Constitutive activity of the cation channel TRPM8 regulates the function and differentiation of human monocytes
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ABSTRACT:
PROVIDER: PRJNA543501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9082110_1.fastq.gz | Fastqsanger.gz | |||
| SRR9082110_2.fastq.gz | Fastqsanger.gz | |||
| SRR9082120_1.fastq.gz | Fastqsanger.gz | |||
| SRR9082120_2.fastq.gz | Fastqsanger.gz | |||
| SRR9082111_1.fastq.gz | Fastqsanger.gz |
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Project description:This study investigated the impact of TRPM8 activity on human monocyte differentiation and function. CD14+ peripheral blood monocytes were isolated from healthy volunteers and differentiated into macrophages using M-CSF, in the presence or absence of 10μM AMTB (TRPM8 antagonist). RNA seq was performed on CD14+ monocytes and macrophages differentiated in vehicle(Mo-M-DMSO) or AMTB (Mo-M-AMTB). To assess the transcriptional changes that normally occur in monocyte to macrophage differentiaiton we compared the Mo-M-DMSO and CD14+ monocyte samples. 3109 genes were significantly down-regulated and 3403 up-regulated in Mo-M-DMSO samples compared to CD14+ monocytes. To investigate the impact of AMTB upon macrophage differentiation we compared the Mo-M-DMSO and Mo-M-AMTB. 556 genes were significantly lower and 421 genes were significantly higher in Mo-M-AMTB samples compared to Mo-M-DMSO samples. 331 out of the 556 genes lower in Mo-M-AMTB samples were genes that were normally up-regulated during differentiaiton and 253 out of the 421 genes higher in the Mo-M-AMTB samples were genes that were normally down-regulated during differentiation indicating that AMTB predominantly acts to inhibit aspects of the differentiation programme.
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Project description:The synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP) melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon. The aim of this study was to determine whether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)—a CD4+ T cell–driven murine model of MS—we found that both wild-type (WT) and TRPM8-deficient EAE mice were protected from disease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4+ T cells, with the peripheral expansion of autoantigen-restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8-/- and TRP ankyrin-1-/- T cell proliferation by icilin was consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4+ T cells to one that was indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent anti-inflammatory role for icilin in lymphocyte-mediated neuroinflammation and highlight clear pleiotropic effects of the compound beyond classic TRP channel activation.
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Project description:Magnesium is essential for cellular life, but how it is homeostatically controlled still remains poorly understood. Here we report that members of CNNM family, which have been controversially implicated in both cellular Mg2+ influx and efflux, selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. Co-expression of CNNMs with the channel markedly increased uptake of divalent cations, which is prevented by an inactivating mutation to the channel’s pore. Knockout of Trpm7 in cells or application of the TRPM7-channel inhibitor NS8593 also interfered with CNNM-stimulated divalent cation uptake. Conversely, knockout of CNNM3 and CNNM4 in HEK-293 cells significantly reduced TRPM7-mediated divalent cation entry, without affecting TRPM7 protein expression or its cell surface levels. Furthermore, we found that cellular overexpression of Phosphatases of Regenerating Liver (PRLs), a known CNNMs binding partner, stimulated TRPM7-dependent divalent cation entry and that CNNMs were required for this activity. Whole-cell electrophysiological recordings demonstrated that deletion of CNNM3 and CNNM4 from HEK-293 cells interfered with heterologously expressed and native TRPM7 channel function. We conclude that CNNMs employ the TRPM7 channel to mediate divalent cation influx and that CNNMs also possess separate TRPM7-independent Mg2+ efflux activities that contribute to CNNMs’ control of cellular Mg2+ homeostasis.
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Project description:Characterizing the impact of pharmacological and shRNA-mediated silencing of EAG2 in medulloblastoma. Medulloblastoma (MB) is the most common pediatric CNS malignancy. Previously, we demonstrated that overexpression of the ion channel EAG2, identified in a subset of histological and molecular subtypes of this disease, functionally contributes to tumor progression (PMID: 22855790). Here, we demonstrate the evolutionarily conserved function of EAG2 potassium channel in promoting brain tumor growth and metastasis, delineate downstream pathways and uncover a co-option mechanism for different potassium channels to regulate mitotic cell volume and tumor progression. We show that EAG2 potassium channel is enriched at the trailing edge of migrating MB cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identify the FDA- approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings thus illustrate the potential of targeting ion channels in cancer treatment.
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Project description:A cataract-causing mutation in the TRPM3 cation channel disrupts calcium dynamics in the lens
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Project description:TRPM3 belongs to the melastatin sub-family of transient receptor potential (TRPM) cation channels and has been shown to function as a steroid-activated, heat-sensitive, calcium ion (Ca2+) channel. A missense substitution (p.I65M) in the TRPM3 gene of humans (TRPM3) and mice (Trpm3) has been shown to underlie an inherited form of early-onset, progressive cataract. Here we model the pathogenetic effects of this cataract-causing mutation using ‘knock-in’ mutant mice and human cell-lines. Trpm3 and its intron-hosted micro-RNA gene (Mir204) were strongly co-expressed in the lens epithelium and other non-pigmented and pigmented ocular epithelia. Homozygous Trpm3-mutant lenses displayed elevated cytosolic Ca2+ levels and an imbalance of sodium (Na+) and potassium (K+) ions coupled with increased water content. Homozygous TRPM3-mutant human lens epithelial (HLE-B3) cell-lines and Trpm3-mutant lenses exhibited increased levels of phosphorylated mitogen-activated protein kinase 1/extracellular signal-regulated kinase 2 (MAPK1/ERK2/p42) and MAPK3/ERK1/p44. Mutant TRPM3-M65 channels displayed an increased sensitivity to external Ca2+ concentration and an altered dose response to pregnenolone sulfate (PS) activation. Trpm3-mutant lenses shared downregulation of genes involved in insulin/peptide secretion and upregulation of genes involved in Ca2+ dynamics. By contrast, Trpm3-deficient lenses did not replicate the pathophysiological changes observed in Trpm3-mutant lenses. Collectively, our data suggest that a cataract-causing substitution in the TRPM3 cation channel elicits a deleterious gain-of-function, rather than a loss-of-function, mechanism in the lens.
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