Control of serotonin transporter phosphorylation by conformational state.
Proceedings of the National Academy of Sciences of the United States of America May 17, 2016 Yuan-Wei Zhang, Benjamin E Turk, Gary Rudnick 53 citations
The serotonin transporter (SERT) clears serotonin from synapses, and mutations in human SERT are linked to psychiatric disorders and autism. Phosphorylation at a specific site, threonine 276 near the cytoplasmic end of transmembrane helix 5, regulates SERT activity. Agents that stabilize the outward-open conformation of SERT, such as sodium ions and cocaine, decrease phosphorylation, while agents that stabilize the inward-open conformation, such as serotonin and ibogaine, increase phosphorylation. The opposing effects of cocaine and ibogaine are reversible by an excess of the other inhibitor. These findings suggest that serotonin transport itself activates a regulatory mechanism, possibly involving unwinding of the helix to allow phosphorylation.