Antidepressants and Antipsychotic Drugs Colocalize with 5-HT<sub>3</sub>Receptors in Raft-Like Domains

Eisensamer, B.; Uhr, Manfred; Meyr, Sabrina; Gimpl, Gerald; Deiml, Tobias; Rammes, Gerhard; Lambert, Jeremy J.; Zieglgänsberger, W.; Holsboer, Florian; Rupprecht, Rainer

doi:10.1523/jneurosci.2460-05.2005

Cited by 81 publications

(92 citation statements)

References 77 publications

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“…The work from this laboratory on lipid raft and G protein signaling, and the suggestion that antidepressants concentrate in lipid rafts (Eisensamer et al, 2005) combine to suggest that antidepressants translocate Ga s from lipid rafts and, in doing so, alter the dynamic properties of that protein within the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

Czysz

Schappi

Rasenick

2014

Neuropsychopharmacol

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GPCR signaling is modified both in major depressive disorder and by chronic antidepressant treatment. Endogenous Ga s redistributes from raft-to nonraft-membrane fractions after chronic antidepressant treatment. Modification of G protein anchoring may participate in this process. Regulation of Ga s signaling by antidepressants was studied using fluorescence recovery after photobleaching (FRAP) of GFP-Ga s . Here we find that extended antidepressant treatment both increases the half-time of maximum recovery of GFP-Ga s and decreases the extent of recovery. Furthermore, this effect parallels the movement of Ga s out of lipid rafts as determined by cold detergent membrane extraction with respect to both dose and duration of drug treatment. This effect was observed for several classes of compounds with antidepressant activity, whereas closely related molecules lacking antidepressant activity (eg, R-citalopram) did not produce the effect. These results are consistent with previously observed antidepressant-induced translocation of Ga s , but also suggest an alternate membrane attachment site for this G protein. Furthermore, FRAP analysis provides the possibility of a relatively high-throughput screening tool for compounds with putative antidepressant activity.

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Section: Discussionmentioning

confidence: 99%

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

Czysz

Schappi

Rasenick

2014

Neuropsychopharmacol

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“…Redistribution-Due to our earlier observations that G␣ s translocates from rafts after extended exposure to antidepressants (8), and the observations by Rupprecht and colleagues (25), we hypothesized that antidepressants preferentially associate with lipid rafts, and that all monoamine-centric antidepressants share this property. We assessed the accumulation of represen- tative drugs from each antidepressant class: MAO inhibitor (phenelzine), tricyclic antidepressant (desipramine, imipramine, and amitriptyline), and SSRI (escitalopram/inactive stereoisomer R-citalopram and fluoxetine), as well as the atypical antipsychotic aripiprazole, which has some independent antidepressant properties, and the atypical antipsychotic, olanzapine, which does not (26).…”

Section: Gradual Accumulation Of Antidepressant Drugs In Plasma Membrmentioning

confidence: 98%

“…To parallel the experiments by Eisensamer et al (25), escitalopram was added to sucrose density gradients prepared from membrane fractions. Escitalopram, but not R-citalopram, associated with lipid raft fractions of the plasma membrane (Fig.…”

Section: Gradual Accumulation Of Antidepressant Drugs In Plasma Membrmentioning

confidence: 99%

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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“…Recent evidence indicates that SRIs and other antidepressants have 5-HT3-R antagonist properties (Eisensamer et al, 2003(Eisensamer et al, , 2005. Systemic treatment with the 5-HT3-R antagonist ondansetron can augment the antidepressant-like actions of SRIs in the forced swim and tail suspension tests, while the 5-HT3-R agonist 1-(m-chlorophenyl)-biguanide (mCPBG) has the opposite effect (Nakagawa et al, 1998;Redrobe and Bourin, 1997) (cf.…”

Section: -Ht3 Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

242

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains

Cited by 81 publications

References 77 publications

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

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

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

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Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3Receptors in Raft-Like Domains

Cited by 81 publications

References 77 publications

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

Lateral Diffusion of Gαs in the Plasma Membrane Is Decreased after Chronic but not Acute Antidepressant Treatment: Role of Lipid Raft and Non-Raft Membrane Microdomains

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

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

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Antidepressants and Antipsychotic Drugs Colocalize with 5-HT₃Receptors in Raft-Like Domains