Abstract
Chronic antidepressant treatment has been shown to increase adenylyl cyclase activity, in part, due to translocation of Gαs 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 Gαs 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 Gαs in lipid rafts, whereas there was no change in overall Gαs 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 Gαs 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 Gαs and adenylyl cyclase. Thus, escitalopram is potent, rapid and efficacious in translocating Gαs 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.
Footnotes
This study was supported by the National Institutes of Health National Institute of Mental Health [Grant MH78200]; and by a generous gift from AbdulRazzaq Al-Siddiqi.
This contribution represents partial fulfilment for L.Z. toward the Ph.D. in Physiology from Tongii Medical College.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162644.
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ABBREVIATIONS:
- SSRI
- selective serotonin reuptake inhibitor
- 5-HT
- 5-hydroxytryptamine (serotonin)
- Gpp(NH)p
- guanyl-5′-imidodiphosphate
- SERT
- serotonin transporter
- GTPγS
- guanosine 5′-O-(3-thio)triphosphate
- TTX
- Triton X
- DTT
- dithiothreitol
- ACVI
- type VI adenylyl cyclase
- ANOVA
- analysis of variance
- LSD
- least significant difference.
- Received October 13, 2009.
- Accepted December 7, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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