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 localization to late endosomes and lysosomes. Akt2 inhibitor was more effective than Akt1 inhibitor in inhibiting SERT activity. Inhibition of downstream Akt kinase GSK3α/β (glycogen synthase kinase α/β) stimulates SERT function. Akt inhibition leads to a decrease in SERT basal phosphorylation. Our results provide evidence that Akt regulates SERT function and cell-surface expression by regulating the intracellular SERT distribution and plasma membrane availability, which perhaps may be linked to SERT phosphorylation state. Thus any changes in the activation of Akt and/or GSK3α/β could alter SERT-mediated 5-HT clearance and subsequently serotonergic neurotransmission.
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Research Article|
May 05 2015
Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell-surface expression and phosphorylation
Jeyaganesh Rajamanickam;
Jeyaganesh Rajamanickam
1
*Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Balasubramaniam Annamalai;
Balasubramaniam Annamalai
1
†Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
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Troels Rahbek-Clemmensen;
Troels Rahbek-Clemmensen
1
#x2021;Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
§Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Santhanalakshmi Sundaramurthy;
Santhanalakshmi Sundaramurthy
1
*Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Ulrik Gether;
Ulrik Gether
#x2021;Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
§Lundbeck Foundation Center for Biomembranes in Nanomedicine, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Lankupalle D. Jayanthi;
Lankupalle D. Jayanthi
*Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Sammanda Ramamoorthy
Sammanda Ramamoorthy
2
*Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
2To whom correspondence should be addressed (email sramamoorthy@vcu.edu).
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Publisher: Portland Press Ltd
Received:
June 30 2014
Revision Received:
February 26 2015
Accepted:
March 11 2015
Accepted Manuscript online:
March 11 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 468 (1): 177–190.
Article history
Received:
June 30 2014
Revision Received:
February 26 2015
Accepted:
March 11 2015
Accepted Manuscript online:
March 11 2015
Citation
Jeyaganesh Rajamanickam, Balasubramaniam Annamalai, Troels Rahbek-Clemmensen, Santhanalakshmi Sundaramurthy, Ulrik Gether, Lankupalle D. Jayanthi, Sammanda Ramamoorthy; Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell-surface expression and phosphorylation. Biochem J 15 May 2015; 468 (1): 177–190. doi: https://doi.org/10.1042/BJ20140826
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