and VMAT2 are acidic glycoproteins with a molecular weight of approximately 70 kDa. Both isoforms are transmembrane proteins with 12 transmembrane domains (TMDs). VMATs function by loading monoamines—dopamine, serotonin, histamine, norepinephrine, and epinephrine—into transport vesicles. VMATs use the same transport mechanism for all types of monoamines, and transport them from the cytosol into high-concentration storage vesicles. 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. The transporters are also known to continue biochemical modification after loading certain neurotransmitters. 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 vesicular H+-ATPase. The current model of VMAT function proposes that the efflux of two protons (H+) against the H+ gradient is coupled with influx of one monoamine. The first H+ efflux generates a transporter conformation associated with a high-affinity amine-binding site in the cytosolic phase, and the second H+ 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. Studies indicate that the amino acid 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>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. VMAT gene sequence analysis demonstrates that four 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. Specifically, the residues Lys139 and Asp427 are thought to compose an ion pair that promotes high-affinity interaction with VMAT substrates and inhibitors. 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. Kinetics VMATs have a relatively low Vmax, with an