Functional regulation of serotonin transporter, a molecule involved in the pathogenesis of anxiety disorder]

The serotonin transporter (SET) is a member of the Na+/Cl(-)-dependent neurotransmitter transporter family and functions as a membrane protein which terminates the serotonergic neuronal transmission by re-uptaking serotonin into the pre-synaptic terminal. SET is thought to be involved in the pathogenesis of affective disorders, drug abuse and anxiety disorder. We have focused on SET regulation by phosphorylation/dephosphorylation since SET has many putative phosphorylation sites in its intracellular region. Our previous studies have revealed that phorbolesters, activators of PKC, decreased in SET uptake activity. Based on a mutagenesis analysis of PKC phosphorylation sites and an in vivo phosphorylation study of SET, we have concluded that PKC regulates SET activity via an indirect mechanism, probably via alternating actin cytoskeleton status. Recent reports and our investigation have demonstrated that the SET C-terminal region interacts with actin binding proteins, suggesting the crucial roles of this region in functional regulation of SET.