Editing Vesicular monoamine transporter (section)

==Structure and function==
[[File:VMAT transport 01.jpg|thumb|right|A Hydrogen atom from the inside of the vesicle binds, inducing a conformational change in the transporter]]
[[File:VMAT transport two.jpg|thumb|right|The conformational change induced by the hydrogen atom binding enables the monoamine binding to the active transport site]]
[[File:VMAT transport three.jpg|thumb|right|A second hydrogen atom binds from inside the vesicle to the transporter inducing another change]]
[[File:VMAT transport four.jpg|thumb|right|The monoamine is released inside the vesicle and the two hydrogen atoms are released into the cytosol and the transport process starts over again.]]

VMAT1 and VMAT2 are acidic [[glycoprotein]]s with a molecular weight of approximately 70 [[kDa]].<ref name="Wimalasena, K. 2011"/><ref>{{cite journal |vauthors=Liu Y, Peter D, Rogahani A, Schuldiner S, Prive GG, Eisenberg D, Brecha N, Edwards RH | year = 1992 | title = A cDNA that suppresses MPP1 toxicity encodes a vesicular amine transporter | journal = Cell | volume = 70 | issue = 4| pages = 539–551 | doi=10.1016/0092-8674(92)90425-c| pmid = 1505023 | s2cid = 6225156 }}</ref> Both isoforms are [[transmembrane protein]]s with 12 [[transmembrane domain]]s (TMDs).<ref name="Wimalasena, K. 2011"/>

VMATs function by loading monoamines—dopamine, serotonin, histamine, norepinephrine, and epinephrine—into transport vesicles.<ref>Purves, Dale, et al. Neuroscience. Sinauer Associates. 087893646</ref> VMATs use the same transport mechanism for all types of monoamines,<ref name="Henry, J. P. 1994"/> and transport them from the [[cytosol]] into high-concentration storage vesicles.<ref name="Wimalasena, K. 2011"/> Transport vesicles are released into the space between neurons, called the [[synaptic cleft]], where they convey a chemical message to the next neuron. VMATs also function in sorting, storing, and releasing neurotransmitters, and are believed to participate in protecting these neurotransmitters from [[autoxidation]].<ref name="Wimalasena, K. 2011"/> The transporters are also known to continue biochemical modification after loading certain neurotransmitters.<ref name="Wimalasena, K. 2011"/>

Vesicle packing requires a large energy source to store large quantities of neurotransmitters into a small vesicular space at high concentrations. VMAT transport relies on the pH and electrochemical gradient generated by a [[V-ATPase|vesicular H<sup>+</sup>-ATPase]].<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007">{{cite journal |vauthors=Chaudhry FA, Edwards RH, Fonnum F | year = 2007 | title = Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances | url = https://zenodo.org/record/897959| journal = Annu. Rev. Pharmacol. Toxicol. | volume = 48 | pages = 277–301 | doi = 10.1146/annurev.pharmtox.46.120604.141146 | pmid = 17883368 }}</ref> The current model of VMAT function proposes that the efflux of two protons (H<sup>+</sup>) against the H<sup>+</sup> gradient is coupled with influx of one monoamine.<ref name="Wimalasena, K. 2011"/><ref name="Chaudhry FA 2007"/> The first H<sup>+</sup> efflux generates a transporter [[conformational isomerism|conformation]] associated with a high-affinity amine-binding site in the cytosolic phase, and the second H<sup>+</sup> efflux is coupled with a second large [[conformational change]] that leads to amine transport from the cytosolic side into the vesicle, reducing amine-binding affinity.<ref name="Wimalasena, K. 2011"/>

Studies indicate that the amino acid [[Residue (chemistry)#Characteristic units within a molecule|residue]] His419, located on the domain between TMDs X and XI of rat VMAT1, plays a role in energy coupling to the amine transport by assisting the first proton-dependent conformational change.<ref name="Wimalasena, K. 2011"/><ref>Shirvan A, Laskar O, Steiner-Mordoch S, Schuldiner S. (1994). "Histidine-419 plays a role in energy coupling in the vesicular monoamine transporter from rat." ''FEBS Lett',' 356:145–150.</ref> It has been proposed that RES inhibits VMAT by interacting with this conformation.{{Citation needed|date=November 2021}}

VMAT gene sequence analysis demonstrates that four [[Aspartic acid|aspartic acid residues]] in the middle region of TMDs I, VI, X, and XI and one [[lysine]] residue in TMD II have highly conserved gene sequences, suggesting these residues play a critical role in transporter structure and function.<ref name="Wimalasena, K. 2011"/><ref name = "merickel">{{cite journal |vauthors=Merickel A, Kaback HR, Edwards RH | year = 1997 | title = Charged residues in transmembrane domains II and XI of a vesicular monoamine transporter form a charge pair that promotes high affinity substrate recognition | journal = J. Biol. Chem. | volume = 272 | issue = 9| pages = 5403–5408 | doi=10.1074/jbc.272.9.5403| pmid = 9038139 | doi-access = free }}</ref> Specifically, the residues Lys139 and Asp427 are thought to compose an ion pair that promotes high-affinity interaction with VMAT substrates and inhibitors.<ref name="Wimalasena, K. 2011"/><ref name = "merickel"/> The Asp431 residue located in TMD XI is believed to be critical for amine transport, but does not interact with RES binding; it is thought to complete the substrate transport cycle.<ref name="Wimalasena, K. 2011"/><ref>{{cite journal |vauthors=Steiner-Mordoch S, Shirvan A, Schuldiner S | year = 1996 | title = Modification of the pH profile and tetrabenazine sensitivity of rat VMAT1 by replacement of aspartate 404 with glutamate | journal = J. Biol. Chem. | volume = 271 | issue = 22| pages = 13048–13054 | pmid = 8662678 | doi = 10.1074/jbc.271.22.13048 | doi-access = free }}</ref>