Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability DOI Creative Commons
Joshua D. Garcia, Chenyu Wang, Emmie Banks

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

ABSTRACT Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na 1.2 and 1.6. These isoforms are differentially localized to cell compartments, as such thought contribute different aspects of neuronal excitability. But determining their precise roles in excitability has been hampered by a lack tools that allow for selective, acute block each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors channels exhibit state-dependent both 1.6, along with knock-in mice changes or 1.6 structure prevents ASC binding. This allowed acute, potent, reversible individual permitted dissection the unique contributions Remarkably, had contrasting—and some situations, opposing—effects on action potential output, decreasing increasing output. Thus, have regulating excitability, our work may help guide development therapeutics designed temper hyperexcitability through selective blockade.

Language: Английский

Brain Chimeroids reveal individual susceptibility to neurotoxic triggers DOI
Noelia Antón-Bolaños, Irene Faravelli, Tyler Faits

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8019), P. 142 - 149

Published: June 26, 2024

Language: Английский

Citations

35
The contribution of NaV1.6 to the efficacy of voltage‐gated sodium channel inhibitors in wild type and NaV1.6 gain‐of‐function (GOF) mouse seizure control DOI Creative Commons
J. P. Johnson, Thilo Focken,

Parisa Karimi Tari

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(20), P. 3993 - 4011

Published: June 24, 2024

Background and Purpose Inhibitors of voltage‐gated sodium channels (Na V s) are important anti‐epileptic drugs, but the contribution specific channel isoforms is unknown since available inhibitors non‐selective. We aimed to create novel, isoform selective Na v as a means informing development improved antiseizure drugs. Experimental Approach created series compounds with diverse selectivity profiles enabling block 1.6 alone or together 1.2. These novel were evaluated for their ability inhibit electrically evoked seizures in mice heterozygous gain‐of‐function mutation (N1768D/+) Scn8a (encoding 1.6) wild‐type mice. Key Results Pharmacologic inhibition N1768D /+ prevented by 6‐Hz shock. also effective direct current maximal electroshock seizure assay correlated efficacy both models, even without other CNS isoforms. Conclusions Implications Our data suggest driver inhibitor anti‐seizure medicines. Sparing 1.1 inhibitory interneurons did not compromise efficacy. Selective may provide targeted therapies human developmental epileptic encephalopathies treatments idiopathic epilepsies.

Language: Английский

Citations

4
Role of Ion Channels in Alzheimer’s Disease Pathophysiology DOI Creative Commons

Ranjit Bhoi,

Tapan Mitra,

Kallam Tejaswi

et al.

The Journal of Membrane Biology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Ion channels play an integral role in the normal functioning of brain. They regulate neuronal electrical properties like synaptic activity, generation action potentials, maintenance resting membrane potential and plasticity, modulate physiology non-neuronal cells astrocytes microglia. Dysregulation ionic homeostasis channelopathies are associated with various neurological disorders, including Alzheimer's disease (AD). Several families ion AD pathophysiology progression. In this review, we outline current research centered around channel dysregulation during discuss briefly possibility using as therapeutic targets.

Language: Английский

Citations

0
Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability DOI Open Access
Joshua D. Garcia, Chenyu Wang, Emmie Banks

et al.

Published: Feb. 17, 2025

Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na 1.2 and 1.6. These isoforms are differentially localized to cell compartments, as such thought contribute different aspects of neuronal excitability. But determining their precise roles in excitability has been hampered by a lack tools that allow for selective, acute block each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors channels exhibit state-dependent both 1.6, along with knock-in mice changes or 1.6 structure prevents ASC binding. This allowed acute, potent, reversible individual permitted dissection the unique contributions Remarkably, had contrasting—and some situations, opposing—effects on action potential output, decreasing increasing output. Thus, have regulating excitability, our work may help guide development therapeutics designed temper hyperexcitability through selective blockade.

Language: Английский

Citations

0
Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability DOI Open Access
Joshua D. Garcia, Chenyu Wang, Emmie Banks

et al.

Published: Feb. 17, 2025

Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na 1.2 and 1.6. These isoforms are differentially localized to cell compartments, as such thought contribute different aspects of neuronal excitability. But determining their precise roles in excitability has been hampered by a lack tools that allow for selective, acute block each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors channels exhibit state-dependent both 1.6, along with knock-in mice changes or 1.6 structure prevents ASC binding. This allowed acute, potent, reversible individual permitted dissection the unique contributions Remarkably, had contrasting—and some situations, opposing—effects on action potential output, decreasing increasing output. Thus, have regulating excitability, our work may help guide development therapeutics designed temper hyperexcitability through selective blockade.

Language: Английский

Citations

0
In Vitro Inhibition of Voltage-Dependent Sodium Currents by the Antifungal Drug Amorolfine DOI Creative Commons
Mohammad‐Reza Ghovanloo, Sidharth Tyagi, Philip R. Effraim

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108407 - 108407

Published: March 1, 2025

Voltage-gated sodium (Nav) channels are critical for electrical signaling, and their pharmacological modulation can be leveraged the development of therapeutic agents targeting various disorders. The local anesthetic (LA) site on Nav is particularly important, as it a common target many clinically used inhibitors, including anticonvulsants antiarrhythmics. Our goal was to identify novel channel inhibitors by leveraging physicochemical criteria, focusing potential LA binding candidates. We identified amorolfine (AMF), phenyl-propyl morpholine derivative, putative modulator. results demonstrate that AMF acts state-dependent inhibitor channels, with ∼30-fold preference inactivated states. It stabilizes inactivation prevents from conducting, driven through its stabilization inactivation. These findings suggest represents new compound inhibits offering insights into future potentially other ion channels.

Language: Английский

Citations

0
Brief analysis of Nav1.7 inhibitors: Mechanism of action and new research trends DOI
Zhoujun Dong,

Baichen Xiong,

Tian‐Yu Sun

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 118180 - 118180

Published: April 1, 2025

Language: Английский

Citations

0
Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons DOI

Weijie Guo,

Haoyi Yang,

Yuwei Wang

et al.

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 16, 2024

Language: Английский

Citations

0
A patient organization perspective: charting the course to a cure for SCN2A-related disorders DOI Creative Commons

Leah F. Schust,

Jennifer Burke,

Christina SanInocencio

et al.

Therapeutic Advances in Rare Disease, Journal Year: 2024, Volume and Issue: 5

Published: Jan. 1, 2024

The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction Nav1.2, often stemming from genetic mutations gene, leads to SCN2A-related disorders. Individuals harboring pathogenic variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement cortical visual impairment, intellectual disabilities. FamilieSCN2A Foundation, 501(c)(3) patient advocacy organization, is dedicated enhancing lives of those affected by Fueled vision world effective treatments cures all patients Foundation has charted course cure based on their core values urgency, integrity, collaboration, inclusion. Their strategic plan centers building comprehensive research-readiness infrastructure that maximizes probability bringing curative therapies patients. Appreciating statistically most drug development initiatives will fail, creating an number drugs turn net success achieving vision. Through dynamic notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 forging partnerships across disorder ecosystem foundation actively executing its plan. With advancing rapidly thriving diverse, engaged stakeholders, believes outlook bright.

Language: Английский

Citations

0
Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability DOI Creative Commons
Joshua D. Garcia, Chenyu Wang, Emmie Banks

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

ABSTRACT Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na 1.2 and 1.6. These isoforms are differentially localized to cell compartments, as such thought contribute different aspects of neuronal excitability. But determining their precise roles in excitability has been hampered by a lack tools that allow for selective, acute block each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors channels exhibit state-dependent both 1.6, along with knock-in mice changes or 1.6 structure prevents ASC binding. This allowed acute, potent, reversible individual permitted dissection the unique contributions Remarkably, had contrasting—and some situations, opposing—effects on action potential output, decreasing increasing output. Thus, have regulating excitability, our work may help guide development therapeutics designed temper hyperexcitability through selective blockade.

Language: Английский

Citations

0