Chronic Treatment of C6 Glioma Cells with Antidepressant Drugs Results in a Redistribution of Gsα

Donati, Robert J.; Thukral, Chandrashekhar; Rasenick, Mark M.

doi:10.1124/mol.59.6.1426

Cited by 33 publications

(35 citation statements)

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“…These studies have demonstrated that G sα is localized to TX-100-resistant membrane domains and the tips of elongated processes of C6 glioma cells, and this localization is altered after chronic antidepressant treatment [14][15][16]. Similarly, we have observed an altered distribution of G sα in the TX-100-resistant and the TX-100-soluble membrane domains in the prefrontal cortex and cerebellum of depressed suicide subjects compared with control subjects [17].…”

supporting

confidence: 52%

“…In summary, previous studies in both rats and C6 glioma cells demonstrated that chronic antidepressant treatment liberates G sα , but not G iα or G oα , from the inhibitory TX-100-resistant membrane raft domains [14][15][16], increasing its Progress toward a depression biomarker -EDITORIAL future science group future science group www.futuremedicine.com association with adenylyl cyclase [16]. Coupled with postmortem human brain data, these observations demonstrate that the increased localization of G sα in the TX-100-resistant membrane domains of depressed individuals may prevent G sα from associating with and activating adenylyl cyclase, thus preventing the propagation of the cAMP signal.…”

mentioning

confidence: 99%

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Lipid Rafts, G Proteins and the Etiology of and Treatment for Depression: Progress toward a Depression Biomarker

Donati

Rasenick

2008

Future Neurol.

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confidence: 52%

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confidence: 99%

Lipid Rafts, G Proteins and the Etiology of and Treatment for Depression: Progress toward a Depression Biomarker

Donati

Rasenick

2008

Future Neurol.

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“…This has been observed in both rats (7) and cell culture (8,16,30). Moreover, lipid raft disruption through cholesterol depletion or cytoskeletal disruption displaces many raft proteins, but GPCR activation or antidepressant treatment displaces only G␣ s (7).…”

Section: Discussionmentioning

confidence: 93%

Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs

Erb¹,

Schappi

Rasenick

2016

Journal of Biological Chemistry

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Depression is a significant public health problem for which currently available medications, if effective, require weeks to months of treatment before patients respond. Previous studies have shown that the G protein responsible for increasing cAMP (G␣ s ) is increasingly localized to lipid rafts in depressed subjects and that chronic antidepressant treatment translocates G␣ s from lipid rafts. Translocation of G␣ s , which shows delayed onset after chronic antidepressant treatment of rats or of C6 glioma cells, tracks with the delayed onset of therapeutic action of antidepressants. Because antidepressants appear to specifically modify G␣ s localized to lipid rafts, we sought to determine whether structurally diverse antidepressants accumulate in lipid rafts. Sustained treatment of C6 glioma cells, which lack 5-hydroxytryptamine transporters, showed marked concentration of several antidepressants in raft fractions, as revealed by increased absorbance and by mass fingerprint. Closely related molecules without antidepressant activity did not concentrate in raft fractions. Thus, at least two classes of antidepressants accumulate in lipid rafts and effect translocation of G␣ s to the non-raft membrane fraction, where it activates the cAMP-signaling cascade. Analysis of the structural determinants of raft localization may both help to explain the hysteresis of antidepressant action and lead to design and development of novel substrates for depression therapeutics.Depression is the leading cause of long term disability in the industrialized world (1). Although depression is a significant health problem in the United States and antidepressants are heavily prescribed (2), the mechanism of action for these drugs is not understood. Further, nearly a third of those treated with these drugs do not achieve remission of their depression (3). Although most of these drugs do interfere with monoamine uptake or catabolism, they exert this effect within hours, even though most of the compounds require weeks before alleviation of symptoms is observed (4). Thus, other targets for antidepressant drugs may exist (4).Chronic antidepressant treatment engages signaling pathways apart from increasing monoamine density in the synaptic cleft. One of these is an increased accumulation of cellular cAMP and sequelae thereof, such as increased cAMP-response element-binding protein (CREB) phosphorylation and increased transcription of cAMP-regulated genes (e.g. BDNF) (5). Moreover, positron emission tomography (PET) evidence suggests that cAMP is diminished throughout the brain of depressed human subjects (6). Thus, it is possible that some antidepressant effects are mediated through induction of the cAMP-generating system, including G␣ s and adenylyl cyclase.Previous studies demonstrated that chronic antidepressant treatment translocates G␣ s from lipid rafts, whereupon it engages in a more facile activation of adenylyl cyclase (7,8). Lipid rafts are regions of the plasma membrane rich in caveolin, cholesterol, sphingolipids, and cytoskeletal an...

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“…Although it is not possible to directly compare the timedependent effect seen in in vivo experiments with that obtained in vitro, it should be stressed that similar changes as those observed after long-term administration of psychotropic drugs in experimental animals are also present in vitro after their 3-5-days presence (depending on concentration) in culture medium (Donati et al, 2001;Lai et al, 2003). Since no data are available on the effect of chronic treatment with particular antipsychotic drugs on CRH concentration in vivo, the present results can be related only to antipsychotic-induced changes in corticosterone blood level.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

Basta‐Kaim

Budziszewska

Jaworska-Feil

et al. 2005

Neuropsychopharmacol

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Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 mM), haloperidol (0.5-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (1.0-5.0 mM), promazine (5.0 and 10 mM), risperidone (5.0 and 10.0 mM), and raclopride (only at the highest used concentrations, ie 30 and 100 mM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 mM), haloperidol (1.0-5.0 mM), clozapine (1.0-5.0 mM), thioridazine (3.0 and 5.0 mM), and raclopride (30 and 100 mM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 mM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3b level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 mM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.

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Chronic Treatment of C6 Glioma Cells with Antidepressant Drugs Results in a Redistribution of Gsα

Cited by 33 publications

References 32 publications

Lipid Rafts, G Proteins and the Etiology of and Treatment for Depression: Progress toward a Depression Biomarker

Lipid Rafts, G Proteins and the Etiology of and Treatment for Depression: Progress toward a Depression Biomarker

Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs

Antipsychotic Drugs Inhibit the Human Corticotropin-Releasing-Hormone Gene Promoter Activity in Neuro-2A Cells—an Involvement of Protein Kinases

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