Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development
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PROVIDER: PRJNA1190060 | ENA |
REPOSITORIES: ENA
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Project description:Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development [scRNA-Seq]
| PRJNA1191032 | ENA
Project description:Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. We show that Kcnj8, which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (KATP) channel, is highly expressed in murine splenic and uterine NK cells compared to other K+ channels previously identified in NK cells. Kcnj8 expression is highest in the most mature subset of splenic NK cells (CD27-/CD11b+) and in NKG2A+ or Ly49C/I+ educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. Kcnj8 does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells in vivo, or IFN-γ release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27-/CD11b+ NK cells deficient of Kcnj8. Indeed, we found that mice with NK-cell specific Kcnj8 gene ablation have fewer CD11b+CD27- and KLRG-1+ NK cells in the bone barrow and spleen. These results show that the KATP subunit Kir6.1 has a key role in NK-cell development.
2024-11-24 | GSE282716 | GEO
Project description:Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. We show that Kcnj8, which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (KATP) channel, is highly expressed in murine splenic and uterine NK cells compared to other K+ channels previously identified in NK cells. Kcnj8 expression is highest in the most mature subset of splenic NK cells (CD27-/CD11b+) and in NKG2A+ or Ly49C/I+ educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. Kcnj8 does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells in vivo, or IFN-γ release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27-/CD11b+ NK cells deficient of Kcnj8. Indeed, we found that mice with NK-cell specific Kcnj8 gene ablation have fewer CD11b+CD27- and KLRG-1+ NK cells in the bone barrow and spleen. These results show that the KATP subunit Kir6.1 has a key role in NK-cell development.
2024-11-26 | GSE282936 | GEO
Project description:ATP-sensitive potassium (K-ATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic beta-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse K-ATP inhibitors have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of K-ATP channels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. DSP cross-linking mass spectrometry was used to partially confirm cryoEM structures.
2019-11-12 | PXD013873 | Pride
Project description:ATP-sensitive potassium (K-ATP) channels composed of a pore-forming Kir6.2 potassium channel and a regulatory ABC transporter sulfonylurea receptor 1 (SUR1) regulate insulin secretion in pancreatic beta-cells to maintain glucose homeostasis. Mutations that impair channel folding or assembly prevent cell surface expression and cause congenital hyperinsulinism. Structurally diverse K-ATP inhibitors have been shown to act as pharmacochaperones to correct mutant channel expression, but the mechanism is unknown. Here, we compare cryoEM structures of K-ATP channels bound to pharmacochaperones glibenclamide, repaglinide, and carbamazepine. CyanurBiotinDimercaptoPropionylSuccinimide (CBDPS) cross-linking mass spectrometry was used to partially confirm cryoEM structures.
2019-08-12 | PXD014498 | Pride
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.
2015-07-08 | GSE70576 | GEO
Project description:Using whole-cell patch clamp recording and unbiased gene expression profiling in rat dissociated hippocampal neurons cultured at high density, we demonstrate here that chronic activity blockade induced by the sodium channel blocker tetrodotoxin leads to a homeostatic increase in action potential firing and down-regulation of potassium channel genes. In addition, chronic activity blockade reduces total potassium current, as well as protein expression and current of voltage-gated Kv1 and Kv7 potassium channels, which are critical regulators of action potential firing. Importantly, inhibition of N-Methyl-D-Aspartate receptors alone mimics the effects of tetrodotoxin, including the elevation in firing frequency and reduction of potassium channel gene expression and current driven by activity blockade, whereas inhibition of L-type voltage-gated calcium channels has no effect.
2017-09-21 | GSE104052 | GEO
Project description:Slo2 potassium channel function depends on a SCYL1 protein
| PRJNA593043 | ENA
Project description:Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell-cell crosstalk at synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to induction of natural killer (NK) cell anti-tumour activity. Its mechanism of action and broader functions in the immune system are, however, unclear. Here we generated Calhm6-/- mice and report that CALHM6 is important for regulating the early innate control of Listeria monocytogenes infection in vivo. We find that CALHM6 is upregulated in macrophages by pathogen-derived signals, and that it relocates from intracellular compartment to the macrophage-NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti-inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119, but CALHM6 is localized to intracellular compartments in mammalian cells. Our results contribute to understanding of neurotransmitter-like signal exchange between immune cells that fine-tunes the timing of innate immune responses.
2023-02-01 | GSE223008 | GEO
Project description:Sequencing cancer genomes is predicted to uncover therapeutic tumor vulnerabilities. This has been complicated by the abundance of genetic alterations which are either non-functional, or only important in tumor initiation or progression. Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective cancer therapy. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and apply this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we discovered candidate maintenance genes including the voltage-gated potassium channel Kcnb2. Genetic knockout of Kcnb2 impairs MB growth. Kcnb2 mediates potassium efflux in MB-propagating cells to govern cell volume. Loss of Kcnb2 leads to chronic osmotic swelling and decreased plasma membrane tension, which elevates endocytosis to dampen Egfr signaling, thereby mitigating proliferation of MB-propagating cells. Kcnb2 is largely dispensable for mouse development and synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance genes, and elucidate a mechanism by which a potassium channel integrates biomechanical and biochemical signaling to promote MB aggression.
2024-09-16 | GSE277172 | GEO