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Vesicular monoamine transporter 2

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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.[5] SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.[6] In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.[7]

SLC18A2
Identifiers
AliasesSLC18A2, SVAT, SVMT, VAT2, VMAT2, solute carrier family 18 member A2, Vesicular monoamine transporter 2, PKDYS2
External IDsOMIM: 193001; MGI: 106677; HomoloGene: 2298; GeneCards: SLC18A2; OMA:SLC18A2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6571

214084

Ensembl

ENSG00000165646

ENSMUSG00000025094

UniProt

Q08630

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[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Distribution of VMAT2 in the human brain.

Binding sites and ligands

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SLC18A2 is believed to possess at least two distinct binding sites, which are characterized by tetrabenazine (TBZ) and reserpine binding to the transporter.[8] Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on SLC18A2 to inhibit its function.[8] SLC18A2 inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through SLC18A2; 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 SLC18A2 while inhibiting uptake through SLC18A2, 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 SLC18A2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.[9]

Researchers have found that inhibiting the dopamine transporter (but not SLC18A2) will block the effects of amphetamine and cocaine; while, in another experiment, observing that disabling SLC18A2 (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 SLC18A2 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.[10]

List of VMAT2 Inhibitors

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  1. Lobelane[11][12]
  2. Quinlobelane[13]
  3. UKCP-110[14]
  4. CT-005404[15]
  5. GZ-11608[16]
  6. 4-Benzyl-1-(3,4-dimethoxyphenethyl)piperidine [15565-25-0][17]
  7. PC118857804[18]
  8. Valbenazine
  9. JPC-141 (PC155541952)[19]
  10. arylpiperidinylquinazolines (APQs)[18]

Inhibition

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SLC18A2 is essential for enabling the release of neurotransmitters from the axon terminals of monoamine neurons into the synaptic cleft. If SLC18A2 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 SLC18A2 immunoreactivity. Those with cocaine-induced mood disorders displayed a significant loss of SLC18A2 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.[20]

Induction

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To date, no agent has been shown to directly interact with SLC18A2 in a way that promotes its activity. A VMAT2 positive allosteric modulator remains an elusive target in addiction and Parkinson's disease research.[21][22] 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.[23][24]

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Main article: God gene

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.[25][26] Hamer himself notes that SLC18A2 plays at most a minor role in influencing spirituality.[27] Furthermore, Hamer's claim that the SLC18A2 gene contributes to spirituality is controversial.[27] 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.[27][28]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000165646 – Ensembl, May 2017
  2. ^ a b c 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". Pflügers 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): 262–6. Bibcode:2012Natur.490..262T. doi:10.1038/nature11466. PMC 3944587. PMID 23034651.
  8. ^ a b 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): 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. ^ 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". J Pharmacol Exp Ther. 332 (2): 612–21. doi:10.1124/jpet.109.160275. PMC 2812121. PMID 19855096.
  12. ^ 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". Bioorg Med Chem. 21 (21): 6771–7. doi:10.1016/j.bmc.2013.08.001. PMC 3914663. PMID 23993667.
  13. ^ Vartak AP, Gabriela Deaciuc A, Dwoskin LP, Crooks PA (June 2010). "Quinlobelane: a water-soluble lobelane analogue and inhibitor of VMAT2". Bioorg Med Chem Lett. 20 (12): 3584–7. doi:10.1016/j.bmcl.2010.04.117. PMC 3726001. PMID 20494575.
  14. ^ 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". J Pharmacol Exp Ther. 335 (3): 841–51. doi:10.1124/jpet.110.172742. PMC 2993560. PMID 20805303.
  15. ^ 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.
  16. ^ 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". J Pharmacol Exp Ther. 371 (2): 526–543. doi:10.1124/jpet.119.258699. PMC 6863457. PMID 31413138.
  17. ^ 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". Bioorg Med Chem Lett. 26 (13): 2997–3000. doi:10.1016/j.bmcl.2016.05.025. PMC 4946565. PMID 27212067.
  18. ^ a b 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". J Med Chem. 61 (20): 9121–31. doi:10.1021/acs.jmedchem.8b00542. PMID 30240563.
  19. ^ 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". Biochem Pharmacol. 228: 116189. doi:10.1016/j.bcp.2024.116189. PMC 11546627. PMID 38580165.
  20. ^ 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.
  21. ^ 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): 790–9. doi:10.1021/acschemneuro.5b00010. PMC 4489556. PMID 25746685.
  22. ^ 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): 9977–82. Bibcode:2014PNAS..111.9977L. doi:10.1073/pnas.1402134111. PMC 4103325. PMID 24979780.
  23. ^ 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: 111–6. doi:10.1016/j.jep.2015.11.034. PMID 26615766.
  24. ^ Wang X, Marmouzi I, Finnie PS, Støve SI, Bucher ML, Lipina TV, et al. (October 2023). "Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants". bioRxiv: 2023.10.09.561601. doi:10.1101/2023.10.09.561601. PMC 10592782. PMID 37873339.
  25. ^ Hamer DH (2004). The God gene: how faith is hardwired into our genes. Garden City, N.Y: Doubleday. ISBN 0-385-50058-0.
  26. ^ 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.
  27. ^ a b c 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.
  28. ^ Zimmer C (October 2004). "Faith-Boosting Genes: A search for the genetic basis of spirituality". Scientific American. doi:10.1038/scientificamerican1004-110.

Further reading

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