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Modulation of calcium signalling on demand to decipher the molecular mechanisms of primary aldosteronism

ABSTRACT: Modulation of calcium signalling on demand to decipher the molecular mechanisms of primary aldosteronism

PROVIDER: PRJNA1188188 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31402400_1.fastq.gz	Fastqsanger.gz
	SRR31402400_2.fastq.gz	Fastqsanger.gz
	SRR31402401_1.fastq.gz	Fastqsanger.gz
	SRR31402401_2.fastq.gz	Fastqsanger.gz
	SRR31402402_1.fastq.gz	Fastqsanger.gz

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Modulation of calcium signalling on demand to decipher the molecular mechanisms of primary aldosteronism

Project description:Background. Primary aldosteronism is the most common form of secondary hypertension. The most frequent genetic cause of aldosterone producing adenoma (APA) are somatic mutations in the potassium channel KCNJ5. They affect the ion selectivity of the channel, with sodium influx leading to cell membrane depolarization and activation of calcium signalling, the major trigger for aldosterone biosynthesis. Methods. To investigate how KCNJ5 mutations lead to the development of APA, we established an adrenocortical cell model in which sodium entry into the cells can be modulated “on demand” using chemogenetic tools (H295R-S2 α7-5HT3 cells). We investigated their functional and molecular characteristics with regard to aldosterone biosynthesis and cell proliferation. Results. A clonal cell line with stable expression of the chimeric α7-5HT3 receptor in H295R-S2 cells was obtained. Increased sodium entry through the α7-5HT3 receptor upon stimulation with uPSEM-817 led to cell membrane depolarization, opening of voltage-gated Ca2+ channels and increased intracellular Ca2+ concentrations, resulting in the stimulation of CYP11B2 expression and increased aldosterone biosynthesis. Increased intracellular sodium influx did not increase proliferation, but rather induced apoptosis. RNA sequencing and steroidome analyses revealed unique profiles associated with Na+ entry, with only partial overlap with angiotensin II or potassium induced changes. Conclusion. H295R-S2 α7-5HT3 cells are a new model reproducing the major features of cells harbouring KCNJ5 mutations. Increased expression of CYP11B2 and stimulation of the mineralocorticoid biosynthesis pathway are associated with a decrease of cell proliferation and an increase of apoptosis, indicating that additional events may be required for the development of APA.

2025-01-19 | GSE282358 | GEO

Tetrandrine regulates NAADP-mediated calcium signalling through a novel LIMP-2-dependent, sphingosine-mediated mechanism

Project description:Tetrandrine (Tet) is a highly potent inhibitor of Ebola virus replication by blocking NAADP-dependent calcium release through endolysosomal two-pore channels (TPCs) and is a moderately potent anti-tumor agent. Using a clickable, photoaffinity probe of Tet, we identified lysosomal integral membrane protein-2 (LIMP-2) as the genuine molecular target of Tet and a novel regulator for NAADP-dependent calcium release. Tet binds to the ectodomain of LIMP-2 and inhibits its cholesterol and sphingosine transport function, resulting in the alteration of lipid profiles and metabolic pathways in cells and development of acute hypercholesterolemia and hepatosteatosis in mice. Cells treated with Tet or depleted for LIMP-2 similarly inhibits NAADP-dependent calcium release, which can be restored by eliminating lysosomal cholesterol and sphingosines. Importantly, addition of sphingosine dose-dependently triggers lysosomal calcium release through TPCs, and restores NAADP-dependent calcium release in Tet-treated or LIMP-2-depleted cells. At higher concentrations, Tet induced apoptosis associated with unfolded protein response activation in a LIMP-2-independent manner. We identified Tet as the first known inhibitor of LIMP-2, discerned its pharmacological principle in regulating calcium signalling and cell death, and discovered a novel LIMP-2-regulated, sphingosine-dependent lysosomal calcium signalling pathway. Our findings have profound implications in the understanding of lysosomal calcium signalling mechanisms and development of Tet and LIMP-2 inhibitors into clinical therapeutics.

2023-03-04 | GSE212648 | GEO

Circulating miRNA expression profiling in primary aldosteronism

Project description:Circulating miRNA expression profiling in primary aldosteronism

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Transcriptional profiling of Aspergillus fumigatus H515 strain in response to alkaline or calcium shift

Project description:The functional coupling of calcium-mediated signalling and alkaline tolerance has been demonstrated in multiple fungi. The applied relevance of such interplay extends most notably to fungal pathogens of man where the physiological pH of serum and tissues exerts considerable alkaline stress. Drugs targeting the calcium-dependent phosphatase, calcineurin, are potent antifungal agents but also perturb human calcineurin signalling, it has therefore been postulated that abrogation of fungal alkaline tolerance could offer a valuable therapeutic adjunct. To study the interdependency of pH- and calcium-mediated intracellular signalling in the major human fungal pathogen A. fumigatus, we examined the transcriptional response following exposure to 200 mM calcium chloride or alkaline pH (pH 8.0).

2015-09-30 | GSE60786 | GEO

Regulation of mitochondrial Ca2+ uniporter expression and calcium signalling by lncRNA Tug1 in cardiomyocytes

Project description:Regulation of mitochondrial Ca2+ uniporter expression and calcium signalling by lncRNA Tug1 in cardiomyocytes

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Regulation of mitochondrial Ca2+ uniporter expression and calcium signalling by lncRNA Tug1 in cardiomyocytes

Project description:Cardiomyocyte Ca2+ is buffered by mitochondria via the mitochondrial calcium uniporter (MCU) complex. The MCU complex consists of pore-forming proteins including the mitochondrial calcium uniporter (MCU), and regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 affected the expression of MCU-associated genes. To further explore this, we knocked down Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes using antisense LNA oligo. This led to increased MCU protein expression yet this did not enhance a marker of mitochondrial Ca2+ uptake. RNA-seq revealed that Tug1 KD increased Mcu and led to differential expression of genes and pathways related to Ca2+ regulation in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to promote Mcu gene expression. Tug1 KD attenuated the increase in CAMKII and CREB phosphorylation in response to ionomycin, a Ca2+ ionophore. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism that may involve CAMKII and CREB. The Tug1 mediated regulation of MCU on mitochondrial Ca2+ uptake, may have functional consequences for cellular Ca2+ handling which could have implications for cardiac disease.

2023-07-22 | GSE237787 | GEO

CRELD2 is a novel modulator of calcium mobilisation and calcineurin-NFAT signalling during osteoclast differentiation

Project description:CRELD2 is a novel modulator of calcium mobilisation and calcineurin-NFAT signalling during osteoclast differentiation

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Tetrandrine regulates NAADP-mediated calcium signalling through a novel LIMP-2-dependent, sphingosine-mediated mechanism

Project description:Tetrandrine regulates NAADP-mediated calcium signalling through a novel LIMP-2-dependent, sphingosine-mediated mechanism

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Circulating miRNAs and Machine Learning for Lateralizing Primary Aldosteronism

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Homeostatic calcium fluxes, ER calcium release, SOCE, and calcium oscillations in cultured astrocytes are interlinked by a small calcium toolkit

Project description:We report the application of RNA-seq for molecular profiling of cultured, cortical astrocytes. Our data set is based on about 40 million unique reads per sample in four independent mRNA preparations. Cortical astrocytes are a prototypical cell model for investigating calcium signaling. For analysis of calcium fluxes, we performed direct calcium imaging in the endoplasmic reticulum and in the cytosol. We describe in our study the physiological profile of homeostatic and agonist-induced calcium fluxes. Furthermore, we show how ER calcium release shapes the cytosolic calcium signal. This transcriptome dataset was used to profile the calcium toolkit of astrocytes. The data suggest that a small number of calcium signaling-related proteins mediate calcium homeostasis in astrocytes.

2021-12-14 | GSE166464 | GEO

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