1. ¹Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
2. ²Basic and Health Science Department, Illinois College of Optometry, Chicago, IL, USA
3. ³Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

Correspondence: Dr MM Rasenick, Department of Physiology & Biophysics, College of Medicine, University of Illinois at Chicago, 835 S Wolcott Ave., M/C 901 Rm. E202, Chicago, IL 60612-7342, USA. Tel: +312 996 6641; Fax: +312 996 1414; E-mail: RAZ@uic.edu

Received 28 September 2004; Revised 28 December 2004; Accepted 11 January 2005; Published online 23 February 2005.

Abstract

Previous studies demonstrated that Gs migrates from a Triton X-100 (TTX-100) insoluble membrane domain to a TTX-100 soluble membrane domain in response to chronic treatment with the antidepressants desipramine and fluoxetine. Antidepressant treatment also causes a Gs redistribution in cells as seen by confocal microscopy. The current studies have focused on examining the possibility that the association between Gs and the plasma membrane and/or cytoskeleton is altered in response to antidepressant treatment, and that this is relevant to both Gs redistribution and the increased coupling between Gs and adenylyl cyclase seen after chronic antidepressant treatment. Chronic treatment of C6 cells with two fuctionally and structurally distinct antidepressants, desipramine and fluoxetine, decreased the Gs content of TTX-100 insoluble membrane domains by as much as 60%, while the inactive fluoxetine analog LY368514 had no effect. Disruption of these membrane domains with the cholesterol chelator methyl--cyclodextrin altered the localization of many proteins involved in the cAMP signaling cascade, but only Gs localization was altered by antidepressant treatment. In addition, microtubule disruption with colchicine elicited the movement of Gs out of detergent-resistant membrane domains in a manner identical to that seen with antidepressant treatment. The data presented here further substantiate the role of Gs as a major player in antidepressant-induced modification of neuronal signaling and also raise the possibility that an interaction between Gs and the cytoskeleton is involved in this process.