Chronic treatment with escitalopram but not R-citalopram translocates Galpha(s) from lipid raft domains and potentiates adenylyl cyclase: a 5-hydroxytryptamine transporter-independent action of this antidepressant compound.
Chronic antidepressant treatment has been shown to increase adenylyl cyclase activity, in part, due to translocation of Galpha(s) from lipid rafts to a nonraft fraction of the plasma membrane where they engage in a more facile stimulation of adenylyl cyclase. This effect holds for multiple classes of antidepressants, and for serotonin uptake inhibitors, it occurs in the absence of the serotonin transporter. In the present study, we examined the change in the amount of Galpha(s) in lipid raft and whole cell lysate after exposing C6 cells to escitalopram. The results showed that chronic (but not acute) escitalopram decreased the content of Galpha(s) in lipid rafts, whereas there was no change in overall Galpha(s) content. These effects were drug dose- and exposure time-dependent. Although R-citalopram has been reported to antagonize some effects of escitalopram, this compound was without effect on Galpha(s) localization in lipid rafts, and R-citalopram did not inhibit these actions of escitalopram. Escitalopram treatment increased cAMP accumulation, and this seemed due to increased coupling between Galpha(s) and adenylyl cyclase. Thus, escitalopram is potent, rapid and efficacious in translocating Galpha(s) from lipid rafts, and this effect seems to occur independently of 5-hydroxytryptamine transporters. Our results suggest that, although antidepressants display distinct affinities for well identified targets (e.g., monoamine transporters), several presynaptic and postsynaptic molecules are probably modified during chronic antidepressant treatment, and these additional targets may be required for clinical efficacy of these drugs.
Zhang
Lanqiu
L
Department of Physiology, University of Illinois Chicago, 835 S Wolcott Ave., M/C 901 Rm. E202, Chicago, IL 60612-7342, USA.
Rasenick
Mark M
MM
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015283:Citalopram / Q000737:chemistry / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000262:Adenylyl Cyclases; D000928:Antidepressive Agents; D015283:Citalopram; D005576:Colforsin; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors