Vesicular monoamine transporter 2

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Solute carrier family 18 (vesicular monoamine), member 2
Identifiers
Symbols SLC18A2 ; SVAT; SVMT; VAT2; VMAT2
External IDs OMIM193001 MGI106677 HomoloGene2298 ChEMBL: 1893 GeneCards: SLC18A2 Gene
Orthologs
Species Human Mouse
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:
119 – 119.04 Mb
Chr 19:
59.26 – 59.3 Mb
PubMed search [1] [2]
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]

Binding sites and ligands[edit]

One binding site is that of dihydrotetrabenazine (DTBZ) and reserpine. Lobeline binds at this site. Dextroamphetamine and dextromethamphetamine bind at distinct sites to the VMAT2, inhibiting its function.[3] 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).[4] Other VMAT2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.[5]

Inhibition of VMAT2[edit]

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.[6]

References[edit]

  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. 
  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". Pflugers Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID 12827358. 
  3. ^ 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)" 
  4. ^ 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. 
  5. ^ Alvers, K. M.; Beckmann, J. S.; Zheng, G.; Crooks, P. A.; Dwoskin, L. P.; Bardo, M. T. (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. PMID 22638813.  edit
  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. 

Further reading[edit]

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