Regulated trafficking of neurotransmitter transporters: common notes but different melodies

The activity of biogenic amine and amino acid neurotransmitters is limited by presynaptic and astrocytic Na + ‐dependent transport systems. Their functional importance is underscored by the observation that these transporters are the targets of broad classes of psychotherapeutic agents, including antidepressants and stimulants. Early studies suggested that the activity of these transporters can be fine tuned by a number of different signaling pathways. In the past five years, several groups have provided compelling evidence that changing the cell surface availability of these transporters contributes to this fine tuning. This regulated trafficking can result in rapid (within minutes) increases or decreases in the plasma membrane expression of these transporters and is independent of transcriptional or translational control mechanisms. Many of the same signaling molecules, including protein kinase C (PKC), tyrosine kinase, phosphatidylinositol 3‐kinase (P13‐K), and protein phosphatase, regulate the transporters for different neurotransmitters. In addition to these classical receptor activated pathways, transporter substrates also regulate activity and cell surface expression of these transporters. In fact, some of the transporters form complexes with signaling molecules. Given the functional and genetic similarities of these transporters, it is not surprising that the same signaling molecules regulate their trafficking, but except for the molecules, the actual effects on individual transporters are remarkably different. It␣is as if the same musical notes have been rearranged into several different melodies.