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

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

PROVIDER: PRJNA745173 | ENA |

REPOSITORIES: ENA

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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

Regulation of fin regeneration by a voltage-gated sodium channel

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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

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

Severe deficiency of the voltage-gated sodium channel Na<sub>V</sub>1.2 elevates neuronal excitability in adult mice.

Project description: Not available

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CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability.

Project description: Not available

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Kv7.2 LC-MSMS - Updating in vivo and in vitro phosphorylation and methylation sites of voltage-gated Kv7

Project description:Voltage-gated Kv7.2 potassium channels regulate neuronal excitability. The gating of Kv7 channels is regulated by various mediators and neurotransmitters acting via G protein-coupled receptors; the underlying signalling cascades involve phosphatidylinositol-4,5-bisphosphate (PIP2), Ca2+/Calmodulin and phosphorylation. Recent studies have reported that PIP2 sensitivity of Kv7.2 channels is affected by two PTMs, phosphorylation and methylation, harboured in the PIP2 binding domains. Here this project aimed to update phosphorylation and methylation sites on Kv7.2 from heterologous cells, the rat brain and GST-fusion Kv7.2 N- and C-terminal ends proteins.

2017-08-25 | PXD005567 | Pride

Regulation of fin regeneration by a voltage-gated sodium channel

Project description:We compare the brain and fin RNA-seq profiles of wild-type and scn8ab mutant zebrafish, which exhibit locomotion and fin regeneration defects.

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