Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antidepressive Agents / metabolism
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Antidepressive Agents / pharmacology
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Biogenic Monoamines / metabolism
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Biogenic Monoamines / pharmacology
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Biotinylation
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism*
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Cell Line
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Central Nervous System Agents / metabolism
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Central Nervous System Agents / pharmacology*
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Cocaine / metabolism
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Cocaine / pharmacology
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Dextroamphetamine / metabolism
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Dextroamphetamine / pharmacology
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Enzyme Activation
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Humans
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Ligands
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins*
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Models, Biological
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Nerve Tissue Proteins*
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Neurotransmitter Agents / metabolism
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Neurotransmitter Agents / pharmacology*
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Phosphorylation
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Protein Kinase C / metabolism
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Protein Kinases / metabolism
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Selective Serotonin Reuptake Inhibitors / metabolism
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / metabolism*
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Serotonin / pharmacology
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Serotonin Antagonists / pharmacology
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Serotonin Plasma Membrane Transport Proteins
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Tetradecanoylphorbol Acetate / pharmacology
Substances
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Antidepressive Agents
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Biogenic Monoamines
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Carrier Proteins
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Central Nervous System Agents
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Ligands
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Neurotransmitter Agents
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SLC6A4 protein, human
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Serotonin
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Protein Kinases
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Protein Kinase C
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Cocaine
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Tetradecanoylphorbol Acetate
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Dextroamphetamine