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Loss of voltage dependent anion channel 1 affects mitochondrial bioenergetics in rat dopamine cells

ABSTRACT: Loss of voltage dependent anion channel 1 affects mitochondrial bioenergetics in rat dopamine cells

PROVIDER: PRJNA486658 | ENA |

REPOSITORIES: ENA

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Loss of voltage dependent anion channel 1 affects mitochondrial bioenergetics in rat dopamine cells

Project description:Voltage dependent anion channel 1 (VDAC1) is a multi-functional protein that regulates mitochondrial membrane potential, calcium regulation, and apoptosis. VDAC1 also interacts with a number of signaling pathways important for energy homeostasis and proteins involved in neurodegenerative diseases such as alpha-synuclein. To identify novel signaling pathways dependent upon VDAC1 protein in dopamine cells, we used CRISPR-Cas9 gene editing in rat immortalized dopaminergic N27 cells. Western blot confirmed that VDAC1 protein levels were reduced ~90%. Mitochondrial bioenergetics was assessed to determine if there was functional loss of mitochondrial function without VDAC1. Loss of VDAC1 resulted in lower ATP-linked and maximum respiration, and spare respiratory capacity. Transcriptomics was conducted in these cells to identify the pathways perturbed by loss of VDAC. This study sheds novel insight into the different regulatory roles mediated by VDAC1 in dopamine cells.

2019-07-31 | GSE118737 | GEO

Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis

Project description:Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis

| PRJNA707551 | ENA

Impact of the Voltage-Gated Calcium Channel Antagonist Nimodipinedipine on the Development of Oligodendrocyte Precursor Cells

Project description:We investigated the effects of nimodipine, a L-type voltage-gated calcium channel antagonist, on the expression profile of myelin genes in the oligodendrocyte precursor cell (OPC) line Oli-Neu. We performed gene expression profiling analysis using data obtained from RNA-seq of four biological replicates for treatment and four replicates for control condition.

2023-03-30 | GSE221939 | GEO

Regulation of fin regeneration by a voltage-gated sodium channel

Project description:Regulation of fin regeneration by a voltage-gated sodium channel

| PRJNA775662 | ENA

Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis

Project description:Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this novel role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

2021-03-09 | GSE168487 | GEO

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Project description:Scn2a encodes voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs excitability contributing to autism. This paradigm, however, does not explain why 20~30% of patients with NaV1.2 deficiency still develop seizures. Here we report a counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a unique NaV1.2-deficient mouse model, we found enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by the genetic restoration of Scn2a expression in adult mice. RNA-sequencing revealed that the downregulation of multiple potassium channels including KV1.1, and KV channel openers alleviated hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures.

2021-07-13 | GSE179818 | GEO

TMC4 is a novel chloride channel involved in high-concentration salt taste sensation

Project description:Taste substances are received by taste receptors expressed in taste cells. “Salty taste” sensation is evoked when sodium and chloride ions are present together in the oral cavity. The presence of an epithelial cation channel that receives Na+ has previously been reported. However, no molecular entity involving Cl- receptors has been elucidated. We report the strong expression of transmembrane channel-like 4 (TMC4) in the circumvallate and foliate papillae projected to the glossopharyngeal nerve, mediating a high-concentration of NaCl. Electrophysiological analysis using HEK293T cells revealed that TMC4 was a voltage-dependent Cl- channel and the consequent currents were completely inhibited by NPPB, an anion channel blocker. This channel could be activated without an increase in intracellular calcium ion. TMC4 allowed permeation of organic anions including gluconate, but their current amplitudes at positive potentials were less than that of Cl-. Tmc4-deficient mice showed significantly weaker glossopharyngeal nerve response to high-concentration of NaCl than the wild-type littermates. These results indicated that TMC4 is a novel chloride channel that responds to high-concentration of NaCl.

2021-09-14 | GSE175806 | GEO

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Project description:Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

| PRJNA745173 | ENA

Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability

Project description:Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a novel physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors.

2023-12-13 | PXD038505 | Pride

N-methyl-D-aspartate receptors mediate activity-dependent down-regulation of potassium channel genes during the expression of homeostatic intrinsic plasticity

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

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