Vesicular monoamine transporter 2

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The vesicular monoamine transporter 2 (VMAT2) also known as solute carrier family 18 member 2 (SLC18A2) is a protein that in humans is encoded by the SLC18A2 gene.[1] VMAT2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.[2] In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, VMAT2 function is also necessary for the vesicular release of the neurotransmitter GABA.[3]

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.[4] Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on VMAT2 to inhibit its function.[4] VMAT2 inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through VMAT2; the inhibition of VMAT2 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 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.[5]

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. Sufferers of 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.[6]

In popular culture

Geneticist Dean Hamer has suggested that a particular allele of the VMAT2 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.[7][8] Hamer himself notes that VMAT2 plays at most a minor role in influencing spirituality.[9] Furthermore, Hamer's claim that the VMAT2 gene contributes to spirituality is controversial.[9] 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.[9][10]

References

  1. Surratt CK, Persico AM, Yang XD, Edgar SR, Bird GS, Hawkins AL, Griffin CA, Li X, Jabs EW, Uhl GR (March 1993). "A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs". FEBS Lett. 318 (3): 325–30. doi:10.1016/0014-5793(93)80539-7. PMID 8095030.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  2. 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 Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID 12827358.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  3. Tritsch NX, Ding JB, Sabatini BL (2012). "Dopaminergic neurons inhibit striatal output through non-canonical release of GABA". Nature. 490 (7419): 262–6. doi:10.1038/nature11466. PMC 3944587. PMID 23034651.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  4. 4.0 4.1 Sulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". Prog. Neurobiol. 75 (6): 406–33. doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613. 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)<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  5. Alvers KM, Beckmann JS, Zheng G, Crooks PA, Dwoskin LP, Bardo MT (2012). "The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats". Psychopharmacology. 224 (2): 255–62. doi:10.1007/s00213-012-2748-3. PMC 3680349. PMID 22638813.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  6. Little KY, Krolewski DM, Zhang L, Cassin BJ (January 2003). "Loss of striatal vesicular monoamine transporter protein (VMAT2) in human cocaine users". Am J Psychiatry. 160 (1): 47–55. doi:10.1176/appi.ajp.160.1.47. PMID 12505801.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  7. Hamer DH (2004). The God gene: how faith is hardwired into our genes. Garden City, N.Y: Doubleday. ISBN 0-385-50058-0.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  8. Kluger J, Chu J, Liston B, Sieger M, Williams D (2004-10-25). "Is God in our genes?". TIME. Time Inc. Retrieved 2007-04-08.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  9. 9.0 9.1 9.2 Silveira LA (2008). "Experimenting with spirituality: analyzing The God Gene in a nonmajors laboratory course". CBE Life Sciences Education. 7 (1): 132–45. doi:10.1187/cbe.07-05-0029. PMC 2262126. PMID 18316816.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  10. Zimmer C (October 2004). "Faith-Boosting Genes: A search for the genetic basis of spirituality". Scientific American.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

Further reading

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  • Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP, Goldstein DB (2009). "Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis". Eur. J. Hum. Genet. 17 (7): 946–57. doi:10.1038/ejhg.2008.264. PMC 2986499. PMID 19156168.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija RK, Mulligan RS, Ellis JR, Ackermann U, O'Keefe G, Jones G, Kung HF, Pontecorvo MJ, Skovronsky D, Rowe CC (2010). "In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with (18)F-AV-133". J. Nucl. Med. 51 (2): 223–8. doi:10.2967/jnumed.109.070094. PMID 20080893.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Saisho Y, Harris PE, Butler AE, Galasso R, Gurlo T, Rizza RA, Butler PC (2008). "Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas". J. Mol. Histol. 39 (5): 543–51. doi:10.1007/s10735-008-9195-9. PMC 2566800. PMID 18791800.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Tsolakis AV, Grimelius L, Stridsberg M, Falkmer SE, Waldum HL, Saras J, Janson ET (2009). "Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach". Eur. J. Endocrinol. 160 (6): 941–9. doi:10.1530/EJE-09-0001. PMID 19289536.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Harris PE, Ferrara C, Barba P, Polito T, Freeby M, Maffei A (2008). "VMAT2 gene expression and function as it applies to imaging beta-cell mass". J. Mol. Med. 86 (1): 5–16. doi:10.1007/s00109-007-0242-x. PMID 17665159.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Roe BE, Tilley MR, Gu HH, Beversdorf DQ, Sadee W, Haab TC, Papp AC (2009). "Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene". PLoS ONE. 4 (8): e6704. doi:10.1371/journal.pone.0006704. PMC 2724734. PMID 19693267.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Sørensen KD, Wild PJ, Mortezavi A, Adolf K, Tørring N, Heebøll S, Ulhøi BP, Ottosen P, Sulser T, Hermanns T, Moch H, Borre M, Ørntoft TF, Dyrskjøt L (2009). "Genetic and epigenetic SLC18A2 silencing in prostate cancer is an independent adverse predictor of biochemical recurrence after radical prostatectomy". Clin. Cancer Res. 15 (4): 1400–10. doi:10.1158/1078-0432.CCR-08-2268. PMID 19228741.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Watabe M, Nakaki T (2008). "Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells". Mol. Pharmacol. 74 (4): 933–40. doi:10.1124/mol.108.048546. PMID 18599602.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Catlow K, Ashurst HL, Varro A, Dimaline R (2007). "Identification of a gastrin response element in the vesicular monoamine transporter type 2 promoter and requirement of 20 S proteasome subunits for transcriptional activity". J. Biol. Chem. 282 (23): 17069–77. doi:10.1074/jbc.M611421200. PMID 17442673.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Yosifova A, Mushiroda T, Stoianov D, Vazharova R, Dimova I, Karachanak S, Zaharieva I, Milanova V, Madjirova N, Gerdjikov I, Tolev T, Velkova S, Kirov G, Owen MJ, O'Donovan MC, Toncheva D, Nakamura Y (2009). "Case-control association study of 65 candidate genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population". J Affect Disord. 117 (1–2): 87–97. doi:10.1016/j.jad.2008.12.021. PMID 19328558.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Tabakoff B, Saba L, Printz M, Flodman P, Hodgkinson C, Goldman D, Koob G, Richardson HN, Kechris K, Bell RL, Hübner N, Heinig M, Pravenec M, Mangion J, Legault L, Dongier M, Conigrave KM, Whitfield JB, Saunders J, Grant B, Hoffman PL (2009). "Genetical genomic determinants of alcohol consumption in rats and humans". BMC Biol. 7: 70. doi:10.1186/1741-7007-7-70. PMC 2777866. PMID 19874574.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Zheng G, Dwoskin LP, Crooks PA (2006). "Vesicular monoamine transporter 2: role as a novel target for drug development". AAPS J. 8 (4): E682–92. doi:10.1208/aapsj080478. PMC 2751365. PMID 17233532.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Crowley JJ, Lipsky RH, Lucki I, Berrettini WH (2008). "Variation in the genes encoding vesicular monoamine transporter 2 and beta-1 adrenergic receptor and antidepressant treatment outcome". Psychiatr. Genet. 18 (5): 248–51. doi:10.1097/YPG.0b013e3283052ff7. PMID 18797399.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Guo JT, Chen AQ, Kong Q, Zhu H, Ma CM, Qin C (2008). "Inhibition of vesicular monoamine transporter-2 activity in alpha-synuclein stably transfected SH-SY5Y cells". Cell. Mol. Neurobiol. 28 (1): 35–47. doi:10.1007/s10571-007-9227-0. PMID 17985233.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Talkowski ME, Kirov G, Bamne M, Georgieva L, Torres G, Mansour H, Chowdari KV, Milanova V, Wood J, McClain L, Prasad K, Shirts B, Zhang J, O'Donovan MC, Owen MJ, Devlin B, Nimgaonkar VL (2008). "A network of dopaminergic gene variations implicated as risk factors for schizophrenia". Hum. Mol. Genet. 17 (5): 747–58. doi:10.1093/hmg/ddm347. PMC 3777405. PMID 18045777.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Verney C, Lebrand C, Gaspar P (2002). "Changing distribution of monoaminergic markers in the developing human cerebral cortex with special emphasis on the serotonin transporter". Anat. Rec. 267 (2): 87–93. doi:10.1002/ar.10089. PMID 11997877.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Perlis RH, Moorjani P, Fagerness J, Purcell S, Trivedi MH, Fava M, Rush AJ, Smoller JW (2008). "Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study". Neuropsychopharmacology. 33 (12): 2810–9. doi:10.1038/npp.2008.6. PMID 18288090.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
  • Caudle WM, Richardson JR, Wang MZ, Taylor TN, Guillot TS, McCormack AL, Colebrooke RE, Di Monte DA, Emson PC, Miller GW (2007). "Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration". J. Neurosci. 27 (30): 8138–48. doi:10.1523/JNEUROSCI.0319-07.2007. PMID 17652604.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links