Vesicular monoamine transporter 2
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 acts to transport monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.[2]
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[edit] Binding sites and ligands
One binding site is that of dihydrotetrabenazine (DTBZ). Lobeline binds at this site. Dextroamphetamine and dextromethamphetamine bind at distinct sites to the VMAT2, inhibiting its function. 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).[3]
[edit] 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. Dopamine, specifically, is highly neurotoxic to most cellular structures, due to its ability to auto-oxidize in the presence of oxygen radicals. Dopamine, and other neurotransmitters, are metabolized via various processes into various substances, by enzymes such as monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and dopamine beta hydroxylase (DBH). Vesicles normally protect dopamine from auto-oxidation and metabolism by monoamine oxidase and COMT. Impaired VMAT2 function/activity may contribute to symptoms of depression, anxiety, restless leg syndrome, akathisia, Parkinson's disease, social anxiety, and many other conditions, via inhibition of normal dopamine release into the synapse. Long-term use of amphetamine and methamphetamine causes long-lasting reductions in VMAT2 expression/activity, similar to chronic use of cocaine. This reduction of VMAT2 activity contributes significantly to the neurotoxic effects of amphetamine and methamphetamine. 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.[4]
[edit] VMAT2 function in mice
Mice bred without VMAT2 display marked depression and hypoactivity symptoms, and die within a few days of birth. Their brains exhibit a significant decrease of monoamine and catecholamine content, compared to wild-type mice. Depolarization does not normalize behavior in VMAT2-KO mice, compared to wild-type mice. Amphetamine, however, decreases the functional deficits caused by VMAT-deletion, indicating that monoamines/catecholamines, such as dopamine, are still present in the presynaptic cytoplasm, but not packaged into vesicles necessary for normal depolarization/exocytosis-induced release. In wild-type mice and humans, amphetamine inhibits VMAT2 function and reverses the dopamine transporter (DAT), causing the release of unprotected free cytoplasmic dopamine into the synaptic cleft. VMAT-2 deletion mimics the VMAT-2 inhibition caused by amphetamine, allowing amphetamine to simply reverse the DAT, releasing dopamine, and subsequently reducing functional deficits in VMAT2-KO mice. VMAT2-KO mice also display significantly increased neurotoxicity in response to amphetamine, due to the unprotected metabolism and auto-oxidation of dopamine in the presynaptic cytoplasm of dopamine neurons.[5][6]
[edit] In popular culture
Geneticist Dean Hamer has suggested that 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] However Hamer's claim that the VMAT2 gene contributes to spirituality is controversial.[9] Hamer's study has not been published in the peer reviewed literature and the correlation is not statistically significant.[10]
[edit] 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.
- ^ 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.
- ^ 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.
- ^ Takahashi N, Miner LL, Sora I, Ujike H, Revay RS, Kostic V, Jackson-Lewis V, Przedborski S, Uhl GR (September 1997). "VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity". Proc. Natl. Acad. Sci. U.S.A. 94 (18): 9938–43. doi:10.1073/pnas.94.18.9938. PMC 23302. PMID 9275230. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=23302.
- ^ Luo X, Persico AM, Lauder JM (2003). "Serotonergic regulation of somatosensory cortical development: lessons from genetic mouse models". Dev. Neurosci. 25 (2-4): 173–83. doi:10.1159/000072266. PMID 12966215.
- ^ Hamer, Dean H. (2004). The God gene: how faith is hardwired into our genes. Garden City, N.Y: Doubleday. ISBN 0-385-50058-0.
- ^ Kluger, Jeffrey; Jeff Chu, Broward Liston, Maggie Sieger, Daniel Williams (2004-10-25). "Is God in our genes?". TIME. Time Inc.. http://www.time.com/time/printout/0,8816,995465,00.html. Retrieved 2007-04-08.
- ^ Silveira LA (2008). "Experimenting with spirituality: analyzing The God Gene in a nonmajors laboratory course". CBE Life Sci Educ 7 (1): 132–45. doi:10.1187/cbe.07-05-0029. PMC 2262126. PMID 18316816. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2262126.
- ^ Zimmer, Carl (October 2004). "Faith-Boosting Genes: A search for the genetic basis of spirituality". Scientific American. http://www.sciam.com/article.cfm?articleID=000AD4E7-6290-1150-902F83414B7F4945.
[edit] Further reading
- Need AC, Keefe RS, Ge D, et al. (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. PMID 19156168.
- Okamura N, Villemagne VL, Drago J, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2566800.
- Tsolakis AV, Grimelius L, Stridsberg M, et al. (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, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2724734.
- Sørensen KD, Wild PJ, Mortezavi A, et al. (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, et al. (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, et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2777866.
- 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2751365.
- 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, et al. (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, et al. (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, et al. (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, et al. (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.
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