Monoamine Transporter - Structure and Mechanism

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.