Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell surface expression and phosphorylation

The serotonin (5-HT) transporter (SERT) controls serotonergic neurotransmission in the brain by rapid clearance of 5-HT from the synaptic cleft into presynaptic neurons. SERTs are primary target for antidepressants for therapeutic intervention of mood disorders. Our previous studies have identified the involvement of several signaling pathways and protein kinases in regulating SERT function, trafficking and phosphorylation. However, whether the protein kinase B/Akt regulates SERT function is not known. Here, we made novel observation that inhibition of Akt resulted in the down regulation of SERT function through the regulation of SERT trafficking and phosphorylation. Akt inhibitor Akt X reduced the endogenously phosphorylated Akt and significantly decreased 5-HT uptake and 5-HT uptake capacity. Furthermore, SERT activity is also reduced by small interfering RNA downregulation of total and phospho-Akt levels. The reduction in SERT activity is paralleled by lower level of surface SERT protein, reduced SERT exocytosis with no effect on SERT endocytosis and accumulation of SERT in intracellular endocytic compartments with the most prominent localization to late endosomes and lysosomes. Akt2 inhibitor was more effective than Akt1 inhibitor in inhibiting SERT activity. Inhibition of downstream Akt kinase GSK3a/ß stimulates SERT function. Akt inhibition leads to decrease in SERT basal phosphorylation. Our results provide evidence that Akt regulates SERT function and cell surf...
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research