Epithelial sodium channel inhibition as a targeted therapy for skin inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1099584 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Inflammatory skin disease is characterized by a pathologic inflammatory interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is often used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify novel targets, potentially impacting epidermal pathways, we carried out a non-biased informatics screen to identify drug entities with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease as model, we utilized pharmacologic, transcriptomic and proteomic characterization to find that benzamil, the benzyl derivative of the FDA-approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Orthogonal validation across transgenic, chemically induced and xenograft models of skin inflammation indicate that benzamil perturbs pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1, reduce STAT3 and NFκβ signaling and downstream cytokine production in keratinocytes. Inhibition of sodium channels prevents excess Rac1-NCK1 binding, rescues pro-inflammatory signaling pathways in patient keratinocytes without systemic immunosuppression, and can effectively be accomplished through both systemic and topical intervention. We show that small molecule inhibition of epithelial sodium channels is a potent novel therapeutic avenue for treating skin inflammation.
2025-08-01 | GSE263841 | GEO
Project description:Sodium channels are essential for cardiac conduction and excitability. The sodium current is primarily carried by the voltage gated sodium channel isoform NaV1.5. Using a novel NaV1.5 chimeric construct, our study reveals a unique chamber-specific distribution of non-NaV1.5 sodium channel isoforms, and we performed spatial sequencing of murine hearts to assess the transcriptional changes associated with our chimeric channel.
2026-04-09 | GSE319481 | GEO
Project description:Sodium channels are essential for cardiac conduction and excitability. The sodium current is primarily carried by the voltage gated sodium channel isoform NaV1.5. Using a novel NaV1.5 chimeric construct (NaV1.5-GX), our study reveals a unique chamber-specific distribution of non-NaV1.5 sodium channel isoforms, and we performed bulk RNA sequencing of murine ventricles to assess if acute NaV1.5 inhibition changed the trascriptional profile of the ventricular myocytes.
2026-04-09 | GSE319426 | GEO
Project description:The voltage-gated sodium channel NaV1.7 plays a critical role in pain pathways. As well as action potential propagation, NaV1.7 regulates neurotransmitter release, integrates depolarizing inputs over long periods and regulates transcription. In order to better understand these functions, we generated an epitope-tagged NaV1.7 mouse that showed normal NaV1.7 channel activity and normal pain behavior. Analysis of NaV1.7 complexes affinity-purified under native conditions by mass spectrometry revealed 267 NaV1.7 associated proteins including known and novel interactors such as sodium channel β3 subunit (Scn3b) and collapsin response mediator protein (Crmp2). Selected NaV1.7 protein interactors, such as Crmp2, membrane-trafficking protein synapototagmin-2 (Syt2), G protein-regulated inducer of neurite outgrowth 1 (Gprin1), L-type amino acid transporter 1 (Lat1) and transmembrane P24 trafficking protein 10 (Tmed10) were validated using co-immunoprecipitation and functional assays. The information provided with this physiologically normal epitope-tagged mouse should provide useful insights into the downstream mechanisms associated with NaV1.7 channel function.
2018-01-15 | PXD005155 | Pride
Project description:Voltage-gated sodium channels regulate neuronal excitability and fast synaptic transmission in the postnatal and adult brain. The gene SCN2A, encoding the sodium channel Nav1.2, regulates synaptic development and variants in SCN2A are associated with autism spectrum disorders (ASD). The expression pattern of SCN2A begins during fetal cortical development, prior to the onset of synaptic transmission, but it is unknown whether SCN2A regulates early cortical development through mechanisms independent of synaptic transmission. Here we reveal that isogenic and ASD patient-derived human forebrain organoids modelling a loss of SCN2A function display impaired excitatory and inhibitory neurogenesis, leading to a developmental imbalance. Unexpectedly, we find precocious generation of cortical inhibitory neurons is driven by elevated sonic hedgehog (SHH) signaling and is reversible through pharmacological inhibition. Functionally, these developmental phenotypes arise due to sodium channel dysfunction and lead to abnormal neuronal network activity. Our results identify a new mechanisim for cortical excitatory and inhibitory neurogenesis involving SCN2A, and reveal that early neurogenesis deficits precedes postnatal neural circuit dysfunction in SCN2A-associated disorders.
2026-06-09 | GSE292644 | GEO
Project description:Regulation of fin regeneration by a voltage-gated sodium channel
| PRJNA775662 | ENA
Project description:The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a disruption of the epidermal barrier, water is lost resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Nax functions as the sodium sensor. With increased extracellular sodium, Nax up-regulates prostasin which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. The same pathways are present in lung epithelial cells. A signal transduction pathway mediated directly through Nax and secondarily through ENaC results in production of secretory inflammatory mediators. These mediators result in epithelial proliferation and restoration of epidermal homeostasis, but can also have negative effects including excess inflammation and ultimately leads to activation of fibroblasts.
2015-01-29 | GSE65366 | GEO
Project description:Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability [Spatial Transcriptomics]
| PRJNA1423520 | ENA
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
Project description:Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability [bulk RNA-seq]
| PRJNA1423278 | ENA