Chronic treatment of C6 glioma cells with antidepressant drugs results in a redistribution of Gsα

Previous studies have demonstrated that chronic treatment of C6 glioma cells with the antidepressants desipramine and fluoxetine increases the Triton X-100 solubility of the G protein Gs alpha (Toki et al., 1999). The antidepressants also caused a 50% decrease in the amount of Gs alpha localized to caveolae-enriched membrane domains. In this study, laser scanning confocal microscopy reveals that Gs alpha is localized to the plasma membrane as weil as the cytosol in both treated and control cells. However, striking differences are seen in the distribution of Gs alpha in the long cellular processes after chronic treatment with these antidepressant drugs. Control cells display Gs alpha along the entire process with an especially high concentration of that G protein at the distal ends. Desipramine- or fluoxetine-treated cells show a more centralized clustering of Gs alpha in the Golgi region of the cell and a drastic reduction of Gs alpha in the cellular processes. There is no change in the distribution of Go alpha after desipramine treatment and the antipsychotic drug chlorpromazine does not alter Gs alpha. These results suggest that antidepressant-induced changes in the association of Gs alpha with the plasma membrane may translate into altered cellular localization of this signal transducing protein. Thus, modification of the coupling between Gs-coupled receptors and adenylyl cyclase may underlie both antidepressant therapy and depressive illnesses. This report also suggests that modification of the membrane domain occupied by Gs alpha might represent a mechanism for chronic antidepressant effects.