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

The Biochemical Journal
Jeyaganesh RajamanickamSammanda Ramamoorthy

Abstract

The serotonin [5-HT (5-hydroxytryptamine)] transporter (SERT) controls serotonergic neurotransmission in the brain by rapid clearance of 5-HT from the synaptic cleft into presynaptic neurons. SERTs are primary targets for antidepressants for therapeutic intervention of mood disorders. Our previous studies have identified the involvement of several signalling pathways and protein kinases in regulating SERT function, trafficking and phosphorylation. However, whether Akt/PKB (protein kinase) regulates SERT function is not known. In the present study, we made the 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 {10-(4'-[N-diethylamino)butyl]-2-chlorophenoxazine} reduced the endogenously phosphorylated Akt and significantly decreased 5-HT uptake and 5-HT-uptake capacity. Furthermore, SERT activity is also reduced by siRNA down-regulation of total and phospho-Akt levels. The reduction in SERT activity is paralleled by lower levels of cell-surface SERT protein, reduced SERT exocytosis with no effect on SERT endocytosis and accumulation of SERT in intracellular endocytic compartments with the most prominent local...Continue Reading

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Citations

Mar 30, 2016·Neurochemistry International·Anne VuorenpääUlrik Gether
Sep 4, 2016·Pharmacological Reviews·Daniel P Bermingham, Randy D Blakely
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Jan 10, 2020·ACS Chemical Neuroscience·Balasubramaniam AnnamalaiSammanda Ramamoorthy
May 17, 2021·Neurochemistry International·Aarti Sharma, Sidharth Mehan

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