Editing Monoamine transporter (section)

==Structure and mechanism==
[[File:Dopamine Transporter Crystal Structure.png|thumb|Dopamine transporter crystal structure. Extracellular, transmembrane, and intracellular regions shown in turquoise, blue, and pink, respectively. Based on structure from Penmansta et al. (Nature, 2013)]]
Monoamine transporters are members of the group of Na <sup>+</sup>/Cl <sup>−</sup> -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family.<ref name="pmid31270469">{{cite journal |vauthors=Cheng MH, Bahar I |title=Monoamine transporters: structure, intrinsic dynamics and allosteric regulation |journal=Nat. Struct. Mol. Biol. |volume=26 |issue=7 |pages=545–556 |date=2019 |pmid=31270469 |pmc=6712983 |doi=10.1038/s41594-019-0253-7 }}</ref> MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops.  The NH<sub>2</sub> and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by [[Cyclic adenosine monophosphate|cAMP]]-dependent protein kinase, protein kinase C (PKC) and Ca<sup>2+</sup>/calmodulin-dependent protein kinase.<ref name=rama/><ref name=Torres/>

MATs are responsible for the uptake of monoamines by the sequential binding and co-transport of Na <sup>+</sup> and Cl <sup>−</sup> ions. The ion concentration gradient generated by the plasma membrane Na<sup>+</sup>/K<sup>+</sup> ATPase provides the driving force for the transporter-mediated monoamine uptake.<ref name=Torres/><ref name=gainet>{{cite journal | last1 = Gainetdinov | first1 = Raul | last2 = Caron | first2 = Marc | year = 2003 | title = Monoamine Transporters: From Genes to Behavior | journal = Annual Review of Pharmacology and Toxicology | volume = 43 | pages = 261–264 | doi=10.1146/annurev.pharmtox.43.050802.112309| pmid = 12359863 | s2cid = 6613675 }}</ref> In the case of NET and SERT one Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported along with one DA. When ionic gradients are altered (extracellular K<sup>+</sup> increases or extracellular Na<sup>+</sup> or Cl<sup>−</sup> decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron.<ref name=Torres/>

To return to an outwardly facing conformation SERT requires the transport of intracellular K<sup>+</sup>. There is no evidence that the other transporters have such a requirement.<ref name=Torres/>

Phosphorylation plays a key role in MAT function. When SERT is phosphorylated by the PKC-dependent pathway SERT internalization occurs. The internalization of SERT reduces 5-HT uptake.<ref name=rama/>  Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs.

{| class="wikitable"
|-
! MAT !! Gene !! Size !! Human Chromosome
|-
| DAT || hDAT || 620 amino acids || 5p15.3<ref name=rama/>
|-
| SERT || hSERT || 630 amino acids || 17q11.2<ref name=rama/>
|-
| NET || hNET || 617 amino acids || 16q12.2<ref name=rama/>
|}