Editing Vesicular monoamine transporter (section)

===Ligand-binding affinities and structures===
Two known binding sites for VMAT inhibitors include the RES binding site and the TBZ binding site. Some evidence suggests these two sites may overlap or exist as two separate conformations of the same binding site.<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007"/> VMAT inhibitors tend to fall into two classes: those that interact with the RES binding site and those that interact with the TBZ binding site.<ref name="Chaudhry FA 2007"/>

RES, methoxytetrabenazine (MTBZ), and the drug [[amiodarone]] bind to the RES binding site. TBZ (also called Nitoman and Xenazine), [[dihydrotetrabenazine]] (DTBZOH), ketanserin (KET), and the drug [[lobeline]] bind to the TBZ binding site. Amphetamine, methamphetamine and GZ-7931 are also known to interact with VMAT2.<ref name="Wimalasena, K. 2011"/><ref name="Miller GW 1999">{{cite journal |vauthors=Miller GW, Gainetdinov RR, Levey AI, Caron MG | year = 1999 | title = Dopamine transporters and neuronal injury | journal = Trends in Pharmacological Sciences | volume = 20 | issue = 10| pages = 424–429 | doi = 10.1016/S0165-6147(99)01379-6 | pmid = 10498956 }}</ref><ref name="Fleckenstein AE 2009">{{cite journal |vauthors=Fleckenstein AE, Volz TJ, Hanson GR | year = 2009 | title = Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: Neurotoxic and therapeutic implications | journal = Neuropharmacology | volume = 56 | issue = Suppl 1| pages = 133–138 | doi=10.1016/j.neuropharm.2008.07.002| pmid = 18662707 | pmc = 2634813}}</ref><ref name="en.wikipedia.org">[[Vesicular monoamine transporter 2#Binding sites and ligands]]</ref>

Inhibitor affinity varies among VMAT isoforms. RES and KET have higher inhibitory affinity for VMAT2–mediated 5HT transport than for that of VMAT1; TBZ seems to inhibit VMAT2 exclusively.<ref name="Wimalasena, K. 2011"/>

The residues asp33 and ser180, 181, and 182 are believed to be involved in substrate recognition, and interact with the [[Protonation|protonated]] amino group and [[Hydroxyl|hydroxyl group]] on the [[catechol]] or [[indole]] rings.<ref name="Chaudhry FA 2007"/>

Cocaine and [[methylphenidate]] (MPD, also known as Ritalin and Concerta) are believed to interact with VMAT2 to cause a shift in VMAT2 "from a plasmalemmal membrane-associated fraction to a vesicle-enriched, nonmembrane-associated fraction."<ref name="Fleckenstein AE 2007">{{cite journal |vauthors=Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR | year = 2007 | title = New insights into the mechanism of action of amphetamines | journal = Annu Rev Pharmacol Toxicol | volume = 47 | pages = 681–98 | doi = 10.1146/annurev.pharmtox.47.120505.105140 | pmid=17209801}}</ref>

====RES binding site====
Consistent with catecholamine-binding affinity, RES has a threefold higher affinity for VMAT2 than for VMAT1.<ref name="Chaudhry FA 2007"/><ref name="Erickson JD 1996"/> The RES binding site is known to be [[hydrophobic]], which is thought to contribute to ligand binding affinity.<ref name="Wimalasena, K. 2011"/> Methamphetamine binds to the RES site on VMATs.<ref name="VMAT2 amph vs meth" />

The current working model proposes that RES and the substrate bind to a single site in a pH-gradient modulated [[Conformation activity relationship|conformational]] structure of the transporter. The conformation occurs after the transport of one H<sup>+</sup> across the membrane and into the vesicle; proton transport drives the substrate recognition site from the lumen to the cytoplasmic surface of the vesicle for RES and substrate binding.<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007"/><ref name = "Darchen">{{cite journal |vauthors=Darchen F, Scherman D, Henry JP | year = 1989 | title = Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter | journal = Biochemistry | volume = 28 | issue = 4| pages = 1692–1697 | doi=10.1021/bi00430a040| pmid = 2719928 }}</ref> Methoxytetrabenazine (MTBZ) may bind to the RES binding site, based on studies indicating that RES significantly inhibited MTBZ-binding.<ref name="Wimalasena, K. 2011"/> Amiodarone is also believed to inhibit monoamine vesicular uptake by binding to the RES binding site.<ref name="Wimalasena, K. 2011"/>

====TBZ binding site====
TBZ and dihydrotetrabenazine (DTBZOH) are believed to bind to a different binding site from the RES/substrate binding site, or to a different conformation of the RES/substrate binding site.<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007"/><ref>{{cite journal |vauthors=Liu Y, Edwards RH | year = 1997 | title = The role of vesicular transport proteins in synaptic transmission and neural degeneration | journal = Annu. Rev. Neurosci. | volume = 20 | pages = 125–156 | doi=10.1146/annurev.neuro.20.1.125| pmid = 9056710 }}</ref> This site is believed to be located at the [[N-terminus]], based on studies done in bovine VMAT2.<ref name="Chaudhry FA 2007"/> Tyr434 and asp461 are identified as being responsible for the high-affinity interaction of TBZ, serotonin, and histamine in VMAT2.<ref name="Chaudhry FA 2007"/> Unlike methamphetamine, amphetamine binds to the TBZ site on hVMAT2.<ref name="VMAT2 amph vs meth">{{cite journal |vauthors=Sulzer D, Sonders MS, Poulsen NW, Galli A |title=Mechanisms of neurotransmitter release by amphetamines: a review |journal=Prog. Neurobiol. |volume=75 |issue=6 |pages=406–433 |date=April 2005 |pmid=15955613 |doi=10.1016/j.pneurobio.2005.04.003 |s2cid=2359509 |quote=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)}}</ref>

Unlike RES inhibition, TBZ inhibition is only affected by very high concentrations of monoamines; however, single injections of RES can inhibit TBZ binding.<ref name="Chaudhry FA 2007"/> [[ketanserin]] (KET)<ref name="Wimalasena, K. 2011"/><ref name = "Darchen"/> and [[lobeline]]<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007"/> also bind to the TBZ binding site conformation.