GABA regulates electrical activity and tumor initiation in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA992460 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25195340_1.fastq.gz | Fastqsanger.gz | |||
| SRR25195340_2.fastq.gz | Fastqsanger.gz | |||
| SRR25195341_1.fastq.gz | Fastqsanger.gz | |||
| SRR25195341_2.fastq.gz | Fastqsanger.gz | |||
| SRR25195342_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogenes can only initiate tumors in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors on keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multi-electrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte co-cultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.
2023-07-12 | GSE236806 | GEO
Project description:Oncogenes can initiate tumors only in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors in keratinocytes. Electron microscopy demonstrates specialized cell-cell junctions between keratinocytes and melanoma cells, and multielectrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte cocultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that GABAergic signaling across the skin microenvironment regulates the ability of oncogenes to initiate melanoma.SignificanceThis study shows evidence of GABA-mediated regulation of electrical activity between melanoma cells and keratinocytes, providing a new mechanism by which the microenvironment promotes tumor initiation. This provides insights into the role of the skin microenvironment in early melanomas while identifying GABA as a potential therapeutic target in melanoma. See related commentary by Ceol, p. 2128. This article is featured in Selected Articles from This Issue, p. 2109.
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Project description:Different electrophysiological approaches are combined with a genomic screening in order to analyze, in GT1-7 neuroendocrine cells, the impact of SiO2 nanoparticles (NPs; 503nm in diameter) on electrical activity and gene expression. It is found that 20 µg mL-1 NPs induce depolarization of the membrane potential, with a modulation of the firing of action potentials. Recordings of electrical activity with Multielectrode Arrays provide further evidence that the NPs evoke a temporary increase in firing frequency, without affecting the functional behaviour on a longer time scale (hours). Finally, NPs incubation up to 24 h does not induce any change in gene expression
2018-04-20 | GSE98032 | GEO
Project description:Objective: To assess the development of neuronal subtypes and the emergence of evoked electrical activity within the developing human ENS. Methods: Human foetal gut samples were obtaining via the MRC-Wellcome Trust Human Developmental Biology Resource (UK). Characterisation of the developing ENS was performed by immunohistochemistry, calcium imaging, RNAseq and qRT-PCR Results: Human foetal colon samples displayed robust Tuj1 immunohistochemistry by embryonic week (EW) 12 with a dense neuronal network at the level of the myenteric plexus. At EW12 expression of excitatory neurotransmitter markers (VAChT and Sub P) was observed. By contrast, inhibitory neurotransmitter markers (nNOS and VIP) were not observed until EW14. Co-labeling with synaptic markers (SYN1/SNAP-25) demonstrated the development of synaptic contacts by EW12. However, electrical train stimulation (40V,2s,20Hz of 300?s electrical pulses) did not evoke activity within the myenteric plexus of EW12 foetal gut (n=0/3). Similarly, the majority of EW14 gut tissues assessed (80%), demonstrated no response to electrical stimulation (n=4/5). Interestingly, at EW16 Tuj1+ expression, in the myenteric plexus, was observed within discrete ganglia and was combined with the emergence of calcium transients (F/F0=1.273±0.024;n=3), upon electrical stimulation (n=3/3), which were abolished after the addition of 1uM TTX (n=3/3). RNAseq and qRT-PCR analysis between EW12-16 revealed increases in expression in genes involved in neurotransmission and action potential generation including SCN9A and KCNQ3. Conclusion: Here we demonstrate the temporal development of human enteric neuronal subtypes from EW12-14 and the subsequent emergence of coordinated electrical activity within the human foetal ENS at approximately EW16.
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Project description:Major depressive disorder with suicide behavior (sMDD) is a severe mood disorder, bringing tremendous burden to family and society. Although reduced gamma aminobutyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared to controls. Transcriptomic sequencing revealed a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal acitivity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.
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Project description:au05-03_gaba - ler vs pop2-1: gaba over-accumulation effects - The analysis aims at identifying genes that are differentially regulated by the over-accumulation of GABA observed in the mutant pop2-1 in response to treatment with exogenous GABA and that may explain the singular phenotype of the mutant in this condition. Designed experiment consisted in comparison of transcriptomes of Arabidopsis thaliana Landsberg erecta ecotype and its mutant pop2-1 (impaired in GABA transaminase activity) during a kinetic of endogenous GABA accumulation. For this purpose, 10-day-old plants grown on half strength Hoagland's agar medium were transferred to agar plates supplemented with 1 mM GABA. We isolated RNA from plants treated for 0, 1 and 4 days. Treatments were made in duplicate. Keywords: gene knock-out, time course 6 dye-swap - CATMA arrays
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Project description:Cancer-cell intrinsic electrical activity drives small-cell lung cancer progression
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Project description:Elevated or ectopic expression of neuronal receptors and ion channels promotes tumor progression in many cancer types; neuroendocrine (NE) transformation of various adenocarcinomas has also been associated with increased aggressiveness. Whether the defining neuronal feature, namely electrical excitability, exists in cancer cells and whether this impacts cancer progression remains mostly unexplored. Small cell lung cancer (SCLC) is an archetypical example of highly aggressive NE cancers and is comprised of two major distinct subtypes of cancer cells: NE cells and non-NE cells. Here, we show that the NE cells are excitable, like neurons, while non-NE cells cannot fire action potentials, like astrocytes and other non-excitable cells. Action potential firing in NE cells directly promotes SCLC malignancy; however, the high ATP demand of electrical activity also leads to an unusual dependency on oxidative phosphorylation (OXPHOS) in NE cells. This finding contrasts with most cancer cells reported in the literature, which are non-excitable and heavily rely on aerobic glycolysis. Additionally, we find that non-NE cells metabolically support NE cells to supply their high ATP demand, promoting their excitability and malignancy, a process akin to the astrocyte-neuron metabolite shuttle. Lastly, we observe drastic changes in the innervation landscape during SCLC progression, which coincide with increased intratumoral heterogeneity (ITH) and elevated neuronal protein expression in SCLC cells, suggesting an induction of a tumor autonomous vicious cycle driven by cancer cell-intrinsic electrical activity, which confers long-term tumorigenic capability and metastatic potential.
2024-11-07 | GSE270281 | GEO
Project description:Metabolic programs of immune cells are closely linked to their effector functions , where physiological molecules provide environmental cues and guidance. Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels and glucose is themain source of energy and a precursor for many biomolecules in T cells, whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system. Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4+ T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABAA receptors activated currents and GABA-dependent Ca2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4+ T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4+ T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4+ T cells function.
2024-08-10 | PXD041654 | Pride
Project description:Neurotransmitters have been well-documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrated that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-FAD-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of Bcl2l11 and Dusp2, lowering the formation of NLRP3-ASC-Caspase-1 complex. Meanwhile, GABA-succinate axis lowers succinylation of mitochondrial proteins to promote mitochondrial oxidative phosphorylation (OXPHOS). We also found that GABA alleviates the LPS-induced sepsis as well as high-fat diet-induced obesity in mice. Our study proves that GABA is potential in lessening the pro-inflammatory macrophage responses associating with metabolic reprogramming and protein succinylation, thus providing a strategy for treating macrophage-related inflammatory diseases.
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