PFPC Daily - March 27, 2005


Donati RJ, Rasenick MM - "Chronic Antidepressant Treatment Prevents
Accumulation of Gsalpha in Cholesterol-Rich, Cytoskeletal-Associated,
Plasma Membrane Domains (Lipid Rafts)" Neuropsychopharmacology 2005
Feb 23

Previous studies demonstrated that Gsalpha 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 Gsalpha redistribution in cells as seen by confocal
microscopy. The current studies have focused on examining the
possibility that the association between Gsalpha and the plasma
membrane and/or cytoskeleton is altered in response to antidepressant
treatment, and that this is relevant to both Gsalpha redistribution
and the increased coupling between Gsalpha 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 Gsalpha 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-beta-cyclodextrin
altered the localization of many proteins involved in the cAMP
signaling cascade, but only Gsalpha localization was altered by
antidepressant treatment. In addition, microtubule disruption with
colchicine elicited the movement of Gsalpha 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 Gsalpha as a major player in
antidepressant-induced modification of neuronal signaling and also
raise the possibility that an interaction between Gsalpha and the
cytoskeleton is involved in this process.