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Science 30 July 1999:
Vol. 285. no. 5428, pp. 763 - 766
DOI: 10.1126/science.285.5428.763
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Reports

Phosphorylation and Sequestration of Serotonin Transporters Differentially Modulated by Psychostimulants

Sammanda Ramamoorthy, Randy D. Blakely *

Many psychotropic drugs interfere with the reuptake of dopamine, norepinephrine, and serotonin. Transport capacity is regulated by kinase-linked pathways, particularly those involving protein kinase C (PKC), resulting in transporter phosphorylation and sequestration. Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy. Ligands that can permeate the transporter, such as serotonin or the amphetamines, prevented PKC-dependent SERT phosphorylation. Nontransported SERT antagonists such as cocaine and antidepressants were permissive for SERT phosphorylation but blocked serotonin effects. PKC-dependent SERT sequestration was also blocked by serotonin. These findings reveal activity-dependent modulation of neurotransmitter reuptake and identify previously unknown consequences of amphetamine, cocaine, and antidepressant action.

Department of Pharmacology and Center for Molecular Neuroscience, School of Medicine, Vanderbilt University, Nashville, TN 37232-6420, USA.
*   To whom correspondence should be addressed. E-mail: randy.blakely{at}mcmail.vanderbilt.edu

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S. Apparsundaram, U. Sung, R. D. Price, and R. D. Blakely (2001)
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Regulation of the Human Norepinephrine Transporter by Cocaine and Amphetamine.
M.-Y. Zhu, S. Shamburger, J. Li, and G. A. Ordway (2000)
J. Pharmacol. Exp. Ther. 295, 951-959
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Cocaine and Antidepressant-Sensitive Biogenic Amine Transporters Exist in Regulated Complexes with Protein Phosphatase 2A.
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J. Neurosci. 20, 7571-7578
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Searching for the Chicken's Egg in Transporter Gene Polymorphisms.
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Arch Gen Psychiatry 57, 739-740
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K. M Buckley, H. E Melikian, C. J Provoda, and M. T Waring (2000)
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K. D. Sims, D. J. Straff, and M. B. Robinson (2000)
J. Biol. Chem. 275, 5228-5237
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S. Duan, C. M. Anderson, B. A. Stein, and R. A. Swanson (1999)
J. Neurosci. 19, 10193-10200
   Abstract »    Full Text »    PDF »
Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level.
S. Benmansour, M. Cecchi, D. A. Morilak, G. A. Gerhardt, M. A. Javors, G. G. Gould, and A. Frazer (1999)
J. Neurosci. 19, 10494-10501
   Abstract »    Full Text »    PDF »
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A. Geerlings, E. Nunez, B. Lopez-Corcuera, and C. Aragon (2001)
J. Biol. Chem. 276, 17584-17590
   Abstract »    Full Text »    PDF »
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C. Riedel, O. Levy, and N. Carrasco (2001)
J. Biol. Chem. 276, 21458-21463
   Abstract »    Full Text »    PDF »
Functional Regulation of gamma -Aminobutyric Acid Transporters by Direct Tyrosine Phosphorylation.
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C. Saunders, J. V. Ferrer, L. Shi, J. Chen, G. Merrill, M. E. Lamb, L. M. F. Leeb-Lundberg, L. Carvelli, J. A. Javitch, and A. Galli (2000)
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Psychostimulants Differentially Regulate Serotonin Transporter Expression in Thalamocortical Neurons.
T. L. Whitworth, L. C. Herndon, and M. W. Quick (2002)
J. Neurosci. 22, RC192
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