title: Antidepressant-induced differential ubiquitination of β-arrestins 1 and 2 in mononuclear leucocytes of patients with depression.
abstract: β-Arrestins 1 and 2, cytosolic proteins known to mediate receptor desensitization, endocytosis and G protein-independent signalling, are post-translationally modified by ubiquitination regulating their ability to serve as adaptors and scaffolds. β-Arrestins were suggested to play a role in the pathophysiology of depression and in antidepressant mechanism of action. To determine whether a depressive episode or antidepressant treatment induce significant selective differences in β-arrestin 1 and 2 levels or their ubiquitination patterns in leucocytes of patients with depression, 46 outpatients diagnosed with a depressive episode were examined before and after 4-wk antidepressant treatment compared with age- and gender-matched control subjects. β-Arrestin levels were measured by immunoblotting using anti-arrestin antibodies. Ubiquitination of β-arrestins was measured using anti-ubiquitin antibodies followed by an immunoprecipitation step and immunoblotting using anti-arrestin antibodies. Antidepressants induced selective alterations in leucocyte β-arrestin 1 and 2 levels and ubiquitination. The levels of β-arrestin 1 and 2 and their ubiquitinated forms in leucocytes of yet untreated patients with depression were significantly decreased in a symptom severity correlated manner compared to control subjects. Antidepressants normalized β-arrestin 1 and 2 levels and uncovered novel differences between the two isoforms: (a) while antidepressants normalized ubiquitination of β-arrestin 1, ubiquination of β-arrestin 2 was unaffected; (b) while under antidepressants ubiquitination extent of β-arrestin 1 positively correlated with its level, an inverse picture of negative correlation was found between ubiquitination extent of β-arrestin 2 and its level. We conclude that antidepressants may serve as a tool to detect functional differences between the two β-arrestin isoforms and that through these differential effects antidepressants can induce specific alterations in alternative cellular signalling.
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty for Health Sciences, Ben-Gurion University of the Negev, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Golan
authors.forename: Gabriel
authors.initials: G
authors.lastname: Schreiber
authors.forename: Sofia
authors.initials: S
authors.lastname: Avissar
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019390:Arrestins / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D018709:Statistics, Nonparametric; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*; D055815:Young Adult; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; C000605254:ARRB2 protein, human; D000928:Antidepressive Agents; D019390:Arrestins; D025801:Ubiquitin; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins