title: The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients.
abstract: There is insufficient serotonergic neuronal function in the pathophysiology of major depressive disorder (MDD). Serotonin transporter (SERT) plays a critical role in terminating the function of serotoninergic neurons. SERT is linked to vulnerability to MDD and is an important target for antidepressants. The expression of SERT in lymphocytes and platelets is associated with their expression in central nervous system. Most of the clinical studies that have analyzed the role of SERT in depression have focused on absolute expression of SERT in the brain or peripheral tissue. Our study has shown that the SERT protein is ubiquitinated, which has been implicated through the SERT stability and depressive behaviors in mice. In our study, we have used lymphoblasts derived from the peripheral blood lymphocytes to quantitatively examine SERT protein expression and ubiquitination in fluvoxamine-responsive and fluvoxamine-resistant MDD patients. We found that the protein levels of SERT were higher in the fluvoxamine-resistant MDD patients. Ubiquitinated protein levels of SERT were lower in the fluvoxamine-resistant MDD patients. The proteasome inhibitor failed to increase the protein levels of SERT in both fluvoxamine-responsive and fluvoxamine-resistant MDD patients. In sum, these findings suggest that the downregulation of the ubiquitination of SERT protein induces insufficient degradation of SERT by proteasome, which resulted in the upregulation of SERT protein in fluvoxamine-resistant MDD patients. Although further studies with various populations will be required to generalize results, SERT protein expression, ubiquitination, and the responsiveness of SERT expression to proteasome inhibitor are potential biomarkers for the diagnosis of MDD and antidepressant efficacy.
authors: Division of Clinical Sciences and Neuropsychopharmacology, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi, Japan.
authors: Akihiro
authors: A
authors: Mouri
authors: Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.
authors: Masashi
authors: M
authors: Ikeda
authors: Department of Clinical Pharmacy, Fujita Health University School of Medicine, Aichi, Japan.
authors: Takenao
authors: T
authors: Koseki
authors: Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.
authors: Nakao
authors: N
authors: Iwata
authors: Nabeshima Laboratory, Faculty of Pharmacy, Meijo University, Nagoya, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan; Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Aichi, Japan. Electronic address: tnabeshi@meijo-u.ac.jp.
authors: Toshitaka
authors: T
authors: Nabeshima
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D016666:Fluvoxamine / Q000627:therapeutic use*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D061988:Proteasome Inhibitors / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017211:Treatment Failure; D054875:Ubiquitination; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D007976:Leupeptins; D061988:Proteasome Inhibitors; D050486:Serotonin Plasma Membrane Transport Proteins; D016666:Fluvoxamine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Biomarker; Lymphoblast; Major depressive disorder; Serotonin transporter; Ubiquitination