Vesicular monoamine transporter 2

SLC18A2
Identifiers
AliasesSLC18A2, SVAT, SVMT, VAT2, VMAT2, solute carrier family 18 member A2, Vesicular monoamine transporter 2, PKDYS2
External IDsOMIM: 193001; MGI: 106677; GeneCards: SLC18A2
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

6571

214084

Ensembl

ENSG00000165646

ENSMUSG00000025094

UniProt

Q05940

Q8BRU6

RefSeq (mRNA)

NM_003054

NM_172523

RefSeq (protein)

NP_003045

NP_766111

Location (UCSC)Chr 10: 117.24 – 117.28 MbChr 19: 59.25 – 59.28 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse
Distribution of VMAT2 in the human brain.

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. VMAT2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, VMAT2 function is also necessary for the vesicular release of the neurotransmitter GABA.

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. 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.

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.

Although most amphetamines and other monoamine releasing agents (MRA) act on VMAT2, several MRAs, including phentermine, phenmetrazine, and benzylpiperazine (BZP), are inactive at VMAT2. Others, including cathinones like mephedrone, methcathinone, and methylone, also show only weak VMAT2 activity (e.g., ~10-fold weaker than the corresponding amphetamines). MRAs acting on VMAT2 additionally continue to induce monoamine release in in-vitro systems in which VMAT2 is absent or inhibited.

List of VMAT2 inhibitors

  1. Lobelane
  2. Quinlobelane
  3. UKCP-110
  4. CT-005404
  5. GZ-11608
  6. 4-Benzyl-1-(3,4-dimethoxyphenethyl)piperidine [15565-25-0]
  7. PC118857804
  8. Valbenazine
  9. Tetrabenazine
  10. Deutetrabenazine
  11. JPC-141 (PC155541952)
  12. arylpiperidinylquinazolines (APQs)
  13. Carvedilol

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).

In one study, cocaine users with cocaine-induced mood disorders displayed a significant loss of VMAT2; 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.

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. However, it has been observed that certain tricyclic and tetracyclic 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.

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. 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. 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000165646 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025094 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, et al. (March 1993). "A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs". FEBS Letters. 318 (3): 325–330. Bibcode:1993FEBSL.318..325S. doi:10.1016/0014-5793(93)80539-7. PMID 8095030. S2CID 8062412.
  6. ↑ Eiden LE, Schäfer MK, Weihe E, Schütz B (February 2004). "The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine". Pflugers Archiv. 447 (5): 636–640. doi:10.1007/s00424-003-1100-5. PMID 12827358. S2CID 20764857.
  7. ↑ Tritsch NX, Ding JB, Sabatini BL (October 2012). "Dopaminergic neurons inhibit striatal output through non-canonical release of GABA". Nature. 490 (7419): 262–266. Bibcode:2012Natur.490..262T. doi:10.1038/nature11466. PMC 3944587. PMID 23034651.
  8. 1 2 Sulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Progress in Neurobiology. 75 (6): 406–433. doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613. S2CID 2359509. 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)
  9. ↑ Alvers KM, Beckmann JS, Zheng G, Crooks PA, Dwoskin LP, Bardo MT (November 2012). "The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats". Psychopharmacology. 224 (2). Berl: 255–262. doi:10.1007/s00213-012-2748-3. PMC 3680349. PMID 22638813.
  10. ↑ Freyberg Z, Sonders MS, Aguilar JI, Hiranita T, Karam CS, Flores J, et al. (February 2016). "Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain". Nature Communications. 7 10652. Bibcode:2016NatCo...710652F. doi:10.1038/ncomms10652. PMC 4757768. PMID 26879809.
  11. ↑ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708. PMID 25548026.
  12. ↑ Partilla JS, Dempsey AG, Nagpal AS, Blough BE, Baumann MH, Rothman RB (October 2006). "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". The Journal of Pharmacology and Experimental Therapeutics. 319 (1): 237–246. doi:10.1124/jpet.106.103622. PMID 16835371.
  13. ↑ Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". Journal of Psychopharmacology. 35 (5). Oxford, England: 512–536. doi:10.1177/0269881120920420. PMC 8155739. PMID 32909493.
  14. ↑ Pifl C, Reither H, Hornykiewicz O (May 2015). "The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter". European Journal of Pharmacology. 755: 119–126. doi:10.1016/j.ejphar.2015.03.004. PMID 25771452.
  15. ↑ Cozzi NV, Sievert MK, Shulgin AT, Jacob P, Ruoho AE (September 1999). "Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines". European Journal of Pharmacology. 381 (1): 63–69. doi:10.1016/s0014-2999(99)00538-5. PMID 10528135.
  16. ↑ Simmler LD (2018). "Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones". Synthetic Cathinones. Current Topics in Neurotoxicity. Vol. 12. Cham: Springer International Publishing. pp. 97–115. doi:10.1007/978-3-319-78707-7_6. ISBN 978-3-319-78706-0. 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).
  17. ↑ Halberstadt AL, Brandt SD, Walther D, Baumann MH (March 2019). "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology. 236 (3). Berl: 989–999. doi:10.1007/s00213-019-05207-1. PMC 6848746. PMID 30904940. 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.
  18. ↑ Nickell JR, Krishnamurthy S, Norrholm S, Deaciuc G, Siripurapu KB, Zheng G, et al. (February 2010). "Lobelane inhibits methamphetamine-evoked dopamine release via inhibition of the vesicular monoamine transporter-2". The Journal of Pharmacology and Experimental Therapeutics. 332 (2): 612–621. doi:10.1124/jpet.109.160275. PMC 2812121. PMID 19855096.
  19. ↑ Ding D, Nickell JR, Deaciuc AG, Penthala NR, Dwoskin LP, Crooks PA (November 2013). "Synthesis and evaluation of novel azetidine analogs as potent inhibitors of vesicular [3H]dopamine uptake". Bioorganic & Medicinal Chemistry. 21 (21): 6771–6777. doi:10.1016/j.bmc.2013.08.001. PMC 3914663. PMID 23993667.
  20. ↑ Vartak AP, Gabriela Deaciuc A, Dwoskin LP, Crooks PA (June 2010). "Quinlobelane: a water-soluble lobelane analogue and inhibitor of VMAT2". Bioorganic & Medicinal Chemistry Letters. 20 (12): 3584–3587. doi:10.1016/j.bmcl.2010.04.117. PMC 3726001. PMID 20494575.
  21. ↑ Beckmann JS, Siripurapu KB, Nickell JR, Horton DB, Denehy ED, Vartak A, et al. (December 2010). "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". The Journal of Pharmacology and Experimental Therapeutics. 335 (3): 841–851. doi:10.1124/jpet.110.172742. PMC 2993560. PMID 20805303.
  22. ↑ Rotolo RA, Presby RE, Tracy O, Asar S, Yang JH, Correa M, et al. (February 2021). "The novel atypical dopamine transport inhibitor CT-005404 has pro-motivational effects in neurochemical and inflammatory models of effort-based dysfunctions related to psychopathology". Neuropharmacology. 183 108325. doi:10.1016/j.neuropharm.2020.108325. PMID 32956676.
  23. ↑ Lee NR, Zheng G, Leggas M, Janganati V, Nickell JR, Crooks PA, et al. (November 2019). "GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine". The Journal of Pharmacology and Experimental Therapeutics. 371 (2): 526–543. doi:10.1124/jpet.119.258699. PMC 6863457. PMID 31413138.
  24. ↑ Nickell JR, Culver JP, Janganati V, Zheng G, Dwoskin LP, Crooks PA (July 2016). "1,4-Diphenalkylpiperidines: A new scaffold for the design of potent inhibitors of the vesicular monoamine transporter-2". Bioorganic & Medicinal Chemistry Letters. 26 (13): 2997–3000. doi:10.1016/j.bmcl.2016.05.025. PMC 4946565. PMID 27212067.
  25. 1 2 Provencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, et al. (October 2018). "Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter". Journal of Medicinal Chemistry. 61 (20): 9121–9131. doi:10.1021/acs.jmedchem.8b00542. PMID 30240563.
  26. ↑ Chandler CM, Nickell JR, George Wilson A, Culver JP, Crooks PA, Bardo MT, et al. (October 2024). "Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats". Biochemical Pharmacology. 228 116189. doi:10.1016/j.bcp.2024.116189. PMC 11546627. PMID 38580165.
  27. ↑ Racz R, Kozell LB, Eshleman AJ, Bloom SH, Wolfrum KM, Schmachtenberg JL, et al. (January 2026). "Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs". ACS Pharmacology & Translational Science. 9 (1): 80–88. doi:10.1021/acsptsci.5c00538. PMC 12797167. PMID 41536287.
  28. ↑ Little KY, Krolewski DM, Zhang L, Cassin BJ (January 2003). "Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users". The American Journal of Psychiatry. 160 (1): 47–55. doi:10.1176/appi.ajp.160.1.47. PMID 12505801.
  29. ↑ Lohr KM, Stout KA, Dunn AR, Wang M, Salahpour A, Guillot TS, et al. (May 2015). "Increased Vesicular Monoamine Transporter 2 (VMAT2; Slc18a2) Protects against Methamphetamine Toxicity". ACS Chemical Neuroscience. 6 (5): 790–799. doi:10.1021/acschemneuro.5b00010. PMC 4489556. PMID 25746685.
  30. ↑ Lohr KM, Bernstein AI, Stout KA, Dunn AR, Lazo CR, Alter SP, et al. (July 2014). "Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo". Proceedings of the National Academy of Sciences of the United States of America. 111 (27): 9977–9982. Bibcode:2014PNAS..111.9977L. doi:10.1073/pnas.1402134111. PMC 4103325. PMID 24979780.
  31. ↑ Coetzee DD, López V, Smith C (January 2016). "High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor". Journal of Ethnopharmacology. 177: 111–116. doi:10.1016/j.jep.2015.11.034. PMID 26615766.
  32. ↑ Wang X, Marmouzi I, Finnie PS, Støve SI, Bucher ML, Lipina TV, et al. (2024). "Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants". Neuropsychopharmacology. 49 (11): 1783–1791. bioRxiv 10.1101/2023.10.09.561601. doi:10.1038/s41386-024-01914-2. PMC 10592782. PMID 39060436.
  33. ↑ Hamer DH (2004). The God gene: how faith is hardwired into our genes. Garden City, N.Y: Doubleday. ISBN 0-385-50058-0.
  34. ↑ Kluger J, Chu J, Liston B, Sieger M, Williams D (25 October 2004). "Is God in our genes?". TIME. Time Inc. Archived from the original on 30 September 2007. Retrieved 8 April 2007.
  35. 1 2 3 Silveira LA (2008). "Experimenting with spirituality: analyzing The God Gene in a nonmajors laboratory course". CBE Life Sciences Education. 7 (1): 132–145. doi:10.1187/cbe.07-05-0029. PMC 2262126. PMID 18316816.
  36. ↑ Zimmer C (October 2004). "Faith-Boosting Genes: A search for the genetic basis of spirituality". Scientific American. doi:10.1038/scientificamerican1004-110.

Further reading