Structure and Mechanism
Monoamine transporters are members of the group of Na +/Cl - -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family. MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH2 and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by cAMP-dependent protein kinase, protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase.
MATs are responsible for the uptake of monoamines by the sequential binding and co-transport of Na + and Cl - ions. The ion concentration gradient generated by the plasma membrane Na+/K+ ATPase provides the driving force for the transporter-mediated monoamine uptake. In the case of NET and SERT one Na+ and one Cl- ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na+ and one Cl- ion are transported along with one DA. When ionic gradients are altered (extracellular K+ increases or extracellular Na+ or Cl- decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron.
To return to an outwardly facing conformation SERT requires the transport of intracellular K+. There is no evidence that the other transporters have such a requirement.
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. Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs.
| MAT | Gene | Size | Human Chromosome |
|---|---|---|---|
| DAT | hDAT | 620 amino acids | 5p15.3 |
| SERT | hSERT | 630 amino acids | 17q11.2 |
| NET | hNET | 617 amino acids | 16q12.2 |
Read more about this topic: Monoamine Transporter
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