Fluoxetine-induced transactivation of the platelet-derived growth factor type β receptor reveals a novel heterologous desensitization process

Kruk, Jeff S.; Vasefi, Maryam; Gondora, Nyasha; Ahmed, Nawaz; Heikkila, John J.; Beazely, Michael A.

doi:10.1016/j.mcn.2015.02.013

Cited by 5 publications

(4 citation statements)

References 42 publications

(64 reference statements)

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“…Of these, Pdgfrb stood out as the receptor with the largest number of differential interactions (5/20 interactions). SSRI treatment in vitro activates Pdgfrb via serotonin receptors (Htr1a, Htr2b) , resulting in increased neuroprotective growth factor signalling [ 100 ]. In addition, mossy cells have an established role in adult neurogenesis [ 101 , 102 ] and mediate anti-anxiolytic and neurogenic responses to antidepressants [ 103 ].…”

Section: Resultsmentioning

confidence: 99%

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

et al. 2022

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Depression and anxiety are major global health burdens. Although SSRIs targeting the serotonergic system are prescribed over 200 million times annually, they have variable therapeutic efficacy and side effects, and mechanisms of action remain incompletely understood. Here, we comprehensively characterise the molecular landscape of gene regulatory changes associated with fluoxetine, a widely-used SSRI. We performed multimodal analysis of SSRI response in 27 mammalian brain regions using 310 bulk RNA-seq and H3K27ac ChIP-seq datasets, followed by in-depth characterisation of two hippocampal regions using single-cell RNA-seq (20 datasets). Remarkably, fluoxetine induced profound region-specific shifts in gene expression and chromatin state, including in the nucleus accumbens shell, locus coeruleus and septal areas, as well as in more well-studied regions such as the raphe and hippocampal dentate gyrus. Expression changes were strongly enriched at GWAS loci for depression and antidepressant drug response, stressing the relevance to human phenotypes. We observed differential expression at dozens of signalling receptors and pathways, many of which are previously unknown. Single-cell analysis revealed stark differences in fluoxetine response between the dorsal and ventral hippocampal dentate gyri, particularly in oligodendrocytes, mossy cells and inhibitory neurons. Across diverse brain regions, integrative omics analysis consistently suggested increased energy metabolism via oxidative phosphorylation and mitochondrial changes, which we corroborated in vitro; this may thus constitute a shared mechanism of action of fluoxetine. Similarly, we observed pervasive chromatin remodelling signatures across the brain. Our study reveals unexpected regional and cell type-specific heterogeneity in SSRI action, highlights under-studied brain regions that may play a major role in antidepressant response, and provides a rich resource of candidate cell types, genes, gene regulatory elements and pathways for mechanistic analysis and identifying new therapeutic targets for depression and anxiety.

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Section: Resultsmentioning

confidence: 99%

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

et al. 2022

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“…Fluoxetine has strong affinity for serotonin receptors – particularly the 5-hydroxytryptamine (5-HT)2 receptors at the concentrations used here. [ 40 41 ] Previous studies have shown that increased concentrations of serotonin can affect osteogenesis in vitro through 5-HT2 or 5-HT1 receptors and via the nuclear factor-κB or runt-related transcription factor 2 pathways,[ 18 19 42 ] an effect that has been also reported in vivo . [ 43 ] In contrast, amitriptyline and venlafaxine have a weaker affinity for serotonin receptors and higher affinity for a variety of receptors and neurotransmitters, which could explain the divergent effect observed in this study.…”

Section: Discussionmentioning

confidence: 97%

The Effect of Antidepressants on Mesenchymal Stem Cell Differentiation

et al. 2018

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BackgroundUse of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism.MethodsHuman MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT.ResultsWe found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival.ConclusionsThis study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.

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“…This transactivation turned out to be Src and PLC dependent [75,76]. Furthermore, the SSRI fluoxetine could transactivate the PDGFR beta via activation of 5-HT2B receptors which blocked the 5-HT-induced transactivation likely through desensitization [77]. Both D2R and D4R were capable of transactivating PDGFR beta via tyrosine phosphorylation.…”

Section: Do Gpcr-platelet-derived Growth Factor Receptor (Pdgfr) Heteroreceptor Complexes Exist?mentioning

confidence: 96%

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

Borroto-Escuela

Ambrogini²,

Narváez

et al. 2021

Cells

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The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

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Fluoxetine-induced transactivation of the platelet-derived growth factor type β receptor reveals a novel heterologous desensitization process

Cited by 5 publications

References 42 publications

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

Integrative multi-omics landscape of fluoxetine action across 27 brain regions reveals global increase in energy metabolism and region-specific chromatin remodelling

The Effect of Antidepressants on Mesenchymal Stem Cell Differentiation

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

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