Vesicular monoamine transporter 2
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Distribution of VMAT2 in the human brain.
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
One binding site is that of dihydrotetrabenazine (DTBZ) and reserpine. Lobeline binds at this site. Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites to on VMAT2 to inhibit its function.[4] Although the amphetamines inhibit VMAT2 presynaptically leading to diminished neurotransmitter, the primary mechanism for the enhancement of extracellular monoamines, like dopamine, is reversal of the dopamine transporter (DAT).[5] Other VMAT2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.[6]
Inhibition of VMAT2
VMAT2 is essential in the presynaptic neuron's ability to facilitate the release of neurotransmitters into the synaptic cleft. If VMAT2 function is inhibited or compromised, neurotransmitters, such as dopamine, cannot be released via normal transport (exocytosis, action potential) into the synapse. VMAT2 function inhibition can have many various effects on neurotransmitter function. Specifically of importance is its effect on the neurotransmitter dopamine.
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.[7]
References
- ↑ 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.
- ↑ 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 Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID 12827358.
- ↑ 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.
- ↑ 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). It should be noted that tetrabenazine and reserpine are thought to bind to different sites on VMAT (Schuldiner et al., 1993a)
- ↑ Jones SR, Gainetdinov RR, Wightman RM, Caron MG (March 1998). "Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter". J. Neurosci. 18 (6): 1979–86. PMID 9482784.
- ↑ 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 (Berl.) 224 (2): 255–62. doi:10.1007/s00213-012-2748-3. PMID 22638813.
- ↑ 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.
Further reading
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. PMID 18045777.
- 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.
- 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.
- 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.
External links
- Vesicular Monoamine Transporter 2 at the US National Library of Medicine Medical Subject Headings (MeSH)
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