Slo2 potassium channel function depends on a SCYL1 protein
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593043 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10574840_1.fastq.gz | Fastqsanger.gz | |||
| SRR10574840_2.fastq.gz | Fastqsanger.gz | |||
| SRR10574841_1.fastq.gz | Fastqsanger.gz | |||
| SRR10574841_2.fastq.gz | Fastqsanger.gz | |||
| SRR10574842_1.fastq.gz | Fastqsanger.gz |
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Project description:Slo2 potassium channels play important roles in neuronal function, and their mutations in humans cause epilepsies and profound cognitive defects. However, little is known how Slo2 function is regulated by other proteins. In a genetic screen for suppressors of a sluggish phenotype caused by a hyperactive C. elegans Slo2 (SLO-2), mutants of adr-1, a gene important to RNA editing, were isolated. SLO-2 current in motor neurons is substantially decreased in the mutants. However, slo-2 transcripts have no detectable RNA editing events and exhibit a similar expression level in wild type and adr-1 mutants. In contrast, mRNA level of scyl-1, which encodes an orthologue of mammalian SCYL1 (a pseudokinase), is greatly reduced in adr-1 mutants due to deficient RNA editing at a single adenosine in its 3’-UTR. SCYL-1 physically interacts with SLO-2 in neurons. Single-channel open probability of SLO-2 in neurons is reduced by ~50% in scyl-1 knockout whereas that of human Slo2.2/Slack is doubled by SCYL1 in a heterologous expression system. These results suggest that SCYL-1/SCYL1 is an evolutionarily conserved regulator of Slo2 channels.
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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.
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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.
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Project description:Slo2 potassium channels play important roles in neuronal function, and their mutations in humans may cause epilepsies and cognitive defects. However, it is largely unknown how Slo2 is regulated by other proteins. Here we show that the function of C. elegans Slo2 (SLO-2) depends on adr-1, a gene important to RNA editing. ADR-1 promotes SLO-2 function not by editing the transcripts of slo-2 but those of scyl-1, which encodes an orthologue of mammalian SCYL1. Transcripts of scyl-1 are greatly decreased in adr-1 mutants due to deficient RNA editing at a single adenosine in their 3'-UTR. SCYL-1 physically interacts with SLO-2 in neurons. Single-channel open probability (Po) of neuronal SLO-2 is ~50% lower in scyl-1 knockout mutant than wild type. Moreover, human Slo2.2/Slack Po is doubled by SCYL1 in a heterologous expression system. These results suggest that SCYL-1/SCYL1 is an evolutionarily conserved regulator of Slo2 channels.
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