Down-regulation of the rat serotonin transporter upon exposure to a selective serotonin reuptake inhibitor

The serotonin transporter (SERT) terminates serotonergic neurotransmission by rapid reuptake of 5-hydroxytryptamine (5-HT) into the nerve terminal or axonal varicosities. SERT represents the target of various antidepressants which inhibit 5-HT transport and are widely used for the pharmacotherapy of depression. Here, we have analyzed the function of SERT stably expressed in HEK 293 cells upon exposure to citalopram, a selective serotonin reuptake inhibitor (SSRI), with respect to 5-HT transport activity and protein expression as estimated by ligand binding experiments. Our results show that long-term exposure to an SSRI causes a down-regulation of transport activity as revealed by a reduction of the maximal transport rate, without affecting substrate affinity, accompanied by a decrease in ligand binding sites.

[1]  Kohji Sato,et al.  The recombinant GABA transporter GAT1 is downregulated upon activation of protein kinase C , 1995, FEBS letters.

[2]  J. Krystal,et al.  Psychopharmacology: The Third Generation of Progress , 1989, The Yale Journal of Biology and Medicine.

[3]  R. Blakely,et al.  Protein Kinase C Activation Regulates Human Serotonin Transporters in HEK-293 Cells via Altered Cell Surface Expression , 1997, The Journal of Neuroscience.

[4]  R. Blakely,et al.  Phosphorylation and Regulation of Antidepressant-sensitive Serotonin Transporters* , 1998, The Journal of Biological Chemistry.

[5]  S. Amara,et al.  Regulated Trafficking of the Human Dopamine Transporter , 1999, The Journal of Biological Chemistry.

[6]  R. Blakely,et al.  Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. , 1998, The Journal of pharmacology and experimental therapeutics.

[7]  A Frazer,et al.  Effects of Chronic Antidepressant Treatments on Serotonin Transporter Function, Density, and mRNA Level , 1999, The Journal of Neuroscience.

[8]  H. Betz,et al.  Localization of the Serotonin Transporter in Rat Spinal Cord , 1996, The European journal of neuroscience.

[9]  P. Schloss,et al.  Immunocytochemical detection of the serotonin transporter in rat brain , 1996, Neuroscience.

[10]  M. Quick,et al.  Regulation of γ-Aminobutyric Acid (GABA) Transporters by Extracellular GABA* , 1999, The Journal of Biological Chemistry.

[11]  R. Blakely,et al.  Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. , 1999, Science.

[12]  K. Sasaki,et al.  Modulation of Serotonin Transporter Activity by a Protein Kinase C Activator and an Inhibitor of Type 1 and 2A Serine/Threonine Phosphatases , 1997, Journal of neurochemistry.

[13]  D. Williams,et al.  The serotonin transporter: a primary target for antidepressant drugs , 1998, Journal of psychopharmacology.

[14]  G. Rudnick,et al.  An extracellular loop region of the serotonin transporter may be involved in the translocation mechanism. , 1997, Biochemistry.

[15]  R. Blakely,et al.  Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins , 1998, Biological Psychiatry.

[16]  R. Blakely,et al.  Down‐Regulation of the Human Norepinephrine Transporter in Intact 293‐hNET Cells Exposed to Desipramine , 1998, Journal of neurochemistry.

[17]  H. Betz,et al.  Distinct Effects of Imipramine on 5‐Hydroxytryptamine Uptake Mediated by the Recombinant Rat Serotonin Transporter SERT1 , 1998, Journal of neurochemistry.

[18]  A. Levey,et al.  Identification and characterization of antidepressant-sensitive serotonin transporter proteins using site-specific antibodies , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  G. Ordway,et al.  Down‐Regulation of Norepinephrine Transporters on PC12 Cells by Transporter Inhibitors , 1997, Journal of neurochemistry.

[20]  C. Montigny,et al.  Desensitization of the neuronal 5-HT carrier following its long-term blockade , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  K. Lesch,et al.  [The serotonin hypothesis of depression]. , 1990, Fortschritte der Neurologie-Psychiatrie.

[22]  R. Adams,et al.  Modulation of a Recombinant Glycine Transporter (GLYT1b) by Activation of Protein Kinase C , 1995, Journal of neurochemistry.

[23]  C. Tanaka,et al.  Phorbol ester-induced inhibition of GABA uptake by synaptosomes and by Xenopus oocytes expressing GABA transporter (GAT1) , 1994, Neuroscience Research.

[24]  G. Uhl,et al.  Phorbol esters alter functions of the expressed dopamine transporter. , 1994, European journal of pharmacology.

[25]  J. Gomeza,et al.  Regulation by phorbol esters of the glycine transporter (GLYT1) in glioblastoma cells. , 1995, Biochimica et biophysica acta.

[26]  H. Betz,et al.  Heterogeneity of antidepressant binding sites on the recombinant rat serotonin transporter SERT1. , 1995, Biochemistry.