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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

  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.{{cite journal}}: CS1 maint: date and year (link)
  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.{{cite journal}}: CS1 maint: date and year (link)
  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.
  4. ^ 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){{cite journal}}: CS1 maint: date and year (link)
  5. ^ 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.{{cite journal}}: CS1 maint: date and year (link)
  6. ^ 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.
  7. ^ 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.{{cite journal}}: CS1 maint: date and year (link)

Further reading

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