TY - JOUR T1 - Antidepressants Increase β-Arrestin2 Ubiquitinylation and Degradation by the Proteasomal Pathway in C<sub>6</sub> Rat Glioma Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 970 LP - 976 DO - 10.1124/jpet.109.160218 VL - 332 IS - 3 AU - Moran Golan AU - Gabriel Schreiber AU - Sofia Avissar Y1 - 2010/03/01 UR - http://jpet.aspetjournals.org/content/332/3/970.abstract N2 - β-Arrestins, regulators of G protein-coupled receptor-G protein coupling and receptor desensitization and internalization, function also as scaffolding proteins mediating cellular signaling events. β-Arrestin1 was previously implicated by us in the pathophysiology of depression and in the mechanism of action of antidepressants (ADs). The ubiquitously expressed β-arrestins1 and 2 are structurally highly homologous. There has been extensive investigation of these two proteins to determine whether they serve different roles in receptor signaling. In this study, we show that treatment of C6 rat glioma cells with ADs of various types for 3 days resulted in decreased β-arrestin2 levels. In contrast, β-arrestin2 mRNA expression was found to be up-regulated by ADs. To unravel the mechanism for these opposite effects several possible β-arrestin2 post-transcriptional events and modifications were examined. C6 rat glioma cells transfected with β-arrestin1-targeted short hairpin RNA showed similar effects of ADs on β-arrestin2 levels. AD-induced decreases in β-arrestin2 protein levels were not due to cytosolic membrane translocation. Immunoprecipitation experiments showed that ADs were able to increase coimmunoprecipitation of ubiquitin with β-arrestin2. AD-induced increases in β-arrestin2 ubiquitinylation led to its degradation by the proteasomal pathway, as the proteasome inhibitor N-[(phenylmethoxy)carbonyl]-l-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-l-leucinamide (MG-132) prevented antidepressant-induced decreases in β-arrestin2 protein levels.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -