Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.
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.
Ramamoorthy
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Department of Pharmacology and Center for Molecular Neuroscience, School of Medicine, Vanderbilt University, Nashville, TN 37232-6420, USA.
Blakely
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D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism / Q000494:pharmacology; D019921:Biotinylation; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000378:metabolism / Q000494:pharmacology*; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology; D003913:Dextroamphetamine / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008954:Models, Biological; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D002491:Central Nervous System Agents; D003042:Cocaine; D003913:Dextroamphetamine; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D011493:Protein Kinase C; D011494:Protein Kinases; D012701:Serotonin; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013755:Tetradecanoylphorbol Acetate; C493230:SLC6A4 protein, human