25548026 | pmc = 4297708 | doi = 10.1016/j.drugalcdep.2014.12.005 | url = }}{{cite journal | vauthors = Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB | title = Interaction of amphetamines and related compounds at the vesicular monoamine transporter | journal = J Pharmacol Exp Ther | volume = 319 | issue = 1 | pages = 237–246 | date = October 2006 | pmid = 16835371 | doi = 10.1124/jpet.106.103622 | url = }} Others, including cathinones like mephedrone, methcathinone, and methylone, also show only weak VMAT2 activity (e.g., ~10-fold weaker than the corresponding amphetamines).{{cite journal | vauthors = Oeri HE | title = Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy | journal = J Psychopharmacol | volume = 35 | issue = 5 | pages = 512–536 | date = May 2021 | pmid = 32909493 | pmc = 8155739 | doi = 10.1177/0269881120920420 | url = }}{{cite journal | vauthors = Pifl C, Reither H, Hornykiewicz O | title = The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter | journal = Eur J Pharmacol | volume = 755 | issue = | pages = 119–126 | date = May 2015 | pmid = 25771452 | doi = 10.1016/j.ejphar.2015.03.004 | url = }}{{cite journal | vauthors = Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE | title = Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines | journal = Eur J Pharmacol | volume = 381 | issue = 1 | pages = 63–69 | date = September 1999 | pmid = 10528135 | doi = 10.1016/s0014-2999(99)00538-5 | url = }} MRAs acting on VMAT2 additionally continue to induce monoamine release in in-vitro systems in which VMAT2 is absent or inhibited.{{cite book | last=Simmler | first=Linda D. | title=Synthetic Cathinones | chapter=Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones | publisher=Springer International Publishing | publication-place=Cham | volume=12 | date=2018 | isbn=978-3-319-78706-0 | doi=10.1007/978-3-319-78707-7_6 | page=97–115 | quote = While the determination of drug effects at the isolated target (i.e., DAT, NET, and SERT) can characterize the direct drug action at the target protein, other physiological components can also contribute significantly to the overall effect of the drug. It has been proposed that transporter-mediated, drug-induced efflux of neurotransmitter occurs through effects on the vesicular monoamine transporter 2 (VMAT2), depleting neurotransmitter from the vesicles into the cytosol (Nickell et al. 2014). Accordingly, full assessment of release would require testing the effects of a drug on the membrane transporters (SERT, DAT, and NET) and the effects of a drug at VMAT2. Alternatively, a more physiological system, such as synaptosomes or brain slices, could be used. However, reverse transport can also occur in cell lines that only express the plasma membrane transporters but not VMAT2 (Eshleman et al. 2013; Scholze et al. 2000) and in synaptosomes when VMAT2 is inhibited (Rothman et al. 2001). }}{{cite journal | vauthors = Halberstadt AL, Brandt SD, Walther D, Baumann MH | title = 2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors | journal = Psychopharmacology (Berl) | volume = 236 | issue = 3 | pages = 989–999 | date = March 2019 | pmid = 30904940 | pmc = 6848746 | doi = 10.1007/s00213-019-05207-1 | url = | quote = In contrast to assay systems involving non-neuronal cells transfected with transporter proteins, synaptosomes possess all of the cellular machinery necessary for neurotransmitter synthesis, release, metabolism, and reuptake. Synaptosomes, however, do not model all of the effects of amphetamine-type agents because the use of reserpine removes any contribution of the vesicular monoamine transporter VMAT2 (SLC18A2) to the release process. In addition to acting as a substrate for plasma membrane monoamine transporters, amphetamine also binds to VMAT, resulting in the redistribution of monoamines from vesicular stores to the cytoplasm (Sulzer et al. 1995; Partilla et al. 2006; Freyberg et al. 2016). Although transporter substrates can induce monoamine release in the absence of VMAT binding (Fon et al. 1997), it is important to recognize that 2-aminoindans may have effects in intact nerve terminals that are not fully replicated in synaptosomes. Follow-up studies will be conducted to evaluate whether 2-aminoindans are capable of interacting with VMAT. }}

=List of VMAT2 Inhibitors=

Lobelane{{cite journal |vauthors=Nickell JR, Krishnamurthy S, Norrholm S, Deaciuc G, Siripurapu KB, Zheng G, Crooks PA, Dwoskin LP |title=Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2 |journal=J Pharmacol Exp Ther |volume=332 |issue=2 |pages=612–21 |date=February 2010 |pmid=19855096 |pmc=2812121 |doi=10.1124/jpet.109.160275 }}{{cite journal |vauthors=Ding D, Nickell JR, Deaciuc AG, Penthala NR, Dwoskin LP, Crooks PA |title=Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake |journal=Bioorg Med Chem |volume=21 |issue=21 |pages=6771–7 |date=November 2013 |pmid=23993667 |pmc=3914663 |doi=10.1016/j.bmc.2013.08.001 }}
Quinlobelane{{cite journal |vauthors=Vartak AP, Gabriela Deaciuc A, Dwoskin LP, Crooks PA |title=Quinlobelane: a water-soluble lobelane analogue and inhibitor of VMAT2 |journal=Bioorg Med Chem Lett |volume=20 |issue=12 |pages=3584–7 |date=June 2010 |pmid=20494575 |doi=10.1016/j.bmcl.2010.04.117 |pmc=3726001 }}
UKCP-110{{cite journal |vauthors=Beckmann JS, Siripurapu KB, Nickell JR, Horton DB, Denehy ED, Vartak A, Crooks PA, Dwoskin LP, Bardo MT |title=The novel pyrrolidine nor-lobelane analog UKCP-110 [cis-2,5-di-(2-phenethyl)-pyrrolidine hydrochloride] inhibits VMAT2 function, methamphetamine-evoked dopamine release, and methamphetamine self-administration in rats |journal=J Pharmacol Exp Ther |volume=335 |issue=3 |pages=841–51 |date=December 2010 |pmid=20805303 |pmc=2993560 |doi=10.1124/jpet.110.172742 }}
CT-005404{{cite journal |vauthors=Rotolo RA, Presby RE, Tracy O, Asar S, Yang JH, Correa M, Murray F, Salamone JD |title=The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology |journal=Neuropharmacology |volume=183 |issue= |pages=108325 |date=February 2021 |pmid=32956676 |doi=10.1016/j.neuropharm.2020.108325 }}
GZ-11608{{cite journal |vauthors=Lee NR, Zheng G, Leggas M, Janganati V, Nickell JR, Crooks PA, Bardo MT, Dwoskin LP |title=GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine |journal=J Pharmacol Exp Ther |volume=371 |issue=2 |pages=526–543 |date=November 2019 |pmid=31413138 |pmc=6863457 |doi=10.1124/jpet.119.258699 }}
4-Benzyl-1-(3,4-dimethoxyphenethyl)piperidine [15565-25-0]{{cite journal |vauthors=Nickell JR, Culver JP, Janganati V, Zheng G, Dwoskin LP, Crooks PA |title=1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2 |journal=Bioorg Med Chem Lett |volume=26 |issue=13 |pages=2997–3000 |date=July 2016 |pmid=27212067 |pmc=4946565 |doi=10.1016/j.bmcl.2016.05.025 }}
[https://pubchem.ncbi.nlm.nih.gov/compound/118857804 PC118857804]{{cite journal |vauthors=Provencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, Tian J, Gonzalez M, Meltzer PC, Janowsky A |title=Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter |journal=J Med Chem |volume=61 |issue=20 |pages=9121–31 |date=October 2018 |pmid=30240563 |doi=10.1021/acs.jmedchem.8b00542 }}
Valbenazine
JPC-141 ([https://pubchem.ncbi.nlm.nih.gov/compound/155541952 PC155541952]){{cite journal |vauthors=Chandler CM, Nickell JR, George Wilson A, Culver JP, Crooks PA, Bardo MT, Dwoskin LP |title=Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats |journal=Biochem Pharmacol |volume=228 |issue= |pages=116189 |date=October 2024 |pmid=38580165 |doi=10.1016/j.bcp.2024.116189 |pmc=11546627 |pmc-embargo-date=October 1, 2025 }}
arylpiperidinylquinazolines (APQs)

Inhibition

VMAT2 is essential for enabling the release of neurotransmitters from the axon terminals of monoamine neurons into the synaptic cleft. If VMAT2 function is inhibited or compromised, monoamine neurotransmitters such as dopamine cannot be released into the synapse via typical release mechanisms (i.e., exocytosis resulting from action potentials).

Cocaine users display a marked reduction in VMAT2 immunoreactivity. Those with cocaine-induced mood disorders displayed a significant loss of VMAT2 immunoreactivity; this might reflect damage to dopamine axon terminals in the striatum. These neuronal changes could play a role in causing disordered mood and motivational processes in more severely addicted users.{{cite journal | vauthors = Little KY, Krolewski DM, Zhang L, Cassin BJ | title = Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users | journal = The American Journal of Psychiatry | volume = 160 | issue = 1 | pages = 47–55 | date = January 2003 | pmid = 12505801 | doi = 10.1176/appi.ajp.160.1.47 }}

Induction

To date, no agent has been shown to directly interact with VMAT2 in a way that promotes its activity. A VMAT2 positive allosteric modulator remains an elusive target in addiction and Parkinson's disease research.{{cite journal | vauthors = Lohr KM, Stout KA, Dunn AR, Wang M, Salahpour A, Guillot TS, Miller GW | title = Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity | journal = ACS Chemical Neuroscience | volume = 6 | issue = 5 | pages = 790–9 | date = May 2015 | pmid = 25746685 | pmc = 4489556 | doi = 10.1021/acschemneuro.5b00010 }}{{cite journal | vauthors = Lohr KM, Bernstein AI, Stout KA, Dunn AR, Lazo CR, Alter SP, Wang M, Li Y, Fan X, Hess EJ, Yi H, Vecchio LM, Goldstein DS, Guillot TS, Salahpour A, Miller GW | title = Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 27 | pages = 9977–82 | date = July 2014 | pmid = 24979780 | pmc = 4103325 | doi = 10.1073/pnas.1402134111 | doi-access = free | bibcode = 2014PNAS..111.9977L }} However, it has been observed that certain tricylcic and tetracylcic antidepressants (as well as a high-mesembrine Sceletium tortuosum extract) can upregulate the activity of VMAT2 in vitro, though whether this is due to a direct interaction is unknown.{{cite journal | vauthors = Coetzee DD, López V, Smith C | title = High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor | journal = Journal of Ethnopharmacology | volume = 177 | pages = 111–6 | date = January 2016 | pmid = 26615766 | doi = 10.1016/j.jep.2015.11.034 }}{{cite journal | vauthors = Wang X, Marmouzi I, Finnie PS, Støve SI, Bucher ML, Lipina TV, Ramsey AJ, Miller GW, Salahpour A | title = Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants | journal = bioRxiv | pages = 2023.10.09.561601 | date = October 2023 | pmid = 37873339 | pmc = 10592782 | doi = 10.1101/2023.10.09.561601 }}

In popular culture

Geneticist Dean Hamer has suggested that a particular allele of the SLC18A2 gene correlates with spirituality using data from a smoking survey, which included questions intended to measure "self-transcendence". Hamer performed the spirituality study on the side, independently of the National Cancer Institute smoking study. His findings were published in the mass-market book The God Gene: How Faith Is Hard-Wired into Our Genes.{{cite book | vauthors = Hamer DH | author-link = Dean Hamer | title = The God gene: how faith is hardwired into our genes | publisher = Doubleday | location = Garden City, N.Y | year = 2004 | isbn = 0-385-50058-0 | url = https://archive.org/details/godgenehowfaithi00hame }}{{cite magazine | url=http://www.time.com/time/printout/0,8816,995465,00.html | archive-url=https://web.archive.org/web/20070930102258/http://www.time.com/time/printout/0,8816,995465,00.html | url-status=dead | archive-date=30 September 2007 | title=Is God in our genes? | access-date = 2007-04-08 | vauthors = Kluger J, Chu J, Liston B, Sieger M, Williams D | date = 2004-10-25 | magazine = TIME | publisher = Time Inc. }} Hamer himself notes that SLC18A2 plays at most a minor role in influencing spirituality. Furthermore, Hamer's claim that the SLC18A2 gene contributes to spirituality is controversial.{{cite journal | vauthors = Silveira LA | title = Experimenting with spirituality: analyzing The God Gene in a nonmajors laboratory course | journal = CBE: Life Sciences Education | volume = 7 | issue = 1 | pages = 132–145 | year = 2008 | pmid = 18316816 | pmc = 2262126 | doi = 10.1187/cbe.07-05-0029 }} Hamer's study has not been published in a peer-reviewed journal and a reanalysis of the correlation demonstrates that it is not statistically significant.{{cite journal | vauthors = Zimmer C | author-link = Carl Zimmer | date = October 2004 | title = Faith-Boosting Genes: A search for the genetic basis of spirituality | journal = Scientific American | doi = 10.1038/scientificamerican1004-110 | url = http://www.sciam.com/article.cfm?articleID=000AD4E7-6290-1150-902F83414B7F4945 | url-access = subscription }}